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  • 1. List of ContributorsN.H. Barmack, Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USAR.H.I. Blanks, Florida Atlantic University, Charles E. Schmidt College of Science, 777 Glades Road, P.O. Box 3091, Boca Raton, FL 33431-0991, USAR. Blumer, Institute of Anatomy, University of Vienna, Waehringerstrase 13, A-1090 Vienna, AustriaU. Buttner, Department of Neurology, Ludwig-Maxmilian University Munich, Klinikum Grosshadern, ¨ Marchioninistr. 15, D-81377 Munich, GermanyJ.A. Buttner-Ennever, Institute of Anatomy, Ludwig-Maximilian University of Munich, Petten Koferstr. ¨ 11, D-80336 Munich, GermanyP.D.R. Gamlin, Department of Vision Sciences, University of Alabama at Birmingham, 924 South 18th Street, Birmingham, AL 35294-4390, USAR.A. Giolli, Department of Anatomy and Neurobiology, University of California, College of Medicine, Irvine, CA 92697-1275, USAJ.K. Harting, Department of Anatomy, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706, USAY. Hata, Department of Systems Neurophysiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, JapanS.M. Highstein, Washington University School of Medicine, Department of Otolaryngology, Box 8115, 4566 Scott Avenue, St. Louis, MO 63110, USAG.R. Holstein, Department of Neurology and Cell Biology, Mount Sinai School of Medicine, Box 1140, One Gustave Levy Place, New York, NY 10029, USAA.K.E. Horn, Institute of Anatomy, Ludwig-Maximilian University of Munich, Pettenkoferstrasse 11, 80336 Munich, GermanyY. Izawa, Department of Systems Neurophysiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, JapanK.Z. Konakci, Center of Anatomy and Cell Biology, Integrative Morphology Group, Medical University Vienna, Waehringerstrasse 13, A-1090 Vienna, AustriaF. Lui, Dipartimento di Scienze Biomediche, Sezione di Fisiologia, Universita di Modena e Reggio Emilia, Via Campi 287, 41100 Modena, ItalyJ.C. Lynch, Department of Anatomy, Ophthalmology and Neurology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USAP.J. May, Department of Anatomy, Ophthalmology and Neurology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USAR.A. McCrea, Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Abbott 09/MC 0926, 947 E. 58th Street, Chicago, IL 60637, USAM. Mock, Department of Anatomy, Visual Sensorimotor Section, Neurological Clinic, University Hospital ¨ Tubingen, D-72076 Tubingen, GermanyR.M. Muri, Perception and Eye Movement Laboratory, Departments of Neurology and Clinical Research, ¨ University of Bern, Inselspital, CH-310 Bern, Switzerland v
  • 2. viJ.D. Porter, National Institutes of Neurological Disorders and Stroke, 6001 Executive Blvd, NINDS/NSC 2142, Bethesda MD 20892, USAY. Shinoda, Department of Systems Neurophysiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, JapanyR.F. Spencer, Departments of Anatomy and Otolaryngology, Medical College of Virginia, Richmond, VA 23298, USA (deceased 2001)Y. Sugiuchi, Department of Systems Neurophysiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, JapanP. Thier, Department of Cognitive Neurology, Hertie-Institute of Clinical Brain Research, University of Tubingen, Hoppe-Seyler 3, 72076 Tubingen, GermanyJ.-R. Tian, Jules, Stein Eye Institute, 3-310 DSERC, UCLA Medical Center, 100 Stein Plaza, Los Angeles, CA 90095-7002, USAB.V. Updyke, Department of Anatomy, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706, USAJ. Voogd, Erasmus Medical Center Rotterdam, Department of Neuroscience, Box 1738, 3000 DR Rotterdam, The Netherlands
  • 3. Preface This book is dedicated to Bernard Cohen who discovered that the paramedian pontine reticular formation (PPRF) was essential for the generation of saccadic eye movements 40 years ago. His work and his unfailing enthusiasm continue to inspire the field of oculomotor and vestibular research.The updated and extended version of ‘Neuroanatomy of the Oculomotor System’ is a set of reviews whichfocus on the functional neuroanatomy and connectivity of the brain areas involved in controlling eyemovements. The first edition of ‘Neuroanatomy of the Oculomotor System’ was published as volume 2 of‘Reviews in Oculomotor Research’. This series outlived its commercial life and has been discontinued. Butwe are delighted to be able to continue the spirit of these reviews in a volume of ‘Progress in BrainResearch’. We chose to publish this updated and extended version as part of this series because it fits wellwith the character of ‘Progress in Brain Research’, and because this series is available in most universitylibraries. The first chapter is written as an introduction to the oculomotor system: it discusses the differenttypes of eye movements, the structures involved in their generation and some clinical aspects; it deals withsaccades, the vestibulo-ocular reflex, optokinetic responses, vergence, smooth pursuit and gaze-holding.Chapter 1 also introduces current concepts such as ‘pulleys’ in the orbit (i.e. the functional consequences ofthe Tenon’s capsule), and integrators for gaze-holding. Each of the various topics is picked up in a laterchapter and the neuroanatomy dealt with in more detail. The subsequent chapters are arranged in a‘bottom –up’ approach; they review the structure and control of eye muscles in the periphery, the nextchapters are on the oculomotor nuclei in the brainstem, then the reticular formation, the vestibular nucleiand cerebellum. The following chapters move on to more rostral structures, the tectum, the pretectum,basal ganglia, thalamus and cerebral cortex. Many new networks influencing eye movements have been discovered, and many new hypotheses havebeen proposed, over the 17 years separating the two editions of this book; and as a consequence six newchapters have been added to the original version. The most provocative of these is Chapter 3, which is areview of eye muscle proprioceptors and their relationship to the control of eye movements. Here we havemade an attempt to integrate the slightly unpopular field of ‘extraocular proprioception’ into the currentconcepts of the oculomotor system, although the evidence for these hypotheses is incomplete. Perhaps it istoo early to come to conclusions on the role of extraocular proprioception, but we have tried to show thatthe established facts can be re-interpreted in the light of recent discoveries in fields such as neuraldevelopment, genetics and neurotrophins etc., which reveal the factors influencing the development ofmuscle spindles, Golgi tendon organs and their neural circuitry. The field of proprioception is fraught withcontroversy, and this is reflected in Chapter 3 by the differing views of the authors on the function of aneural structure unique to eye muscles – the palisade ending. One camp supports the view that they aremotor, the others provide evidence for their sensory nature. Nevertheless, we are convinced that ourdifferences will be resolved in the future by collaborating with each other; and hence the combinedauthorship of Chapter 3. The other five new chapters in this updated and extended version are devoted to the following topics: theinferior olive (Chapter 9), which shows how the olivary climbing fibers impose a topography onto the vii
  • 4. viiicerebellum: the pontine nuclei and nucleus reticularis tegmenti pontis (Chapter10), which likewisedetermine the organization of cerebellar afferents but of the mossy fiber type: the accessory optic nuclei(Chapter 13), which provide optokinetic signals to the brainstem, but whose clinical relevance is completelyunknown up to now: and the basal ganglia (Chapter 14), where functional oculomotor networks can nowbe followed within the circuitry of the forebrain. Finally, a new review of functional magnetic resonanceimaging (fMRI) studies of oculomotor-related structures has also been introduced (Chapter 16). The elevenoriginal chapters have been re-written and updated. In almost all cases they have completely altered theircharacter, depending on whether or not a new scientist, or group of scientists, have taken on the authorship:this holds for the chapters on the oculomotor nuclei (Chapter 4), reticular formation (Chapter 5), thevestibular nuclei (Chapter 6), prepositus hypoglossi (Chapter 7), cerebellum (Chapter 8), the superiorcolliculus (Chapter 11), pretectum (Chapter 12), cerebral cortex (Chapter 15), and spinal cord (Chapter 17).In this respect, the old edition is by no means replaced by the new updated version: the chapters of the oldedition will remain useful in their own right because the new authors review different aspects of thestructure. The old Chapter 2 is a masterly review of the properties of eye muscles: Bob Spencer told me in1987 that he was slow writing it because he had to do a lot of new experiments in order to write it properly.It has now been thoroughly updated but the authorship of the new Chapter 2 was left in its originalconstellation in respect to Robert F. Spencer (1950 – 2001), a great scientist. The idea of this new and extended version was initiated several years ago by Volker Henn (1943–1997),who we still sorely miss. Its production has only been possible with the enormous patience and hardwork ofthe authors, each of which were chosen for their scientific expertise. I have been very fortunate to have hadthe support of Maureen Twaig at Elsevier, as well as the continual encouragement and assistance fromAhmed Messoudi and Rita Buttner in Munich: I am very grateful to all of them. ¨ Jean A. Buttner-Ennever ¨ Munich, April 2005
  • 5. ContentsList of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii 1. Present concepts of oculomotor organization U. Buttner and J.A. Buttner-Ennever (Munich, Germany) . . . . . . . . . . . . . . . . . . . . ¨ ¨ 1 2. Biological organization of the extraocular muscles R.F. Spencer and J.D. Porter (Richmond, VA and Cleveland, OH, USA) . . . . . . . . . 43 3. Sensory control of extraocular muscles J.A. Buttner-Ennever, K.Z. Konakci and R. Blumer (Munich, Germany and Vienna, ¨ Austria) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4. The extraocular motor nuclei: organization and functional neuroanatomy J.A. Buttner-Ennever (Munich, Germany). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ¨ 95 5. The reticular formation A.K.E. Horn (Munich, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6. The Anatomy of the vestibular nuclei S.H. Highstein and G.R. Holstein (St. Louis, MO and New York, NY, USA) . . . . . . 157 7. Nucleus prepositus R.A. McCrea and A.K.E. Horn (Chicago, IL, USA and Munich, Germany) . . . . . . . 205 8. Oculomotor cerebellum J. Voogd and N.H. Barmack (Rotterdam, The Netherlands and Beaverton, OR, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 9. Inferior olive and oculomotor system N.H. Barmack (Beaverton, OH, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26910. The oculomotor role of the pontine nuclei and the nucleus reticularis tegmenti pontis P. Thier and M. Mock (Tubingen, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ¨ 29311. The mammalian superior colliculus: laminar structure and connections P.J. May (Jackson, MS, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 ix
  • 6. x12. The pretectum: connections and oculomotor-related roles P.D.R. Gamlin (Birmingham, AL, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37913. The accessory optic system: basic organization with an update on connectivity, neurochemistry and function R.A. Giolli, R.H.I. Blanks and F. Lui (Irvine, CA and Boca Raton, FL, USA and Modena, Italy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40714. Oculomotor-related pathways of the basal ganglia J.K. Harting and B.V. Updyke (Madison, WI, USA) . . . . . . . . . . . . . . . . . . . . . . . . 44115. Cortico-cortical networks and cortico-subcortical loops for the higher control of eye movements J.C. Lynch and J.-R. Tian (Jackson, MS, USA and Los Angeles, CA, USA) . . . . . . . 46116. MRI and fMRI analysis of oculomotor function R.M. Muri (Bern, Switzerland) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ¨ 50317. Long descending motor tract axons and their control of neck and axial muscles Y. Shinoda, Y. Sugiuchi, Y. Izawa and Y. Hata (Tokyo, Japan). . . . . . . . . . . . . . . . 527Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
  • 7. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 2 Biological organization of the extraocular muscles Robert F. Spencer1 and John D. Porter2,Ã 1 Departments of Anatomy and Otolaryngology, Medical College of Virginia, Richmond, VA 23298, USA2 Departments of Neurology and Neurosciences, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USAAbstract: Extraocular muscle is fundamentally distinct from other skeletal muscles. Here, we review thebiological organization of the extraocular muscles with the intent of understanding this novel muscle groupin the context of oculomotor system function. The specific objectives of this review are threefold. The firstobjective is to understand the anatomic arrangement of the extraocular muscles and their compartmental orlayered organization in the context of a new concept of orbital mechanics, the active pulley hypothesis. Thesecond objective is to present an integrated view of the morphologic, cellular, and molecular differencesbetween extraocular and the more traditional skeletal muscles. The third objective is to relate recent datafrom functional and molecular biology studies to the established extraocular muscle fiber types.Developmental mechanisms that may be responsible for the divergence of the eye muscles from a skeletalmuscle prototype also are considered. Taken together, a multidisciplinary understanding of extraocularmuscle biology in health and disease provides insights into oculomotor system function and malfunction.Moreover, because the eye muscles are selectively involved or spared in a variety of neuromuscular diseases,knowledge of their biology may improve current pathogenic models of and treatments for devastatingsystemic diseases.1. Introduction eye movements. The complexity and precision of eye movements is reflected not only in theThe extraocular muscles (EOMs) are the effector organization of the central oculomotor systemsorgan for voluntary and reflexive movements of described elsewhere in this volume, but also in thethe eyes. Because the area of high acuity vision, the very biology of the EOMs. Since skeletal muscle isfovea, subtends a very small angle of visual space, a highly plastic tissue, readily adapting to usagethe task of gaze control must be accomplished with patterns, one can hypothesize that properties ofhigh precision through the coordinated activity of the novel EOM phenotype exist to meet a complexthe six EOMs. EOM innervation is by motoneu- ‘‘job description’’ of stabilizing and reorienting eyerons in the oculomotor, trochlear, and abducens position for clear vision. The biological organiza-nuclei, which represent the final common pathway tion of EOM is then a consequence of the structureupon which signals from a variety of supranuclear and function of oculomotor systems and, in turn,areas converge to produce five distinct classes of careful analysis of EOM properties can provide fundamental insights into the status of these neuralÃNational Institutes of Neurological Disorders and Stroke, control systems in health and disease. The layered or compartmentalized organization of the EOMs,6001 Executive Blvd, NINDS/NSC 2142, Bethesda MD 20892.Tel.: +1 301 496 1917; Fax: +1 301 402 1501; into distinctive orbital and global layers, also hasE-mail: important connotations for the function of thisDOI: 10.1016/S0079-6123(05)51002-1 43
  • 8. 44novel muscle group. In this review, we seek an was necessary to interpret later cell and molecularunderstanding of EOM biology in the context of studies and to subsequently develop an overalloculomotor system function. model of EOM myofiber function. In spite of recent Knowledge of skeletal muscle biology does not progress, we only now are beginning to appreciatemean that one understands EOM. As we show the full breadth of adaptations of EOM myofiberhere, many of the ‘‘rules’’ that govern skeletal types to their novel role in eye movement control.muscle biology do not apply to EOM. The EOMs A second objective of this review is to integrateof some fish exhibit the most remarkable examples new, multidisciplinary data with establishedof plasticity found in any skeletal muscle. EOM morphologic profiles to begin to construct anprecursor cells take alternative developmental paths overall model of the biology of the diverse EOMto form a weakly electric organ, for navigation, in fiber types.the stargazer (Astroscopus sp.) or a heater organ, Although EOM compartmentalization into thethat keeps the eye and brain warm during deep two distinctive, orbital and global, layers is a long-dives, in billfish (Scombroidei order) (Bennett and recognized and highly conserved feature, itsPappas, 1983; Block and Franzini-Armstrong, functional significance has only recently become1988; Block, 1991). While the EOMs are among clear. Discovery of the EOM pulleys, and thethe fastest muscles in mammals, they also possess unique relationship of the muscle layers to theslow, non-twitch muscle fibers that are character- pulleys and globe, has created a new concept foristic of phylogenetically older avian and amphibian the division of labor in EOM (Demer et al., 2000).muscles and other traits more typically associated A third objective of this review is to relate an-with cardiac muscle or embryonic skeletal muscle. atomic and molecular properties of the two EOMIt is perhaps because of this paradoxical complex- layers to this new hypothesis of orbital function.ity in their structural organization that a funda- Here, we address these objectives by buildingmental enigma remains in regard to EOM function upon the anatomical framework established in ourin normal eye movements and ocular motility dis- prior reviews of EOM (Spencer and Porter, 1988;orders. One objective of this review is to convey an Porter et al., 1995, 1997; Porter and Baker, 1996;integrated view of the morphologic, cellular, and Porter, 2002). Knowledge of the compartmentalmolecular divergence of EOM from prototypical and myofiber type organization of mammalianskeletal muscle. EOM and their relationships to oculomotor system The multinucleate muscle fiber or myofiber is the development, function, and dysfunction representsautonomous structural and functional unit of skel- an essential framework for future studies.etal muscle, but all myofibers are not created equal(Ranvier, 1874). Muscle-to-muscle variability infunction has been ascribed to the relative percent- EOM and orbital gross anatomyage composition of four highly conserved musclefiber types (types I, IIA, IIX, and IIB) (Brooke and The EOMs exhibit remarkable variation in number,Kaiser, 1970; Burke et al., 1971; Peter et al., 1972; arrangement (origin and insertion), and innervationSchiaffino et al., 1989). By contrast, the myofibers throughout phylogeny. From an early prototype ofcomprising EOM are singularly unique because four EOMs, a pattern of six ‘‘primitive’’ EOMs hasthey do not respect any of the traditional skeletal emerged by an evolutionary process of differentiationmuscle fiber type classification schemes. Several or degeneration. The presence of these six muscles,reviews have described the anatomic organization the four recti (superior, inferior, medial, andof EOM fiber types (Peachey, 1971; Mayr, 1978; lateral) and two obliques (superior and inferior),Asmussen, 1979; Chiarandini and Davidowitz, is rather constant across the vertebrate classes1979; Spencer and Porter, 1988; Ruff et al., 1989; from cyclostomes to avians, despite variations inPorter and Hauser, 1993a; Porter et al., 1995, 1997; arrangement and innervation (Isomura, 1981). ThePorter and Baker, 1996). The emergence of a last principal EOM, the levator palpebrae superi-consensus EOM fiber type classification scheme oris, did not make its appearance in phylogeny
  • 9. 45until mammals. These seven EOMs are relatively orbits point outward at approximately 231. Thisconsistent across mammalian species in their gen- relationship is important to understanding of theeral location and innervation pattern, although actions of the EOMs because the origin of theindividual muscle actions show interspecies rectus muscles is at the orbital apex and they insertvariation, particularly apparent in frontal-eyed in a spiral around the ocular limbus in such a(e.g., cat, monkey) versus lateral-eyed (e.g., mouse, fashion that the superior and the inferior rectirat, rabbit) animals. These variations are coincident form an angle of 231 with the anterior-posteriorwith species differences in the forward extension of visual axis in the straight-ahead position. Thethe maxillary process (Fink, 1953) and the relative gross anatomy and general functions of the sixangles of the visual axis and the semicircular canals EOMs are reviewed here.(Simpson and Graf, 1981; Ezure and Graf, 1984). The eye sits within the bony orbit surrounded by Medial rectus and lateral rectus musclesthe EOMs, connective tissue, and orbital fat. Thepositions of the six rectus and oblique EOMs in cat The four rectus muscles have a tenon-and-mortise-and monkey are shown in Fig. 1. Inflections in the like origin from a tendinous ring (annulus of Zinn)muscle paths due to orbital connective tissue which surrounds the optic foramen and a portionorganization impact EOM actions in primary of the superior orbital fissure (Sevel, 1986). Theand secondary gaze positions (see section ‘‘EOM medial rectus muscle exhibits a single head ofpulleys’’). Although the reference visual axes are origin from both the tendinous ring and the duraparallel and directed straight ahead, the bony that surrounds the optic nerve, and lies medial toFig. 1. Drawings illustrating superior and lateral views of monkey and cat orbits, with positions of EOMs and accessory EOMs.Superior oblique tendon and select other muscles are cut away for clarity of drawings. Note similar localization and insertion ofmonkey ALR and cat RBsl. Arrangement of EOMs and accessory EOMs in mouse and rat orbits is similar to that of cat, but theEOMs are surrounded by the Hardarian gland in rodent. ALR, accessory lateral rectus; IO, inferior oblique; IR, inferior rectus; LR,lateral rectus, MR, medial rectus, RB, retractor bulbi (sl, il, sm, and im denote superior lateral, inferior lateral, superior medial, andinferior medial slips, respectively); SO, superior oblique; SR, superior rectus. Drawings by Alex Meredith, PhD.
  • 10. 46the globe as it courses forward to insert just pos- the oculomotor nerve respectively, enter the globalterior to the corneoscleral junction. The lateral re- surface of the proximal portion of each muscle.ctus, arising from the tendinous ring as two distinct Although elevation and depression of the globe areslips, passes lateral to the globe to insert into the the primary actions of the vertical recti, theirsclera via a long, broad tendinous expansion. The origins lie medial to the globe such that they exhibitinnervation of the medial rectus is provided by secondary roles in the horizontal and torsionalthe inferior division of the oculomotor nerve, while planes. With the eyes in the primary position, thethe abducens nerve innervates the lateral rectus primate vertical recti intersect the globe at an anglemuscle. The nerves to both muscles enter proxi- of 231 lateral to the visual axis. Thus the superiormally on their global surfaces. Since the insertions rectus has a secondary role in adduction andof these muscles are symmetrically distributed intorsion, while the inferior rectus assists in ad-around the horizontal meridian on opposite sides duction and extortion. Though the primary actionsof the globe, the medial and lateral recti are of the vertical recti are the same in lateral-eyedfunctional antagonists that serve as the principal mammals, the angle of force of these muscles shiftsadductor and abductor of the eye, respectively. No 201 medial to the visual axis thereby altering theirsecondary actions of these muscles are expressed secondary actions. As a result, in lateral-eyedduring movements initiated from the primary mammals the superior rectus secondarily extortsposition. Slight vertical and torsional components and abducts, while the inferior rectus has a supple-induced in extreme positions of gaze are attribut- mental role in intorsion and abduction. A modifiedable to the actions of the other rectus and oblique distal segment of the superior rectus, the lateralmuscles. The arrangements and actions of the arm, is evident in rabbit and is primarily com-medial and lateral recti are basically identical in prised of orbital layer multiply innervated musclelateral- and frontal-eyed mammals. Expansions of fiber types (Briggs et al., 1988) (see sectiontheir tendons of insertion also have attachments ‘‘Detailed organization of EOM fiber types’’). Ato lacrimal and zygomatic bones (i.e., check similar structure may exist in humans (Kono et al.,ligaments of Lockwood), which were thought to 2002). Unlike the horizontal recti, the superior andserve to restrict extreme movements in the horizontal inferior recti do not have the enthesis connectionsplane. More recently, these ‘‘check ligaments’’ to the orbital walls (Kono et al., 2002).have been incorporated into an overall scheme oforbital connective tissue organization (see section‘‘EOM pulleys’’) and have been termed entheses Superior oblique muscle(Kono et al., 2002). The muscle planes of these andall other EOMs are fixed within the orbit in all The superior oblique muscle, like the four recti,gaze positions (e.g., the horizontal recti do not arises from the tendinous annulus at the apex of thesideslip during up and down gaze) (Miller and orbit. A small fascicle of muscle fibers on the medialRobins, 1987; Miller, 1989). surface of the muscle originates from the medial bony wall of the orbit. Coursing forward from an origin which lies dorsomedial to that of the medialSuperior rectus and inferior rectus muscles rectus, the superior oblique passes through a fib- rocartilaginous ring, the trochlea, and turns laterallyLike the horizontal recti, the vertical (superior and to insert on the superior aspect of the globe. Theinferior) recti originate from the tendinous ring at insertion of this muscle falls posterolateral to thethe apex of the orbit and course forward to insert central point of the globe in frontal-eyed mammals,anterior to the equator of the globe. The superior but anterolateral in lateral-eyed mammals. Therectus, like the medial rectus, muscle has an addi- trochlear nerve, upon entering the superior orbitaltional origin from the dura of the optic nerve fissure, courses medially to enter the superior(Sevel, 1986). The nerves to the superior and portion of the orbital surface of the muscle. Frominferior recti, the superior and inferior divisions of the primary position, the predominant action of
  • 11. 47this muscle in both lateral- and frontal-eyed onto both the skin of the upper eyelid and theanimals is intorsion. Differences in the point of superior tarsal plate. Since a scleral insertion is ab-insertion of the superior oblique in the primate sent, this muscle exerts no direct influence upon theversus the rabbit lead to clear differences in its globe, although an indirect influence is mediated bysecondary actions. The primate superior oblique a partial blending of the levator aponeurosis withsecondarily depresses and abducts the globe, while the tendon of the superior rectus muscle. Innerva-that of the rabbit secondarily elevates and adducts. tion is provided by a branch of the superior divisionAn anomalous muscle, the gracillimus orbitis (of of the oculomotor nerve that passes to the proximalBochdalek) or comes obliqui superioris (of Albin), portion of the muscle either through or lateral towhen present, originates from the proximal dorsal the superior rectus. The levator palpebrae functionssurface of the superior oblique muscle, inserts on in elevation of the upper eyelid. Occasionally,the trochlea and/or its surrounding connective though perhaps not infrequently, two anomaloustissue, and is innervated by a branch of the fourth muscles are associated with the levator palpebrae,nerve (Whitnall, 1921). and, like the latter, are innervated by branches from the superior division of the 3rd nerve (Whitnall, 1921; Isomura, 1977; Sacks, 1985). The tensorInferior oblique muscle trochleae (of Budge) arises from the medial border of the levator muscle and inserts onto the trochleaIn contrast to the origin of the other principal of the superior oblique muscle and/or its surround-EOMs from the annulus of Zinn, the inferior ing connective tissue. A muscle of similar name andoblique muscle arises from the maxillary bone in insertion, but originating from the ventral rim of thethe medial wall of the orbit. The origin of the optic foramen in proximity to the origin of the su-inferior oblique muscle furthermore may display perior rectus muscle and innervated by the fourthconsiderable variation in its anatomical relation- nerve, has been described in the rabbit (Murphyship to the nasolacrimal canal (Whitnall, 1921). et al., 1986). The transversus orbitus attachesThe muscle passes ventral to the tendon of the between the medial and lateral walls of the orbitinferior rectus and inserts on the lateral aspect of connecting with the levator muscle en route.the globe medial to the tendon of the lateral rectus.The insertion of the inferior oblique, like that ofthe superior oblique, is posterior to the equator in Accessory EOMsthe primate and anterior to the equator in therabbit, thereby resulting in the same primary ac- In addition to the seven principal EOMs, manytion, extorsion, but different secondary actions. vertebrates possess accessory EOMs. AccessoryThe inferior oblique of lateral-eyed animals second- EOMs in cat and monkey are shown in Fig. 1. Inarily depresses and adducts, while that of frontal- most species, the accessory muscle takes the formeyed animals elevates and abducts. Innervation is of the retractor bulbi (Hopkins, 1916; Cords, 1924;provided by a branch of the inferior division of the Isomura, 1981). The retractor bulbi is correlatedoculomotor nerve that enters the muscle near its with the presence of a nictitating membrane, andposterior border. these structures are synergistic in reflex retraction of the globe in response to corneal stimulation.Levator palpebrae superioris muscle The retractor bulbi first appears in phylogeny as a continuous sheath that surrounds, or two slipsThe levator palpebrae superioris has a narrow lying dorsal and ventral to, the optic nerve inorigin from the orbital surface of the lesser wing of amphibians. In both amphibians and reptiles, thethe sphenoid bone, just above the optic foramen retractor bulbi is paired with the membranae nic-and the origin of the superior rectus. In its distal titans muscle. In avians, these two muscles are re-course, this muscle crosses the superior aspect of the placed by quadratus membranae nictitans andglobe and fans out to insert via broad aponeuroses pyramidalis muscles. The mammalian retractor
  • 12. 48bulbi muscle variably has two (mouse), three which movements of pulley (by the orbital layer)(dog), or four (rat, rabbit, cat) slips. Innervation and globe (by the global layer) are coordinated butof the retractor bulbi exhibits species-specific not necessarily coincident (Demer et al., 2000). Thepatterns from branches of the oculomotor and/or active pulley system uses orbital layer motor unitsabducens nerves (Spencer and Sterling, 1977; to alter pulley positions and thereby adjust EOMGrant et al., 1979, 1981; Crandall et al., 1981; vector forces in different gaze positions, greatlyMeredith et al., 1981; Evinger et al., 1987). With simplifying the task of central oculomotor controlthe regression of the nictitating membrane to a systems by making commands independent of in-vestigial plica semilunaris in primates, the retrac- itial eye position (Clark et al., 2000). Any role thattor bulbi is reduced to a single homologous slip in the smooth muscle tissues, and their specialized in-the monkey, the accessory lateral rectus muscle, nervation (Demer et al., 1997), might play in pulleywhich is innervated by the abducens nerve (Spencer positional control is poorly understood at this time.and Porter, 1981; Schnyder, 1984). An accessorylateral rectus muscle may render monkeys resistantto esotropia (Boothe et al., 1990) and has been re- The functional context of the EOMsported in humans only in one case of congenitaloculomotor nerve palsy (Park and Oh, 2003). An understanding of the novel biology of the EOMs is incomplete without an appreciation for the demands of ocular motility (for a thoroughEOM pulleys review, see other chapters of this volume and Leigh and Zee, 1999). The reflexive oculomotor controlThe recent discovery of EOM pulleys, and their systems that stabilize images on the retina, therebyinterrelationship with the compartmentalized struc- preventing blur during head/body movement, areture of the EOMs (see section ‘‘Compartmental the phylogenetically oldest and form a base uponorganization of EOM’’), represents a paradigm which the other eye movement systems operate.shift in oculomotor function. Evidence that rectus Thus, the vestibulo-ocular and optokinetic reflexesmuscle bellies remain relatively fixed in the orbit are found in all vertebrates, but visual targetingdespite surgical transposition of their insertions movements, such as saccades and smooth pursuit,provided the first suggestion that EOM muscle appear later in phylogeny and vergence move-paths were fixed relative to the orbit (Miller et al., ments are associated only with the evolution of1993). Subsequent anatomical and imaging studies frontally placed eyes and high acuity specializa-characterized fibroelastic sleeves, or pulleys, repre- tions of the retina (e.g., area centralis, fovea).senting specializations in Tenon’s capsule (Fig. 2). Elaboration of the more sophisticated oculomotorEOM pulleys are located approximately at the control systems correlates with specific, patternedequator of the globe and suspended from the bony changes in EOM biology (see section ‘‘Differencesorbit by collagen/elastin/smooth muscle struts or in EOM fiber types in the same and differententheses (Demer et al., 1995; Porter et al., 1996; species’’). Accessory EOMs are typically restrictedClark et al., 1997; Kono et al., 2002). Adjacent to species with incomplete bony orbits, where re-muscle pulleys are intercoupled by connective flex retraction is required to protect the eye.tissue bands. The pulleys provide inflection points While the oculomotor system is arguably thein EOM paths, thereby serving as functional or- best understood of skeletomotor control systems,igins for each muscle. Species differences in pulley it also is among the most complex. Unlike mostmorphology correlate with known differences in skeletal muscles, which often are tightly role-specific,EOM biology and visuomotor function in rat ver- individual EOMs serve very diverse functionalsus humans (Khanna and Porter, 2001). The recent repertoires and execute eye movements almostfinding that the two distinct EOM compartments continuously throughout waking hours. Binocularor layers have separate insertion points led to alignment and maintenance of steady fixation uponformulation of the active pulley hypothesis, in targets are essential for clear vision and must be
  • 13. 49Fig. 2. Diagrammatic representation of orbital connective tissue relationships to the EOMs and eye, including the specializations ofTenon’s capsule, the rectus muscle pulleys. The connective tissues of the orbit are thickened to form pulleys for the four rectus musclesand inferior oblique. Interconnections between, and anterior and posterior to, the pulleys are the pulley sling. Differential distributionof orbital smooth muscle, collagen, and elastin components of pulleys and associated tissues is indicated. The three coronal views arerepresented at the levels indicated by arrows in the horizontal section. Separate insertions of orbital and global layers upon pulley andglobe, respectively, also are indicated. IO, inferior oblique; IR, inferior rectus; LPS, levator palpebral superioris; LR, lateral rectus;MR, medial rectus; SO, superior oblique; SR, superior rectus (figure courtesy of J.L. Demer and J.M. Miller; see Demer, 2000).accomplished within very fine tolerances or else blur stereotyped discharge patterns (Robinson, 1970),and diplopia (double vision) result. On one hand, including: (a) tight linkage between sustainedEOM responds to polymodal sensory signals to activity and eye position, (b) rapid and large puls-produce slow, smooth changes in eye position in es of motoneuron discharge associated with sac-vestibulo-ocular, optokinetic, vergence, and pursuit cadic eye movements, and (c) an overall high levelmovements that stabilize and/or track visual targets. of motoneuron activity, exceeding that of spinalOn the other hand, in acquiring novel visual targets motoneurons by an order of magnitude. EOMthe EOMs must execute saccadic eye movements fibers then must be responsive over an unprece-that can exceed 6001/s. dented dynamic range that requires adaptations for Skeletal muscle characteristics are directly influ- contraction speed and fatigue resistance well be-enced by the patterned activity of the motoneurons yond that experienced by the more typical skeletalthat innervate them (Pette, 2002). Oculomotor muscles. To this end, EOM utilizes the full rangemotoneurons represent the common output of the of phenotypic options available to adult skeletalcontrol systems described above and have highly muscle plus traits strategically borrowed from
  • 14. 50phylogenetically primitive skeletal muscle, imma- orbital bone and an inner global layer close to theture skeletal muscle, and cardiac muscle. There optic nerve and eye. In some species, a transitionallikely is a causal relationship between the wide zone (e.g., monkey), containing an admixture ofdynamic range of oculomotor control systems and muscle fiber types from either layer, or a connec-the complexity and diversity of EOM. tive tissue band (e.g., rabbit) may be evident between the orbital and global layers. A thin muscle fiberCompartmental organization of EOM layer external to the orbital layer, termed the mar- ginal zone (Wasicky et al., 2000) or peripheralSkeletal muscles are generally heterogeneous in patch layer (Harker, 1972), has been documentedcross-sectional appearance and compartmentalized in some species. In the rectus muscles, the orbitalor layered patterns may be evident. Various func- layer is comprised of smaller diameter fibers andtional advantages of compartmentalization in tra- typically is c-shaped, encompassing the globalditional skeletal muscles have been previously layer except for a gap left adjacent to the opticaddressed (English and Letbetter, 1982; Eason nerve or globe. In the oblique muscles, the orbitalet al., 2000). Likewise, the rectus and oblique EOMs layer often completely encircles the global layer.are characterized by a distinctive compartmentali- The global layer extends the full muscle length,zed organization (Kato, 1938) (Fig. 3A). Each has inserting into the sclera via a well-defined tendon,an outer orbital layer adjacent to the periorbita and while the orbital layer ends before the muscle be- comes tendinous. Recent studies have shown that this early termination of the orbital layer is a con- sequence of its insertion into the muscle pulley, at approximately the equator of the globe (Demer et al., 2000) (Fig. 2). By contrast, neither the le- vator palpebrae superioris nor the accessory EOMs have an orbital layer compartment, a find- ing that correlates with their lack of muscle pulleys. In addition to the clear differences in myofiber diameter, the two EOM layers are distinguished by substantial morphologic and immunocytochemical differences. First, the interrelated features of mitochondrial content, oxidative enzyme activities (e.g., SDH, NADH-TR), and microvascular net- work all are more developed in the orbital layer. Collectively, these traits correlate with the high fatigue resistance and continuous activation of the orbital layer. Second, the orbital layer expresses traits usually associated with developing skeletal muscle. While traditional skeletal myofibers exhibit a developmental transition in expression of embry- onic to neonatal to adult myosin heavy chain iso-Fig. 3. Histological profiles of the EOM layers (A) and fibertypes (B, C) in the monkey lateral rectus muscle. Note general forms, adult orbital layer myofibers retain thefiber type size differences, with the c-shaped orbital layer con- embryonic myosin heavy chain (Myh3) (Wieczorektaining smaller diameter fibers. Profiles of the SIFs (1, 3–5) and et al., 1985; Jacoby et al., 1990; Brueckner et al.,MIFs (2, 6) in the orbital (B) and global (C) layers are indi- 1996). Neural cell adhesion molecule (NCAM), acated. Phase contrast light photomicrographs of semithin cell surface molecule normally downregulated dur-(1 mm) sections highlight differences in mitochondrial contentof different muscle fiber types. 1, orbital SIF; 2, orbital MIF; 3, ing myogenesis, also persists on virtually all orbital,global red SIF; 4, global intermediate SIF; 5, global white SIF; but only some global, layer fibers (McLoon and6, global MIF. Wirtschafter, 1996). A similar pattern is apparent
  • 15. 51for the embryonic (g) acetylcholine receptor (AChR) independently regulated. Instead, myofiber prop-subunit, as it is present at all neuromuscular junc- erties that determine speed and fatigability aretions of orbital layer myofibers, but only at those of co-expressed in specific patterns that led to thesome global layer myofibers (Kaminski et al., 1996). recognition of discrete muscle fiber types. The Because few investigators work on the cell and major myofiber classification schemes (Brookemolecular biology of EOM, observations such as and Kaiser, 1970; Peter et al., 1972; Burke et al.,the orbital layer retention of embryonic traits are 1973; Gauthier and Lowey, 1979; Schiaffino et al.,sparse. To more efficiently identify such orbital and 1989) agree on three to four fiber types in typicalglobal layer specializations, we used laser capture skeletal muscle: (a) slow-twitch, fatigue resistantmicrodissection to isolate EOM layer-specific sam- (red or type I), (b) fast-twitch, fatigue resistantples and then determined their gene expression sig- (intermediate or type IIA), (c) fast-twitch, inter-natures by high-throughput DNA microarray mediate (type IIX), and (d) fast-twitch, fatigableanalyses. Differential expression profiling identified (white or type IIB). Structural and functional181 transcripts with preferential expression in the properties of these four traditional fiber types areorbital or global layer, encompassing genes with a summarized in Table 1. Muscle fiber types havewide range of functions (see Khanna et al., 2004 and distinct functional identities (Close, 1972; Burkeaccession number GSE 907 in the National Center et al., 1974), each with a relatively narrow optimalfor Biotechnology Information (NCBI) Gene Ex- working range such that their collective actionspression Ontology (GEO) database). Among these, are required to achieve typical physiologic wholeseveral slow/cardiac muscle markers were preferen- muscle force-velocity profiles. These four fibertially expressed in the orbital layer (TNNC1, types are found in various proportions in virtuallyMYH7, MYH6, CSRP3, TNNT2, FHL1, NRXN3, every mammalian skeletal muscle. For example,and NEBL). These data suggest that the orbital may slow fatigue-resistant muscles like soleus are prin-be functionally slower than the global layer and that cipally comprised of types I and IIA, while typeproperties of orbital layer fibers alone may explain IIB fibers predominate in fast, fatigable musclesand extend several prior findings of cardiac muscle- like gastrocnemius. It is well recognized that thespecific gene or protein expression in EOM. four discrete myofiber types may represent pheno- Overall, the orbital and global layers are very types along a continuum in variation of myofiberdifferent in their morphologic and gene expression traits. Nonetheless, the fiber type classificationprofiles, consistent with their respective muscle pul- schemes have been an essential means of under-ley and eye movement roles. Preferential expression standing muscle function and are of considerableof the transcription factor, CSRP3 (and transcripts value in diagnosis and muscle disease modeling, asthat are regulated by CSRP3; e.g., FHL1, MYH3) several neuromuscular diseases preferentially in-(Khanna et al., 2004), by the orbital layer is a par- volve specific muscle fiber types.ticularly interesting finding. CSRP3 responds to Initial gene expression profiling studies have sug-muscle stretch by activating transcripts associated gested that differences between muscles that arewith early myogenesis (Knoll et al., 2002). Orbital comprised of predominately type I versus type IIBlayer expression of CSRP3 may mechanistically myofibers are relatively modest (Campbell et al.,link the continuous activity of this layer against 2001). However, more recent data support a greaterelastic elements of muscle pulleys to the orbital degree of divergence among skeletal muscle groupslayer retention of various embryonic traits. than can be explained simply by differences in com- position of stereotypic fiber types (Porter et al.,Traditional skeletal muscle fiber types 2004). These data suggest that there might be more variability among the traditional muscle groups andMost skeletal muscles are comprised of variable myofiber types than is currently known.percentages of four conserved muscle fiber types. Despite the value of the fiber type concept forThe myofiber traits that are responsible for over 130 years (Ranvier, 1874), myofibers presentcontraction speed and fatigue resistance are not in some muscle groups do not appear to respect
  • 16. 52Table 1. Structural and functional profiles of the routine skeletal muscle fiber typesTerminologiesaBrooke and Kaiser (1970) I IIA IIX IIBPeter et al. (1972) Slow-twitch-oxidative Fast-twitch-oxidative Fast-twitch-glycolytic glycolyticBurke et al. (1973) S FR F (int.) FFGauthier and Lowey (1979) Red (slow) oxidative Red (fast) oxidative Intermediate White glycolytic glycolyticSchiaffino et al. (1989) I IIA IIX IIBHistochemical profilesMyosin ATPase (pH 9.4) Low High High HighMyosin ATPase (pH 4.6) High Low Intermediate IntermediateMyosin ATPase (pH 4.3) High Low Intermediate LowSDH (mitochondrial aerobic) High Intermediate–high Intermediate LowNADH-TR (aerobic) High Intermediate–high Intermediate LowLDH (anaerobic) High Intermediate–high Intermediate LowMen-a-GPD (anaerobic) Low High Intermediate HighPAS (glycogen) Low High Intermediate Intermediate–highPhosphorylase Low High High HighOil Red O (lipid) High Low Low LowAlkaline phosphatase High High Low Low(capillaries)Immunocytochemical profilesMyosin heavy chain Myh7 (I/b-cardiac) Myh2 (IIA) Myh1 (IIX) Myh4 (IIB)Ultrastructural profilesbZ-line Wide Wide Narrow NarrowMitochondria Many, small Many, large Moderate, small Few, smallSarcoplasmic reticulum, T- Elaborate, narrow Elaborate, narrow Moderate, small Compact, broad,tubules parallelNeuromuscular junctions Large, widely spaced, Discrete, separate, Long and flat; long, deep folds small, elliptical, shallow, branching, closely sparse folds spaced foldsPhysiological profilescTwitch contraction time (ms) Slow Intermediate Fast FastTwitch tension (g) Very low Low Intermediate HighRelative fatigue resistance Resistant (very) Resistant (moderate) Intermediate Sensitivea Terminology from the major skeletal muscle fiber type classification schemes. bConsenus morphologic traits from multiple studies(Gauthier, 1969; Padykula and Gauthier, 1970; Schiaffino et al., 1970). c Consensus physiological traits derived from multiple studies(Close, 1972; Burke et al., 1973, 1974).traditional classification schemes. The allotype Overview of EOM fiber typesconcept originated as a framework to accountfor the phenotypic range available to skeletal mus- Early morphologic and physiologic studies recog-cle (Hoh et al., 1988, 1989). Three allotypes were nized that myofibers present in mammalian EOMdefined on the basis of their potential to express were atypical. Siebeck and Kruger (1955) identifiedspecialized myosins: masticatory (super fast myo- two basic EOM fiber types, one type similar to thesin), EOM (EOM-specific myosin, designated typical twitch fibers of mammalian skeletal musclesMyh13), and limb (no allotype-specific myosins), (now designated singly innervated fibers or SIFs)and their appearance is dependent upon an inter- and the other similar to slow fibers atypical foraction of muscle lineage with appropriate inner- mammalian skeletal muscle (now designated mul-vation patterns. The distinctive fiber types tiply innervated fibers or MIFs). The SIFs of rectuscomprising the EOM allotype are discussed here. and oblique EOMs are invariably fast-twitch
  • 17. 53(among EOMs, slow-twitch fibers are found only in the six fiber type scheme (McLoon et al., 1999;the levator palpebrae superioris; see Porter et al., Kjellgren et al., 2003a, b). Myosin heavy chain is a1989). MIFs have been found in EOM and a few key determinant of contractile properties; multi-other, highly specialized craniofacial muscles (e.g., ple myosin genes encode proteins differing intensor tympani and laryngeal muscles) (Fernand contraction speed and energetic demands suchand Hess, 1969; Mascarello et al., 1982; Veggetti that an individual skeletal muscle fiber typicallyet al., 1982; Han et al., 1999). We suggest that expresses the one myosin isoform that is bestMIFs, while exceptionally rare in skeletal muscle, suited for its workload. EOM is unique in itsmay be more prevalent among craniofacial muscles broad utilization of options from the myosinthan is currently appreciated. Physiologic studies heavy chain family and its frequent heterogeneityidentified two MIF types in EOM, differing on the in myosin expression within single myofibers.basis of location within the orbital or global layers Specifically, EOM expresses virtually all knownand their physiological ability to propagate action striated muscle isoforms of myosin heavy chain,potentials (Hess and Pilar, 1963; Bach-y-Rita and including traditional adult skeletal (Myh1 or typeIto, 1966; Pilar and Hess, 1966; Pilar, 1967). The IIX, Myh2 or IIA, Myh4 or IIB, and Myh7 or I/b-two types of EOM MIFs resemble the multiply cardiac), developing skeletal (Myh3 or embryonicinnervated fibers that are found in amphibian and Myh8 or perinatal), cardiac-specific (Myh6 or(similar to global layer MIFs) and avian (similar to a-cardiac), and a tissue-specific (Myh13 or EOM-orbital layer MIFs) skeletal muscles (Morgan and specific) isoform (Bormioli et al., 1979; WieczorekProske, 1984). Interestingly, the neuromuscular et al., 1985; Jacoby et al., 1990; Asmussen et al.,junctions associated with SIFs and MIFs appear to 1993; Rushbrook et al., 1994; Brueckner et al.,exhibit very similar molecular organization and 1996; Jung et al., 1998; Winters et al., 1998;both have only modest differences from those of McLoon et al., 1999; Pedrosa-Domellof et al., ¨other skeletal muscles (Khanna et al., 2003b). 2000; Rubinstein and Hoh, 2000; Wasicky et al., Since these early studies, EOM fiber typing has 2000; Briggs and Schachat, 2000, 2002; Schachatevolved such that there now is a consensus on a six and Briggs, 2002). If we are to obtain an overallfiber type classification scheme for mammalian understanding of the properties of EOM fiberEOM (for a historical review, see Spencer and types, it is essential to relate myosin expressionPorter, 1988). There are also several extensive patterns, identified by immuncytochemistry and/orreviews of this fiber classification scheme (Spencer in situ hybridization, to the range of other myo-and Porter, 1988; Porter et al., 1995; Porter and fiber traits. Incorporation of much of the recentBaker, 1996). While any single measure (e.g., myo- myosin expression data into the existing EOMfibrillar ATPase) might lead one to believe that myofiber classification scheme, however, is prob-EOM is comprised of traditional skeletal muscle lematic. Possible species differences in myosinfiber types, broader morphologic/histochemical/ expression patterns, heterogeneity in the batteriesimmunocytochemical profiles show that the estab- of myosin antibodies used, failure to consider factorslished skeletal muscle classification schemes simply such as the longitudinal variations in the same fiber,do not apply to EOM. A reasonable assumption is and the frequent failure to use a fiber type identifyingthat the relatively large number of EOM fiber types, marker (e.g., trichrome stain) in adjacent sectionssix versus the three to four of typical skeletal muscle, serve to complicate any synthesis of myofiber traits.reflects the complexity and variety of eye movements. As noted above, it can be misleading to base EOM fiber types have been extensively charac- fiber classification schemes upon any single trait,terized in monkeys, rabbits, rats, and mice and as this may identify mere variations in the samethere is evidence that human EOMs contain sim- fiber types. Although four SIF types are describedilar fiber types (Wasicky et al., 2000). Recent in mammalian EOM, every fiber cannot be fit tostudies, relying upon myosin heavy chain expres- the absolute criteria of a single type. The aggregatesion patterns alone, have suggested that EOM population of EOM SIFs, therefore, may form amay be more complex in fiber type content than continuum of fast-twitch fibers that differ in
  • 18. 54contraction speed and fatigability (Nelson et al., isoforms that can be clearly linked to specific fiber1986), not unlike the situation for the three fast- types; thus, these likely are incomplete represen-twitch fiber types in traditional skeletal muscles. If tations of the actual expression patterns.fiber typing is to provide a useful tool for under-standing EOM biology, we argue that furtheradditions to the myofiber classification schemes The orbital singly innervated fiber typemust allow for such variability and base any newtypes upon the identification of conserved patterns Orbital SIFs (Figs. 3B and 4A, and Table 2)across a broad range of myofiber traits. represent the predominant fiber type (80%) in the The six established EOM fiber types are desig- orbital layer of rectus and oblique muscles. The or-nated according to their layer distribution (orbital bital SIFs contain small myofibrils, surrounded byor global), innervation type (singly or multiply), abundant sarcoplasmic reticulum, and highand mitochondrial content (red, intermediate, or mitochondrial content (Fig. 5A). At mid-belly, or-white). All EOM SIFs have profiles consistent with bital SIF diameter is largest and the fibers taperfast-twitch function, but atypical for skeletal mus- proximally and distally. Mitochondria form char-cle fast-twitch fibers, contain very little glycogen. acteristically large central and subsarcolemmal clus-Fiber type traits are summarized in Table 2 and in ters. Since mitochondria comprise a rather largethe following section. Fiber type repertoires of the volume of the orbital SIFs (20% by volume), myo-levator palpebrae superioris, retractor bulbi, and fibril volume is exceptionally low (60%) in compar-accessory lateral rectus muscles differ from the ison to the range seen in most skeletal musclesscheme presented here and are discussed elsewhere (70–85%) (Hoppeler and Fluck, 2002). This is con-(Alvarado et al., 1967; Pachter et al., 1976; Spencer sistent with the general EOM trait of low force de-and Porter, 1981; Gueritaud et al., 1986; Porter velopment. The histochemical profile of orbital SIFs et al., 1989). It is important to note that fiber types suggests that they are fast-twitch and fatigue resist-of the retractor bulbi are more like those of limb ant, but also have capacity for anaerobic metabo-musculature; this may have direct disease conse- lism. Orbital SIFs contain unusually high lipidquences, since the retractor does not exhibit the content. A single neuromuscular junction is presentsparing in muscular dystrophy that is seen for EOM at approximately the middle of each fiber, usually(Ragusa et al., 1996; Porter and Karathanasis, encircling the fiber; nerve terminals are embedded in1998; Porter et al., 2001b, 2003b). deep depressions of the sarcolemma and exhibit few, irregular postsynaptic folds (Fig. 6A). Myosin expression in orbital SIFs is heterogene-Detailed organization of EOM fiber types ous, with expression of a unique myosin gene only seen in EOM and laryngeal muscles (Myh13) and aHere, we present a composite view of each of the developmental myosin isoform (Myh3) (Wieczoreksix recognized EOM myofiber types. Two of these et al., 1985; Jacoby et al., 1990; Brueckner et al.,fiber types localize to the orbital layer (one SIF 1996). This myosin expression pattern raises twoand one MIF) and four localize to the global layer critical issues: (a) phylogenetic analysis of Myh13(three SIFs and one MIF). A characteristic feature indicates that it diverged early from an ancestralof EOM is the overall small myofiber diameter myosin and has substantial structural differencesrelative to most other skeletal muscles. The EOM from other fast isoforms (Briggs and Schachat, 2000;fiber types are largely conserved across species; Shrager et al., 2000) and (b) retention of develop-known species differences are addressed in a sub- mental myosin isoforms in adult skeletal muscle issequent section. Morphologic descriptions are rare. Myosin isoforms are specialized to providebased upon rhesus monkey EOM, while histo- specific contractile force/velocity at a specific energychemical and immunocytochemical data are com- cost. The unique myosin expression profile of orbitalpiled from a variety of species. The myosin SIFs is suggestive of a highly specialized role in eyeexpression patterns indicated here are only those movements. Lucas and Hoh (2003) have suggested
  • 19. Table 2. Ultrastructural and histochemical profiles of extraocular muscle fiber types Orbital GlobalFiber type: 1 2 3 4 5 6Ultrastructural profilesMyofibrils Extent Small Large Small Small Small Large Size (mm) Rata 0.24 0.20–0.81 0.26 0.34 0.41 0.61 Monkeyb 0.30 0.36–0.58 0.27 0.41 0.51 0.67 Separation Well delineated Moderately delineated Well delineated Well delineated Well delineated Poorly delineated Volume fractionc (%) 60 78 55 65 71 83Sarcoplasmic recticulum Extent Moderately developed Modestly developed Moderately developed Well developed Well developed Poorly developed Location Predominantly I band I band Predominantly I band Predominantly I band I4A band I bandVolume fraction (%) Ratc 9 6 10 14 16 4 Monkeyb 7.7–17.4 7.0–16.2 9.2 18.3 19.5 4.8T-tubules Extent Well developed Poorly developed Well developed Well developed Well developed Poorly developed Location A/I junction Irregular A/I junction A/I junction A/I junction IrregularMitochondria Number Very many Few–many Many Many Few Few Extent Large Small Large Moderate Small Small Size (mm) Monkeyb 0.13–0.28 0.07–0.14 0.22 0.19 0.20 0.06 Disposition Aggregated Single Aggregated Single Single SingleVolume fraction (%) Ratc 20 6 24 13 5 5 Monkeyb 18.1–27.3 7.9–20.6 22.3 13.8 6.8 6.8Z-line Extent Intermediate Wide Intermediate Narrow Narrow WideWidth (mm) Ratc 73 118 76 54 48 100Histochemical profilesd Trichrome Coarse/granular Granular/fine Coarse/granular Granular Granular/fine Fine Mean diameter (mm) 24.873.8 19.373.2 27.274.7 34.574.6 46.776.2 35.774.1Percentage (%) 80 20 33 25 32 10 Myosin ATPase 9.4 +++ +++ +++ +++ +++ +/–Myosin ATPase 4.6 +/- +++ +/- +/– +/– ++++ SDH +++/++++ ++ ++++ +++ ++ + NADH-TR +++ ++ ++++ +++ ++ + LDH ++/+++ ++ ++++ +++ ++ + 55 Men-a-GPD ++/+++ + ++ +++ ++++ +
  • 20. 56Table 2 (continued ) Orbital GlobalFiber type: 1 2 3 4 5 6 Sudan black ++/+++ + +++ ++ ++ + PAS ++/+++ +/– ++ + + +/– Phosphorylase ++/+++ + +++ + + + Oil RedO ++/+++ + +++ ++ + + Alkaline phosphatase ++++ ++ +++ ++ + + AChE Focal, encircle Multiple Focal Focal Focal MultiplePhysiological profiles Contraction speed Fast Twitch/tonic Fast Fast Fast Tonic Fatigue resistance High Intermediate High Intermediate Low Lowa Quantitative data from Pachter (1983) in rat superior oblique muscle. Ranges for the orbital MIF (2) indicate proximo-distal variations within single fibers examined inserial sections. bQuantitative data from Pachter (1982) in monkey superior rectus muscle. Ranges for the orbital SIF (1) and MIF (2) types indicate proximo-distalvariations within single fibers examined in serial sections. c Quantitative data from Mayr (1973) in rat extraocular muscle. d Histochemical data from cat EOM: SDH,succinct dehydrogenase; NADH-TR, nicotinamide adenine nucleotide dehydrogenase-tetrazolium reductase; LDH, lactic dehydrogenase; Men-a-GPD, menadione-linkeda-glycerophosphate dehydrogenase; PAS, periodic acid-Schiff; AChE, acetyl-cholinesterase. Level: +/– (very low), +(low), ++ (intermediate), +++ (high), ++++(very high).
  • 21. 57Fig. 4. Ultrastructural profiles of the SIF (A) and MIF (B) muscle fibers of the orbital layer, and the red (C), intermediate (D), andwhite (E) SIFs and the MIF (F) of the global layer, of the monkey lateral rectus muscle. Muscle fiber types are differentiated on thebasis of the size, number and distribution of mitochondria, the size and delineation of the myofibrils, and the extent of development ofthe internal membrane system (sarcoplasmic reticulum and T-tubules). c, capillary; mn, myonucleus; s, neuromuscular synaptic ending;a, preterminal axon. Scales: A, C, 10 mm; B, D–F, 5 mm.that EOM contains two distinct forms of the em- 2002; Lucas and Hoh, 2003). The fast isoform of thebryonic myosin heavy chain protein, one potentially sarcoplasmic reticulum calcium ATPase (Atp2a1)unique to EOM, that may represent alternative shows a similar pattern of longitudinal variation,splicing of Myh3 or an alternative gene. Myosin dropping out distal to neuromuscular junction sitesisoforms also show variation along the length of (Jacoby and Ko, 1993). A substantial number ofindividual fibers; Myh13 is expressed only in the vi- orbital layer fibers express the neonatal myosincinity of the neuromuscular junction, while Myh3 is heavy chain isoform (Myh8), although it is currentlyexpressed both proximal and distal to this site unclear which fiber types these are (Wieczorek et al.,(Rubinstein and Hoh, 2000; Briggs and Schachat, 1985; McLoon et al., 1999). The overall orbital SIF
  • 22. 58Fig. 5. Ultrastructural profiles of the mitochondria (m), myofibrillar organization in the A-band (A) and I-band (I), and the de-lineation of the myofibrils by T-tubules (t) and sarcoplasmic reticulum (sr) in the orbital SIF (A) and MIF (B), the global red (C),intermediate (D), and pale (E) SIFs, and the global MIF (F) in the monkey lateral rectus muscle. Scale: A–F, 0.5 mm.profile is consistent with rapid, highly fatigue resist- surpassed only by myocardium (Wooten and Reis,ant muscle contractions. 1972; Wilcox et al., 1981). Consistent with the high mitochondrial andoxidative enzyme content, individual orbital SIFsare ringed by capillaries. The vascular supply of The orbital multiply innervated fiber typethe orbital layer and the high oxidative activity ofthe SIFs may account for the high blood flow in Orbital MIFs (Figs. 3B and 4B, and Table 2) ac-EOM, which exceeds that of skeletal muscle and is count for the remainder of fibers (20%) in the
  • 23. 59Fig. 6. Ultrastructural profiles of neuromuscular junctions associated with the orbital SIF (A) and MIF (B), the global intermediate(C) and pale (D, E) SIFs, and the global MIF (F) in the monkey lateral rectus muscle visualized by the histochemical localization ofacetylcholinesterase. s, neuromuscular synaptic ending; a, preterminal axon; Sch, Schwann cell; mn, myonucleus. Scales: A, B, F, 2 mm;C–E, 5 mm.orbital layer. Like the orbital SIF, this fiber type (fast) and acid (slow) myofibrillar ATPase. Myo-shows considerable structural and biochemical fibrils are larger than those of orbital SIFs andvariation along its length. At mid-belly, the orbit- sarcoplasmic reticulum development is moderateal MIF has traits consistent with twitch contrac- (together, suggestive of slower twitch contractions)tion, exhibiting dual staining with both alkaline (Fig. 5B). By contrast, proximal and distal to the
  • 24. 60fiber mid-section orbital MIFs exhibit slow myofi- layer. The histochemical, ultrastructural (Fig. 5C),brillar ATPase and fine structural characteristics of and myosin heavy chain expression profile of thisslowly contracting fibers (large myofibrils and sparse fiber type is similar to that of the orbital SIF, ex-sarcoplasmic reticulum). Unlike other adult skeletal cept that it does not exhibit the longitudinal var-muscle fibers, multiple nerve terminals are distrib- iations in ultrastructure and does not co-expressuted along the myofiber length. At mid-belly, ne- the developmental myosin isoforms. Instead, globaluromuscular junctions resemble those of the orbital red SIFs express the IIA myosin isoform (Myh2)SIFs (Fig. 6B). By contrast, proximal and distal to (Brueckner et al., 1996; Rubinstein and Hoh, 2000);its center the nerve terminals are small and rest on because of its relationship to the orbital SIF, thisthe sarcolemmal surface or in slight depressions, fiber type may be among a population of globalwith no postjunctional folds. fibers that express Myh13 near their neuromuscular Based on enzyme histochemistry, orbital MIFs junctions (Briggs and Schachat, 2002). Like its or-exhibit only modest oxidative and weak glycolytic bital counterpart, the global red SIF has a highcapacity. Myosin heavy chain expression is consi- mitochondrial volume (420%) and very low myo-stent with this profile in that mid-fiber regions fibril volume fraction (55%), suggesting that thestain for the slow-twitch isoform (type I or Myh7) considerable fatigue resistance is achieved at theand proximal/distal regions stain for both the em- cost of force reduction. Neuromuscular junctionbryonic myosin (Myh3) and Myh7 (Rubinstein morphology is nearly identical to that of the orbitaland Hoh, 2000; Briggs and Schachat, 2002). SIF. Collectively, these observations suggest simi-Immunoreactivity for an avian slow-tonic myosin larities with the skeletal IIA fiber type, but the veryheavy chain also has been linked to orbital MIFs high mitochondrial content and overall histochem-(Pierobon-Bormioli et al., 1980). As noted above, ical profile is very different from typical IIA fibers.orbital layer fibers express the neonatal myosin The global red SIF’s profile suggests that it is fast-heavy chain isoform (Myh8), but it is not clear twitch and highly fatigue resistant.which fiber types these are (Wieczorek et al., 1985;McLoon et al., 1999). Orbital MIFs also exhibitatypical myosin light chain patterns; instead of the The global intermediate singly innervated fibertraditional skeletal muscle slow isoform, they ex-press an embryonic skeletal/atrial isoform of myo- Global intermediate SIFs (Figs. 3C and 4D, andsin light chain 1 (Bicer and Reiser, 2004). Table 2) comprise approximately one-fourth of the Physiological studies suggest that orbital MIFs fibers in the global layer, with rather uniformexhibit twitch capability in mid-belly and non- distribution throughout this layer. Myofibrillartwitch contractions in proximal and distal fiber ATPase and ultrastructural characteristics indicatesegments (Jacoby et al., 1989). Collectively, the that this is a fast-twitch fiber type; myosin isoformheterogeneous features of this fiber type are unlike content is likely IIX (Myh1) (Rubinstein and Hoh,any that previously has been described for skeletal 2000). Moderate levels of oxidative enzymes andmuscle, with parallels only to intrafusal (neuro- anaerobic enzymes are apparent. Numerousmuscular spindle) fibers, and it is difficult to draw medium-sized mitochondria are distributed singlyconclusions regarding its function. or in small clusters. Myofibrillar size and sarcoplas- mic reticulum content are intermediate between the other two types of global SIFs (Fig. 5D). Neuro-The global red singly innervated fiber muscular junctions include clusters of large nerve endings that are located in synaptic depres-Global red SIFs (Figs. 3C and 4C, and Table 2) sions that include regularly spaced postjunctionalrepresent about one-third of the muscle fibers in the folds (Fig. 6C). Overall, this profile fits that of aglobal layer, predominating in the intermediate fast-twitch fiber with an intermediate contractionzone between orbital and global layers and declin- speed and level of fatigue resistance, probablying in frequency with progression into the orbital lying between global red and white SIFs.
  • 25. 61The global white singly innervated fiber There are numerous small superficial grape-like endings distributed along the longitudinal extentGlobal white SIFs (Figs. 3C and 4E, and Table 2) of individual fibers of global MIFs (Fig. 6F).comprise about one-third of the global layer. Global A novel type of sensory nerve terminal, the myo-white SIFs exhibit modest levels of oxidative en- tendinous cylinder or palisade ending, is associatedzymes, high anaerobic metabolic capacity, and a with the myotendinous junction of this fiber type ATPase profile. This fiber type likely ex- Like amphibian muscles, the global MIF typepresses type IIB myosin heavy chain (Myh4) exhibits a slow graded, non-propagated response(Rubinstein and Hoh, 2000). There are few, small following either neural or pharmacologic activa-mitochondria that are singly arranged between the tion (Chiarandini and Stefani, 1979). The findingmyofibrils (Fig. 5E). Neuromuscular junctions are of a phylogenetically primitive muscle fiber type inthe most elaborate of any of the six EOM fiber one of the fastest skeletal muscles is difficult totypes. Multiple axon terminals are clustered togeth- reconcile, unless one considers a potential role iner in deep depressions of the sarcolemma; post- either very fine foveating movements of the eye orjunctional folds are regular, numerous, and deep as part of a specialized proprioceptive apparatus(Fig. 6D, E). The overall fiber profile is consistent (Ruskell, 1978) (cf. Chapter 3).with a fast-twitch type that is used only sporadicallybecause of low fatigue resistance. Differences in EOM fiber types in the same and different speciesThe global multiply innervated fiber Differences between the rectus and oblique musclesGlobal MIFs (Figs. 3C and 4F, and Table 2) con- in the same species appear to be largely attributablestitute the remaining 10% of fibers in the global to variations in the total number of fibers in eachlayer. These fibers contain very few, small mito- muscle. Such muscle-to-muscle variability in myo-chondria that are arranged singly between the myo- fiber number, however, is primarily the result offibrils. Myofibrils are very large and sarcoplasmic differences in orbital, but not global, layers (Ohreticulum development is so poor that myofibril et al., 2001). These authors attributed this finding toseparation is often indistinct (Fig. 5F). The large rectus muscle sharing of a similar mechanical loadmyofibrils mean that the calcium source, the sarco- on the eye-mover global layers, but rectus muscleplasmic reticulum, and the contractile filaments are dissimilarities in load on pulley-mover orbital lay-spatially far apart, resulting in very slow contrac- ers, because of pulley differences in elasticity.tions. Consistent with slow excitation–contraction EOMs of the same species can differ in relativecoupling in this fiber type, the fast calcium ATPase proportions of the six muscle fiber types (Ringelfound in all other EOM fiber types is absent from et al., 1978; Vita et al., 1980; Carry et al., 1982;global MIFs (Jacoby and Ko, 1993). The ultra- McLoon et al., 1999). Similar to the fiber countstructural profile of this fiber resembles that of data, human EOMs show the largest same-speciesslow, tonic muscle fibers in amphibians. Global variation in the orbital layer (medial recti havingMIFs express slow-twitch (type I or Myh7) the highest and lateral recti the lowest percentage of(Brueckner et al., 1996; Rubinstein and Hoh, orbital SIFs; Ringel et al., 1978). Finally, while2000), but do not appear to be immunoreactive complexity of myosin heavy chain expression mayfor avian slow-tonic myosin heavy chain (Pierobon- be confined to the orbital layer in rat (i.e., globalBormioli et al., 1980). There are variable reports layer fibers may express single myosin isoforms;that it expresses the a-cardiac myosin heavy chain Rubinstein and Hoh, 2000), myofibers of the globalisoform (Myh6). Global MIFs express the tradi- layers of rabbit and human EOM may be moretional skeletal muscle slow isoform of myosin light heterogeneous in myosin heavy chain expressionchain 1, but not the skeletal/atrial isoform found in patterns (McLoon et al., 1999; Briggs and Schachat,orbital MIFs (Bicer and Reiser, 2004). 2002; Kjellgren et al., 2003b). Taken together,
  • 26. 62individual muscle variations in the proportion of species in the global muscle fiber types is theirdifferent muscle fiber types, and variability in myo- diameters (although the ratio of global MIF tosin expression patterns of single types, might ex- global SIF diameter appears to be considerablyplain differences in the rate- and tension-related higher in rodents than in higher species). Collec-contractile properties of different EOMs (Meredith tively, differences in global myofiber size andand Goldberg, 1986). number could account for observed differences in Differences between the same muscle in different isometric tension in the cat (Barmack et al., 1971)species are more difficult to assess, since compar- and monkey (Fuchs and Luschei, 1971).isons between studies are based on the interpreta-tion of comparable fiber types with differentnomenclatures and examined by different meth- An integrated view of EOM biologyods. Based upon the range of data published todate, it is reasonable to conclude, however, that Current knowledge of EOM biology is clearly in-analogous fiber types exist across mammalian complete. For example, there is a complex patternspecies. There are, however, suggestions that fib- of myofibril size variation in both orbital and glo-er types in human EOMs may be more complex bal fiber types (Davidowitz et al., 1996a, b) thatthan those of other species (Kjellgren et al., 2003a, has not yet been accounted for in modeling EOMb). While the number of muscle fibers, their diam- function. However, new data from approacheseters, and possibly the proportion of different ranging from orbital anatomy to EOM cell andmuscle fiber types may vary between species, the molecular biology now allow a more integratedextent of development of individual fiber types al- view of EOM. Here, we review the implications ofso may be an important factor that underlies their new data and concepts in EOM and oculomotorphysiological differences. physiology and EOM molecular biology and es- The most dramatic difference between species is tablish the importance of arriving at an integratedin the morphology of the orbital SIF. While the view of EOM myofiber and whole muscle biology.contractile elements of this fiber are similarbetween species, mitochondrial content varies con-siderably (Fig. 7). Orbital SIFs appear to attain Insights from EOM and oculomotor physiologytheir most extensive mitochondrial development inthe primate. Comparisons between SIFs of the One goal of correlative anatomical, molecular, andrabbit and cat suggest that orbital SIF differences physiological studies of EOM has been to uncoverin mitochondrial content may not be related solely any association of specific muscle fiber types withto frontal versus lateral eye placement. A more defined eye movement functions. The segregationparsimonious interpretation is that the morpholo- of function among different EOM motor unitgy of this fiber type is directly related the recent types has been a long-debated issue. An early con-linkage of orbital layer to muscle pulley function cept of EOM suggested that the distinct EOM fiber(Demer et al., 2000), with increased oxidative func- types might be responsible for the different classestion and fatigue resistance necessary for the greater of eye movement. Oculomotor motoneuron activ-pulley development, wider oculomotor range, and ity in alert animals (Robinson, 1970) and intraop-reliance upon eccentric eye positions in primates erative electromyographic studies (Scott andversus rodents (Khanna and Porter, 2001). Consi- Collins, 1973), however, showed that all motoneu-stent with this view, high blood flow may not be a rons and all EOM fiber types participate in all eyegeneral feature of EOMs in all species, but rather movement classes. These findings supported thevaries between species and is especially high in alternative hypothesis, that the heterogeneity ofthose with greater ocular motility (Wilcox et al., the six EOM fiber types is a consequence of their1981). By contrast, differences between species in recruitment at specific eye positions, therebythe morphology of the orbital MIF appear to be requiring a range of contractile and fatigabilitymore subtle. The most apparent difference between properties.
  • 27. 63Fig. 7. Histological profiles of the SIFs (1, 3–5) and MIFs (2, 6) muscle fiber types in the orbital (A–C) and global (D–F) layers of thelateral rectus muscle in the rabbit, cat, and monkey, respectively; the cat retractor bulbi muscle (G); the monkey levator palpebraesuperioris muscle (H); and the proximal portion within 1 mm of the origin of the monkey lateral rectus muscle (I). Phase contrast lightphotomicrographs of semithin (1 mm) sections indicate differences in mitochondrial content of different muscle fiber types. Variationsin the extent of the capillary vascular network that surrounds the muscle fibers also are apparent. Scale: A–I, 25 mm. Skeletal muscles are organized into motor units range of available motor unit sizes; if the average— defined as a single motoneuron plus the muscle motor unit is large, force can be increased or de-fibers that it innervates. Motor unit size is the creased only in large increments, and the oppositenumber of muscle fibers that are innervated by an for small motor units. The small motor unit sizeaverage motoneuron. The ability of a skeletal mus- seen in EOM (ten muscle fibers per motoneuron) iscle to increment force then is dependent upon the consistent with the precise incrementation of force
  • 28. 64that is required in fixation and eye movements to able to discern the functional role(s) served by theprevent double vision (diplopia). The globe repre- two MIF populations in EOM. A recent study hassents a small, fixed and typically unchanging load shown that motoneurons that innervate EOMfor the EOMs, although disease, trauma, or surgical MIFs are small and spatially segregated from SIFintervention can alter resistance. motoneurons in the oculomotor, trochlear, and Isometric twitch contractions occur about twice abducens nuclei (Buttner-Ennever et al., 2001) ¨as fast in EOM versus limb muscle, yet the rela- (cf. Chapter 4). Such differential localization oftionship between speed of sarcomere shortening motoneuron pools not only suggests that MIFsand relative load is about the same for these two may receive premotor signals that are differentmuscle groups (Close and Luff, 1974). To obtain from those of SIF motoneurons, but that it may bethis result, the relationship between shortening possible to separately analyze their afferent inputsspeed and the duration of myofilament activity and physiologic output.must not be the same for twitch fibers in EOM and Under isometric conditions, whole EOMs havelimb muscle. Elegant studies by Goldberg and col- very short contraction and half-relaxation timesleagues have further compared and contrasted compared with other fast muscles. EOM appears toEOM unit types to the better-studied spinal cord be at least as fast as extensor digitorum longusunits, noting the presence of slow, fatigable and (EDL). This finding is surprising since the EDL isnon-twitch types not found at the level of the homogeneously fast, while EOM contains anspinal cord (Meredith and Goldberg, 1986; Nelson admixture of fiber types. Forces during maximalet al., 1986; Shall and Goldberg, 1992; Shall et al., tetanic contractions of EOM are, however, just1995, 1996, 2003; Goldberg and Shall, 1997; fractions of those of limb muscles, even when nor-Goldberg et al., 1997). These studies, however, have malized to myofiber cross-sectional area (Close andnot yet identified motor unit types corresponding to Luff, 1974; Luff, 1981; Frueh et al., 1994). Whileall six EOM fiber types, perhaps reflecting subtle the passive mechanical load for EOM is small, theydifferences in fatigability among the three global must work against co-activated antagonist musclesSIFs. Goldberg also reported that several of the during eye movements. Twitches are unusuallytenets of spinal motor units might not apply to shallow and the twitch-to-tetanus ratio is lowerextraocular units, including different criteria for than in most muscles. These EOM properties mayfatigue, the possibility of individual motor units reflect a combination of factors: (a) faster thancontaining more than one muscle fiber type, and normal calcium transients during contraction, ac-the lack of linear force summation during motor complished by abundant sarcoplasmic reticulumunit recruitment. Finally, the complexity of oculo- (Asmussen and Gaunitz, 1981; Briggs et al., 1988;motor motor units may even include differences in Spencer and Porter, 1988), but novel adaptations incontractile properties of different rectus muscles calcium reuptake mechanisms (Jacoby and Ko,(Meredith and Goldberg, 1986). 1993; Kjellgren et al., 2003a), (b) displacement of Most recordings of oculomotor motoneuron contractile filaments by other intra- and extracel-activity in alert animal models indicate a stereo- lular structures, (c) the presence of less-readily ex-typic, pulse-step activity. By contrast, electromyo- citable non-twitch fibers, and (d) differences ingraphic recordings of orbital and global layers contractile kinetics, a possibility for those fibersduring strabismus surgery show pulse-step activity with EOM-specific myosin (Shrager et al., 2000).only in the global layer (the orbital layer exhibits Any view of the overall functional organizationonly step changes in activity) (Collins, 1971). of EOM is further complicated by findings of myo-While step changes in innervation level may well myous junctions, fiber branching, and failure ofbe appropriate for the orbital layer in control of many fibers to extend the full muscle length (Hines,pulley position, the discrepancy between moto- 1931; Teravainen, 1969; Floyd, 1970; Harker, 1972;neuron discharge and muscle activity patterns is as Mayr et al., 1975; McLoon et al., 1999; Shall et al.,yet unresolved. By contrast, correlated motoneu- 2003). Such myofiber heterogeneity complicatesron and muscle physiological studies might now be interpretation of a range of data from myosin
  • 29. 65heavy chain immunocytochemisty to muscle con- Gene expression profiling studies have furthertractile studies. Non-linearities in muscle architec- characterized EOM as fundamentally distinctture are thought to be responsible for the observed from other skeletal muscle (Porter et al., 2001a;non-linearlity in motor unit force addition (see Cheng and Porter, 2002; Fischer et al., 2002;above and Miller et al., 2002; Shall et al., 2003). Khanna et al., 2003a), extending the definition ofThese data suggest that, in spite of extensive his- the EOM allotype. Figure 8 depicts expressiontologic analyses, further study of EOM cytoarchi- differences between the EOM, masticatory, andtecture is essential to the construction of an hindlimb muscle allotypes. Taken together, theintegrated model of muscle function. genes differentially expressed in comparisons of An operational model for EOM fiber type EOM with masticatory and hindlimb musclesrecruitment has the orbital SIF and global red reflect key aspects of muscle biology, includingSIF types become active within the off-direction of transcriptional regulation, sarcomeric organiza-the muscle plane of action, with progressive re- tion, excitation–contraction coupling, intermedi-cruitment of the global intermediate and then glo- ary metabolism, and immune response (see fullbal white SIFs as excursions progress into muscle dataset under NCBI GEO accession number 1062on-direction (Robinson, 1978). This model ac- and Porter et al., 2001a). Among these data, wecounts for the presumed fatigue resistance of the identified a lack of dependence upon glycogen asvarious SIF types. The two MIF types represent an energy source, consistent with histochemicalmore of a functional enigma, but are presumed to findings, and the utilization of atypical (non-skel-become active around the primary position, with etal muscle) glycolytic enzyme isoforms in EOM.their unparalleled ability to smoothly increment EOM likely has such high glucose demands that itmuscle force contributing to very small, but critical, does not invest energy in storage as glycogen; theadjustments of eye position. The active pulley hy- use of non-muscle enzyme isoforms for glycolysispothesis (Demer et al., 2000) requires reinterpreta- likely confers an energetic advantage for EOMtion of the Robinson model for EOM recruitment. that is not yet understood. These data stronglyWhile the position-dependent recruitment order suggest that EOM is energetically very differentproposed by Robinson may still be correct, orbital from other skeletal muscles, but do not yet relateand global layer fibers are now linked to pulley findings to the muscle fiber type organization.and globe movement, respectively. Expression profiling data provide a broad over- For the future, it is vital to understand both in- view of the unique properties of specific tissues anddividual and composite oculomotor motor unit func- thus can set the agenda for further studies of EOMtion in the context of eye movement types, orbital biology. Although EOM is fundamentally differentanatomy, and the six distinctive EOM fiber types. from other skeletal muscles, expression profiling rejected the notion that EOM may be a distinctInsights from EOM molecular biology histologic muscle tissue type (i.e., EOM properties do not put it on the same level as the divergentThere has been a recent focus upon defining the smooth, cardiac, and skeletal muscle types)molecular biological properties of the EOMs. (Khanna et al., 2003a). Differences between EOMBecause of the nature of the techniques, linking and other skeletal muscles are nonetheless broadmolecular traits to specific EOM fiber types often is and require follow-up using a variety of approaches.not accomplished until protein or mRNA locali- Since our DNA microarray data suggested thatzation is completed. Individual transcript and pro- typical M-line proteins might be absent from EOM,tein localization studies cannot proceed at the same we used a multidisciplinary approach to evaluate thepace as gene expression profiling of entire EOMs or M-line in rodent EOM (Andrade et al., 2003; PorterEOM layers. However, these new molecular data et al., 2003a). The M-line and its associated creatineare nonetheless of considerable value in under- kinase (CK-M) are ubiquitous features of skeletalstanding EOM adaptations to its novel functional and cardiac muscle, maintaining myosin myofila-role and providing a basis for further studies. ments in register, linking the contractile apparatus
  • 30. 66Fig. 8. Expression profiling of EOM versus jaw and hindlimb muscles in mouse. Myofiber schematic showing number of transcripts by gene class that were differentiallyregulated in EOM (A). In all, 287 genes exhibited EOM-specific expression patterns; these are distributed across major function categories important to muscle biology(number of genes per category is shown parenthetically). EST denotes expressed sequence tags or putative genes. Hierarchical cluster of the 287 genes that are differentiallyregulated in EOM (n ¼ 4–5 replicates per muscle) (B). High expression levels are indicated in red, low levels in blue. This shows that there are few genes that are expressedonly in EOM, but that expression of many genes differs in level across the three muscle groups. Dendogram (C) showing distribution of skeletal muscle samples whencompared across all differentially regulated genes shown in B. EOM (E) replicates cluster together and separate from jaw (J) and leg (L) replicates, while jaw and legintermix. The full list of differentially regulated genes is available at:
  • 31. 67to the cytoskeleton for external force transfer, and ontogeny, EOM is distinct from other muscle aslocalizing CK-based energy storage and transfer to early as its embryonic origin. In contrast to thethe site of highest ATP demand. Thus, M-lines are somitic/lateral plate mesodermal origin of mostviewed as essential for fast-twitch muscle fibers. By muscles, the muscle precursor cells or myoblastscontrast, EOM is divergent in lacking both an that form EOM are derived from two pre-oticM-line and associated CK-M. Although an M-line mesodermal pools, the prechordal plate and cra-forms in EOM during myogenesis, it is actively nial paraxial mesoderm (Wachtler et al., 1984;repressed after birth. Transcripts of the major Noden, 1986; Wahl et al., 1994; Noden et al.,M-line structural proteins, myomesin 1 and my- 1999). Individual muscle primordia develop fromomesin 2, follow the same pattern of postnatal several foci in the paraxial mesoderm adjacent todown-regulation. By contrast, an embryonic heart- the midbrain and metencephalon, in a rostrocau-specific EH-myomesin 1 transcript is retained in dal progression. During development of the eye,adult eye muscle; an alternatively spliced exon in the prechordal plate mesoderm is pushed caudalthis transcript likely confers a higher degree of flex- and lateral, where it intermixes with paraxial mes-ibility to the molecule, potentially allowing less rigid oderm and together they form EOM precursors.connections between adjacent myosin filaments. The orbital connective tissues also have a uniqueEOM is also low in CK-M transcripts and total origin, from the neural crest (Johnston et al., 1979;CK enzyme activity. Since EOM exhibits isoform Noden, 1983; Couly et al., 1992).diversity for other sarcomeric proteins, the M-line/ EOM follows the same morphologic staging seenCK-M divergence likely represents a key physiolog- in the development of the more traditional skeletalical adaptation for the unique energetics and func- muscles, myoblasts fusing to form myotubes whichtional demands placed on this muscle group in mature into myofibers (Porter and Baker, 1992;voluntary and reflexive eye movements. Brueckner et al., 1996). Morphologic features of the A variety of other cell and molecular differences distinctive EOM fiber types then appear in the peri-have been ascribed to EOM by expression profiling natal to postnatal period. Fig. 9 summarizes rela-or other specific gene/protein expression analyses. tionships between EOM morphogenesis and keyBut, many of these either have not been localized to landmarks in visual, vestibular, and oculomotorspecific muscle layers or fiber types or have not yet system development. We recently published an in-been pursued further for their significance in EOM tegrated view of postnatal EOM development in rat,function. These include expression of novel patterns relating fine structural development of EOM fiberof tri-iodothyronine (T3) receptor protein distribu- types to global temporal patterns in gene expressiontion (Schmidt et al., 1992) and atypical combina- from DNA microarray (Cheng et al., 2004). Subse-tions of troponin T isoforms (Briggs et al., 1988). quent dissection of these data will help determine theFinally, there is evidence that EOM may undergo mechanisms that are responsible for the divergencelow-level remodeling (McLoon and Wirtschafter, of EOM and traditional skeletal muscle phenotypes.2003; McLoon et al., 2004); this finding may reflect From a mechanistic viewpoint, EOM and otherthe high workload demands of ocular motility, skeletal muscles may diverge because they: (a) ariseleading to constitutive myofiber repair or turnover from fundamentally different muscle precursor cells,that is more accentuated than in other muscles. (b) have identical precursor cells that mature under the influence of different extrinsic signals, or (c) are influenced by a combination of the two mechanisms.Extraocular muscle developmentHead and trunk muscles exhibit considerable dif- EOM exhibits distinct myoblast typesferences in the regulation of muscle developmentor myogenesis. During evolution, craniofacial For traditional skeletal muscles, the distinctivemuscles experienced tremendous specialization to properties of various muscle groups and fiber typesadapt to their highly specific functions. During appear to be specified very early in development.
  • 32. 68Fig. 9. Compilation of morphophysiologic data for EOM development of the rat. Schematic relates morphogenesis of EOM to keyevents in visual, vestibular, and oculomotor system development. Myogenic events are indicated in black; neurogenic and behavioralevents in gray. Prenatal (E) and postnatal (P) ages are indicated on the timescale.Myoblasts from spatially different locations, and Myf5, is regulated by separate promoter elementsthose destined to form different muscle fiber types, in cranial versus somatic muscles (Hadchouel et al.,activate distinctive sets of control genes in develop- 2000; Summerbell et al., 2000), lending support toment (Dietrich et al., 1998; Dietrich, 1999; Calvo the notion of distinct developmental regulatoryet al., 2001; Mitchell and Pavlath, 2002; Schiaffino programs for EOM. Moreover, while MyoD acti-and Serrano, 2002). Moreover, craniofacial muscles vation is delayed in trunk muscles of Myf5–/–appear to exhibit very different myogenic regulatory deficient mice, it is not altered in head muscles ofprograms (e.g., the transcription factors En2 and the same mice (Tajbakhsh et al., 1998). NodenMyoR/Tcf21 specify masticatory muscle; see et al. (1999) documented the initial expression ofDegenhardt and Sassoon, 2001; Lu et al., 2002). Myf5 in EOM myoblasts, rapidly followed byPaired-like homeodomain transcription factor 2 MyoD. However, myosin heavy chain expression(Pitx2) may be an essential regulator of EOM then lagged the onset of MRF expression bymyogenesis. Pitx2 has been detected in EOM as a longer period than in traditional skeletal muscles,early as embryonic day 13.5 (Hjalt et al., 2000) and leading to the suggestion that interactions amongits expression is essential for EOM development EOM myoblasts and surrounding tissues, most(Piedra et al., 1998; Gage et al., 1999; Kitamura likely neural crest-derived cells, act to delay myoblastet al., 1999; Lu et al., 1999; Mootoosamy and withdrawal from mitosis and commitment to fusionDietrich, 2002). into myotubes. In EOM development, Pitx2 may be upstream of Considerable progress in skeletal muscle myogen-the helix-loop-helix myogenic regulatory factors esis has been achieved through the use of myoblast(MRFs). MRFs are essential in muscle develop- cell lines. Cell lines can be induced to form myofibersment, as they coordinate the expression of muscle- in vitro, thereby facilitating study of myogenic reg-specific genes. The first MRF expressed in EOM, ulatory mechanisms. We recently developed a
  • 33. 69myoblast cell line from neonatal EOM (Porter et al., in extrinsic sensory-motor signals having profound2005). Initial genome-wide expression analysis using consequences for EOM development.this cell line strongly suggests that EOM myoblasts We also have shown that specific signaling ofare fundamentally different from those of hindlimb motoneuron to muscle primordia is required formuscles and EOM has mechanistic differences in normal EOM differentiation (Porter and Hauser,regulation of myogenesis. This experimental ap- 1993b). In organotypic nerve–muscle co-cultures,proach is an efficient means of rapidly generating a either oculomotor or spinal motoneurons supportbroad perspective on the developmental regulation EOM development for a 2–3-week period. But,of the distinct EOM tissue type. muscle explants innervated by the correct oculo- motor motoneurons survive indefinitely, while incorrect spinal motoneurons do not supportEpigenetic factors and EOM development long-term survival. These data suggest that oculo- motor motoneurons are essential in directingRodent EOMs are very immature at birth, perhaps critical phases of EOM maturation beyond a rel-because of the imposed delay in eyelid opening, and atively immature myotube stage. The co-cultureseveral EOM traits emerge in parallel with visual model also shows (a) oculomotor motoneuron-spe-and motor system maturation (Porter and Baker, cific activity patterns and/or trophic factors may be1992; Brueckner et al., 1996; Easter and Nicola, critical determinants of the EOM phenotype and1997; Porter and Karathanasis, 1999; Porter et al., (b) it is unlikely that EOM defaults to an ‘‘ordi-2003a) (Fig. 9). We have suggested that the defin- nary’’ skeletal muscle phenotype, since explantsitive EOM properties are shaped by the activation die under the wrong neural influence.patterns experienced in the postnatal period. Taken together, it is likely that the novel EOM Experimental manipulations of visuomotor deve- phenotype is a consequence of the interaction oflopment produce severe deficiencies in visuomotor myoblasts derived from a novel lineage withcoordination (Rothblat et al., 1978; Sparks et al., extrinsic influences (motoneuron activity, diffusi-1986), EOM motor units (Lennerstrand and ble factors, and circulating hormones) that collec-Hanson, 1979), and alter the molecular and con- tively shape the six unique myofiber types presenttractile properties of the EOMs (Lennerstrand, in this muscle group.1979, 1980; Lennerstrand and Hanson, 1979; Kernsand Rothblat, 1981; Brueckner and Porter, 1998). Extraocular muscle and diseaseIn rats, Myh13, the EOM-specific myosin isoform,is modulated by developing visual and vestibular EOM exhibits novel responses to a wide range ofsystems in a critical period fashion (Brueckner and diseases (for reviews, see Porter and Baker, 1996;Porter, 1998; Brueckner et al., 1999). Most recently, Kaminski et al., 2002, 2003). We suggest that thewe have used genome-wide profiling to extend the baseline properties of a skeletal muscle group pre-EOM critical period concept to include a broad condition its disease responsiveness; thus, there is arange of transcripts that respond to dark rearing in direct relationship between the unique EOM phe-rat or to monocular eyelid suture in monkey notype and its unusual responses to metabolic and(Cheng et al., 2003). A subsequent study estab- neuromuscular disease. Here, we briefly reviewlished that the EOM changes associated with dark only some of the diseases where the EOM isrearing are accompanied by physiological changes divergent from most other skeletal muscle contractile properties and delays inoculomotor motoneuron gene expression patterns(McMullen et al., 2004). Finally, a strain of mon- Muscular dystrophykeys that is prone to congenital esotropia exhibitsmaldevelopment of the EOMs (Porter and Baker, EOM is completely spared in Duchenne (Karpati1993). Together, these findings strongly support the and Carpenter, 1986; Kaminski et al., 1992;notion of an EOM critical period, with alterations Khurana et al., 1995; Ragusa et al., 1996, 1997;
  • 34. 70Porter, 1998), limb girdle (Porter et al., 2001b), reports that the fetal AChR subunit may beand congenital (Porter and Karathanasis, 1998) expressed in other adult skeletal muscles. Recentmuscular dystrophy. By contrast, EOM is pref- DNA microarray studies suggest an alternativeerentially affected in oculopharyngeal muscular hypothesis, that EOM may be targeted in comple-dystrophy, which exhibits a different pathogenic ment-mediated disorders because of its lowmechanism from the other muscular dystrophies expression of a negative regulator of the comple-(Brais et al., 1998). Sparing of EOM in the mus- ment response, decay activating factor 2 (Portercular dystrophies is mechanistically interesting, et al., 2001a; Kaminski et al., 2002). EOM thenas knowledge of muscle protective strategies may may have reduced capacity to control any signif-not only advance our understanding of the basic icant complement reaction, resulting in the pro-biology of these muscles but may yield new pensity toward ocular myasthenia. This trait maypatient treatment options. We have systematical- make EOM sensitive to other autoimmune disor-ly tested putative muscle protective mechanisms ders, such as Graves an animal model of Duchenne muscular dys-trophy and showed that EOM does not adapt tothe disease, but instead is spared as a conse- Mitochondrial myopathiesquence of its baseline or constitutive differencesfrom other skeletal muscles (Porter et al., 1998, Ocular signs are the most characteristic clinical2003b, c). The precise EOM traits that confer this feature in mitochondrial myopathies suchprotection are as yet unclear. Important clues as chronic progressive external ophthalmopathy,include the sparing of half of the EOM fiber types Kearns–Sayre syndrome, and a variety of mito-in mice deficient in both dystrophin and utrophin chondrial encephalomyopathies. Analyses of(Porter et al., 1998) and the finding that the re- EOM histopathology in the mitochondrialctus and EOMs are always spared and the levator myopathies, however, are relatively few, oftenpalpebrae superioris and retractor bulbi muscles reporting non-specific alterations, and are difficultare always involved in all mouse models of mus- to interpret because of past failures to understandcular dystrophy. how normal EOM differs from skeletal muscle (Suomalainen et al., 1997). EOM’s dependence upon oxidative energy metabolism may be respon-Myasthenia gravis sible for its targeting in the mitochondrial diseases. During normal mitochondrial respiration, a smallThe EOMs are the earliest affected and often the percentage of the oxygen used is incompletely re-sole target in some patients with myasthenia gra- duced. The resulting reactive oxygen species arevis, an autoimmune disorder of the neuromuscular thought to act locally in mitochondria to alterjunction. In the pathogenesis of myasthenia gravis, membrane properties, disrupt protein functions,a complement-mediated response lyses the postsy- and mutate mitochondrial DNA (mtDNA). Overnaptic membrane, thereby compromising neuro- the course of a lifetime, the functionally compro-muscular transmission. Based upon the hypothesis mised mitochondria accumulate within cells and,that EOM exhibits a reduced safety factor for in theory, are ultimately responsible for the ‘‘rag-synaptic transmission, studies focused upon the ged red’’ muscle fibers that characterize the mito-potential role of a novel pattern of acetylcholine chondrial myopathies. Although EOM has highreceptor (AChR) isoform expression (Kaminski antioxidant capacity (Ragusa et al., 1996, 1997),et al., 1996; Missias et al., 1996; Kaminski and this may not suffice throughout life. Evidence inRuff, 1997; MacLennan et al., 1997) in the etiology support of this view includes: (a) the finding thatof ocular myasthenia gravis. This hypothesis does, the identical mtDNA base substitutions that char-however, have two caveats: (a) although ptosis is a acterize the acquired mitochondrial myopat-frequent symptom, the fetal AChR is not found in hies are observed in all EOMs of elderly controlthe levator palpebrae superioris and (b) there are human subjects (Muller-Hocker et al., 1993) and ¨
  • 35. 71(b) mitochondrial cytochrome c oxidase exhibits manner in which sarcomere length and number isan aging-dependent defect density five to six times regulated in EOM might prove of significant valuegreater in EOM than in limb muscle, diaphragm, for improvements in treatment of strabismus.or even heart (Muller-Hocker et al., 1996). Taken ¨ Aberrant localization of EOM pulleys has beentogether, there is a compelling argument that linked to strabismus. Specifically, vertical disloca-EOM targeting in mitochondrial myopathy directly tion of medial or lateral rectus pulleys can producerelates to the high degree of oxidative stress in this incomitant strabismus (Oh et al., 2002). Similarly,unique muscle group. the predisposition toward deficits in eye elevation with age may be a consequence of progressive in-Strabismus ferior displacement of the horizontal rectus muscle pulleys, rather than any deterioration of EOMThe extent to which alterations in EOM are a function proper (Clark and Demer, 2002).cause or a consequence of strabismus is unknown. Botulinum toxin type A has come into use for aA major difficulty in assessing muscle pathology wide variety of movement disorders, includingassociated with strabismus has been an inability to strabismus. The primary action of botulinum toxinobtain representative samples from routine stra- is transient denervation, via blockade of thebismus surgery. Since the orbital layer ends prior calcium-dependent release of acetylcholine at theto the muscle insertion, surgical resections nor- neuromuscular junction. Despite its transient ef-mally do not yield an adequate sample for patho- fect in many movement disorders (e.g., eyelidlogic analysis. EOM alterations in strabismus do spasm or blepharospasm), single injections ofnot show a consistent pattern in muscle pathology botulinum toxin can be highly effective in perma-(Berard-Badier et al., 1978; Martinez et al., 1980). nent correction of strabismus (Scott, 1980; SpencerAn exception is the overacting muscles seen in et al., 1997; McNeer et al., 1997, 1998, 2000). Thisoveracting inferior oblique and congenital fibrosis result likely is due to observations that botulinumof EOM, in which global intermediate SIFs exhibit toxin produces specific, long-term changes inprominent central mitochondrial aggregates EOM orbital layer SIFs (Spencer and McNeer,(Spencer and McNeer, 1980; Engle et al., 1997). 1987; Stahl et al., 1998; Kranjc et al., 2001). Pre-Structural alterations also have been seen in the cisely how the long-term alteration of a muscleEOM sensory receptors in strabismus (Corsi et al., fiber type that is a prime mover of the muscle pul-1990; Domenici-Lombardo et al., 1992). ley, and not the globe, is effective in treatment of There are reports of various structural and func- eye misalignment represents a key unansweredtional alterations of EOM as a consequence of question. An alternative strategy of strengtheningmuscle resection/recession (Kushner and Vrabec, EOMs using myotrophic growth factors for cor-1987; Christiansen et al., 1988; Rosenbaum et al., rection of ocular misalignment is currently being1994; Scott, 1994). Adaptive changes at the level of explored (McLoon and Christiansen, 2003).the sarcomere would be anticipated both in strabis- Finally, a relatively rare congenital, nonprogres-mus and following surgical correction of strabismus, sive, ocular motility disorder, congenital fibrosis ofbut have been difficult to address and represent an the EOMs (CFEOM) was once thought to be aimportant void in the current literature. The hypo- primarily fibrotic disorder. However, genetic andthetical basis for adjustment of sarcomere number is morphopathologic studies have recently shown thatvalid — chronic changes in the length of a muscle the CFEOMs are of primarily neurogenic originalter the degree of overlap of actin and myosin (Engle et al., 1997; Nakano et al., 2001; Engle, 2002;filaments. If there is too much or too little overlap, Yamada et al., 2003). These findings mechanisticallycontraction is, at best, highly inefficient, or, at link the CFEOMs to congenital Duane syndrome,worst, severely restricted. One report suggests that collectively as congenital cranial dysinnervationEOM actually gains or loses sarcomeres in order to disorders (CCDDs). In each CCDD, a primarilymaintain optimal length of the remaining sarco- motoneuron/axonal defect leads to maldevelopmentmeres (Scott, 1994). A better understanding of the of EOMs, including aberrant innervation of EOMs.
  • 36. 72A side issue potentially relevant to pathogenesis of exceptional disease sensitivity will not only advancethe CCDDs is that the underlying mechanisms of basic knowledge of EOM structure and function,aberrant innervation of EOM may be more complex but can lead to new insights into the pathogenesis ofthan is currently appreciated (Porter and Baker, and treatment for systemic neuromuscular diseases.1997; Chilton and Guthrie, 2004). Moreover, theprecise targeting of the CCDDs to specific oculo- Abbreviationsmotor motoneuron populations suggests that themotoneurons, like EOM, may not be homogeneous, a axonbut rather may exhibit significant cellular/molecular A A-bandheterogeneity (Eberhorn et al., 2003) and may have ALR accessory lateral rectusimportant differences from their counterparts at c capillaryspinal cord level. CCDD congenital cranial dysinnervation disorder CFEOM congenital fibrosis of extraocularCommentary muscle CK creatine kinaseThe EOMs are highly adapted to their role in EOM extraocular musclereflexive and voluntary eye movements. In fulfill- EST expressed sequence tag (putativeing this role, they have evolved to be very different gene)from other skeletal muscles, exploiting more than GEO Gene Expression Ontologythe full range of options that are available to stri- I I-bandated muscle to achieve a demanding set of func- IO inferior obliquetions. Unlike most skeletal muscles, the EOMs IR inferior rectusgenerally are not subject to the adaptive require- LPS levator palpebrae superiorisments of changing load and exercise. Instead, the LR lateral rectusEOM phenotype is, in part, a consequence of the nmj neuromuscular junctiondiversity of oculomotor control systems. To date, m mitochondriacomprehensive morphologic, biochemical, and mn myonucleusmolecular biology profiles are beginning to emerge MIF multiply innervated fiberfor the distinctive EOM layers and myofiber types. MR medial rectusA large part of our current understanding of EOM MRF myogenic regulatory factorfiber types is conditioned by the discovery of the MtDNA mitochondrial DNAmuscle pulleys and interpretation of muscle layer NCBI National Center forand fiber type properties in this functional context. Biotechnology Information An important goal for future studies is to com- RB retractor bulbiplete the biologic profiles of each of the EOM fiber s synaptic terminaltypes and to understand how they function indi- sr sarcoplasmic reticulumvidually and collectively in fixation and eye move- Sch Schwann cellment control. Two connotations of the unique SIF singly innervated fiberEOM phenotype that require further attention are: SO superior oblique(a) the developmental mechanisms responsible for SR superior rectusthe divergence of EOM from ‘‘traditional’’ skeletal t t-tubulemuscles and (b) the EOM properties that precon-dition its response to disease such that this musclegroup can be preferentially spared or targeted in Acknowledgmentsmany diseases (Porter and Baker, 1996; Kaminskiet al., 2003). In particular, the determination of The preparation of this review and the originalmechanistic links between EOM traits and its material presented in it was supported by U.S.
  • 37. 73Public Health Service Research grants R01/R37 Bennett, M.V. and Pappas, G.D. (1983) The electromotorEY02191 (RFS), R01 EY09834 (JDP), R01 system of the stargazer: a model of integrative actions atEY12779 (JDP), and R01 EY015306 (JDP). We synapses. J. Neurosci., 3: 748–761. Berard-Badier, M., Pellissier, J.F., Toga, M., Mouillac, N. andparticularly thank the National Eye Institute for Berard, P.V. (1978) Ultrastructural studies of extraocularits commitment to understanding the biology of muscles in ocular motility disorders. II. Morphologicalthis novel muscle group. Additional support for analysis of 38 biopsies. Albrecht Von Graefes Arch. Klin.this work was provided by grants from the Mus- Exp. Ophthalmol., 208: 193–205.cular Dystrophy Association and a Walt and Lilly Bicer, S. and Reiser, P.J. (2004) Myosin light chain 1 isoforms in slow fibers from global and orbital layers of canine rectusDisney Award for Amblyopia Research, Senior Sci- muscles. Invest. Ophthalmol. Vis. 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  • 45. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 3 Sensory control of extraocular muscles J.A. Buttner-Ennever1,Ã, K.Z. Konakci2 and R. Blumer2 ¨ 1 Institute of Anatomy, Ludwig-Maximilian University of Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany 2 Center of Anatomy and Cell Biology, Medical University of Vienna, Waehringerstrasse 13, A-1090 Vienna, AustriaAbstract: The role of sensory receptors in eye muscles is not well understood, but there is physiological andclinical evidence for the presence of proprioceptive signals in many areas of the central nervous system. It isunclear which structures generate these sensory signals, and which central neural pathways are involved.Three different types of receptors are associated with eye muscles: (1) muscle spindles, (2) palisade endings,and (3) Golgi tendon organs, but their occurrence varies wildly between species. A review of their or-ganization shows that each receptor is mainly confined to a morphologically separate layer of the eyemuscle. The palisade endings — which are unique to eye muscles, are associated with the global layer; andthey have been found in all mammals studied so far. Their function is unknown. The muscle spindles, ifthey are present in a species, lie in the orbital layer, or at its junction to the global layer. Golgi tendonorgans appear to be unique to artiodactyls (i.e., sheep and goats, etc.); they lie in an outer distal marginallayer of the eye muscle, called the ‘‘peripheral patch layer’’ in sheep. The specific association betweenpalisade endings and the multiply innervated type of muscle fibers of the global layer has led to thehypothesis that together they may act as a sensory receptor, and provide a source of central proprioceptivesignals. But other interpretations of the morphological evidence do not support this role.Introduction tension during converged gaze (Miller, 2003), could be explained on the basis of the control ofThe sensory control of eye muscles has been stead- tension in extraocular muscles by proprioceptorsfastly ignored in terms of modeling or integration (Miller, 2003). Stretching the eye muscles, or elec-into the understanding of eye movements, in spite trically stimulating them in animals evokesof the fact that there is a large weight of information responses in areas such as the mesencephalic trige-showing that eye muscle possess a proprioceptive minal nucleus (Alvarado-Mallart et al., 1975),system (reviews: Steinbach, 1987; Ruskell, 1999; superior colliculus (Abrahams, 1979; DonaldsonDonaldson, 2000; Weir et al., 2000; Buttner-Ennever ¨ and Long, 1980), visual cortex (Fiorentini andet al., 2003). For example, spatial localization Maffei, 1977), the cerebellum and nucleus prep-in humans can be altered by either pulling eye ositus (Ashton et al., 1988). Anatomical tracingmuscles (Lewis and Zee, 1993), by strabismus studies have demonstrated projections from thesurgery (Steinbach and Smith, 1981; Dengis et al., eye muscle through the trigeminal ganglion into1998), or section of the trigeminal nerve in the the spinal trigeminal nucleus (Batini et al., 1975;treatment of trigeminal neuralgia (Ventre-Dominey Porter, 1986; Ogasawara et al., 1987; Buisseret-et al., 1996). Anomalous values in eye muscle Delmas and Buisseret, 1990; Buisseret, 1995), in ungulates in the mesencephalic trigeminal nucleusÃCorresponding author. Tel.: +49 89 5160 4851; (Bortolami et al., 1987), in the superior colliculusFax: +49 89 5160 4857; (Ndiaye et al., 2000), the vestibular nuclei (BuisseretE-mail: -Delmas and Buisseret, 1990), prepositus hypoglossiDOI: 10.1016/S0079-6123(05)51003-3 81
  • 46. 82nucleus and the cerebellum (Batini et al., 1974; layer, and he called it the ‘‘peripheral patch layer.’’Kimura et al., 1991). Cutting the ophthalmic nerve A similar layer was described in humans by Wasicky(deafferentation) causes fixation instability (Fiorentini et al. (2000), and called the marginal layer. Its pres-and Maffei, 1977) and reduction in stereoacuity in ence in other species is unclear. The two main eyecat (Maffei and Fiorentini, 1976), and deviation of muscle layers found in all mammals have severaleye position in lambs (Pettorossi et al., 1995). important differences: the global layer insertsLastly, and of most significance, is that eye through the tendon on the sclera of the globe:muscles contain proprioceptive end-organs — whereas the orbital layer inserts onto Tenon’smuscle spindles and Golgi tendon organs. They capsule, which is a ring of fibroelastic connectivealso have palisade endings, but their function is tissue that lies around the equator of the eyeballstill controversial (Ruskell, 1999, Konakci et al., and forms sleeves around the individual eye2005). There are several excellent reviews on this muscles. Recently the role of Tenon’s capsule intopic (Ruskell, 1999; Donaldson, 2000; Weir et al., directing the pulling direction of the eye muscles2000; Lewis et al., 2001). has been widely discussed, and it has been referred Alongside the evidence for the existence of func- to as ‘‘the pulleys’’ (see Chapters 1 and 2) (Portertional proprioception in eye muscles a large body et al., 1996; Demer et al., 2000).of counter evidence exists. No stretch reflex could The types of muscle fibers in each layer havebe recorded in abducens motor units when the been reviewed in Chapter 2; however, it is impor-ipsi-eye was pulled (Keller and Robinson, 1971). tant to point out that the multiply innervatedCutting the ophthalmic nerves in monkey (assumed muscles fibers (MIFs), or nontwitch muscle fibers,to achieve deafferentation) gave very little effect on occur in all three layers. The MIF fiber typesaccades (Guthrie et al., 1983), smooth pursuit, belongs to a whole spectrum of fibers found in thevestibular responses, conjugacy, adaptation, ocular skeletal muscles of lower vertebrates and birdsalignment etc. (Lewis et al., 2001). Finally, the (Morgan and Proske, 1984). Their action poten-presence of eye muscle proprioceptors varies wildly tials are non-propagated, they have a slow tonicbetween species, and in some cases proprioceptors firing rate, and are highly unfatiguable. In mammals,appear not to be present at all (Ruskell, 1999; MIFs are found almost exclusively in eye muscles,Donaldson, 2000). These features do not correlate and then primarily in the global layer where theywith any known eye movement properties, and it run the whole length of the muscle (Mayr et al.,has proved hard to find a clear concept. In this 1975). The muscle fibers of the orbital layer have areview we will present the current neuroanatomical MIF structure at the poles but it changes along itsand morphological evidence for proprioception in length in the central region to a twitch type, singlyeye muscles, suggest various hyptheses, and show innervated muscle fiber (Pachter, 1984). Thisthat there is room for differences in interpretation distinction has some importance when consider-concerning the basis for eye muscle proprioception, ing the association of sensory structures (palisadeeven between the authors of this chapter. endings) to the global MIFs, see below.Layered structure of eye muscles ProprioceptorsEye muscles have an unusual feature, they have Muscle spindlestwo to three separate morphological subdivisions,which have independent developmental features Muscle spindles in eye muscles(Porter et al., 1995). There is an inner ‘‘global’’ All skeletal muscles possess muscle spindles, so it islayer, an outer ‘‘orbital’’ layer, and in sheep curious that in extraocular muscles some animals(artiodactyls) a distinct third muscle layer, first have them, and others lack them: no muscle spin-described by Harker (1972). It lies mainly distally dles have been found in the eye muscles of sub-in a C-shape around the outside of the orbital mammalian species (Maier et al., 1974). Many
  • 47. 83mammalian species do not have muscle spindles in 1991). Each skeletal spindle receives innervationtheir eye muscles: most monkey species including from a sensory afferent in its equatorial region,Macacca fascicularis, dogs, cats, rats, guinea pigs, and the polar regions of the intrafusal muscle fibersand rabbits do not have muscle spindles; whereas receive gamma-motor (g-) innervation to maintainthey have been found in humans (Cilimbaris, 1910; the sensitivity of the muscle spindle during muscleLukas et al., 1994), and a few in some species of shortening. Both intrafusal and extrafusal musclemonkey such as rhesus (Greene and Jampel, 1966; fibers develop by a similar process in the lateMaier et al., 1974), as well as mice (Mahran and gestational period, whereby myoblasts fuse intoSakla, 1965) and all ungulates (artiodactyls) myotubes, however the intrafusal fibers remain(Cilimbaris, 1910; Blumer et al., 2003). An analysis much shorter and thinner (Kucera et al., 1993).of the literature shows that the density of muscle The occurrence of muscle spindles in skeletal musclesspindles in human eye muscles is extremely high has been recently shown to be a highly dynamicand is comparable to the density of muscle process. For example their incidence is criticallyspindles in hand lumbrical and short neck mus- dependent on the timing of the sensory innervationcles (see Table 1) (Lukas et al., 1994). The of the developing spindles. If the sensory afferentdistal–proximal distribution of spindles in the is cut, then, depending on the developmentalindividual muscles in human is shown in Fig. 1. period, muscle spindles may fail to develop, orHowever, when the organization is analyzed in undergo degeneration and hypertrophy into aterms of muscle layers, it becomes obvious from structure indistinguishable from an extrafusal fibercross sections of the eye muscle that muscle spindles (Kucera et al., 1993). Furthermore, the applicationare associated with the orbital layer, or the of nerve growth factor during the redevelopmenttransition zone of the orbital layer with the global of the cut sensory nerve, leads to the formation oflayer: but they are not associated with the countless supernumery muscle spindles (Sekiyaglobal layer (sheep: Harker, 1972; monkey: Greene et al., 1986). Similar changes in the occurrence ofand Jampel, 1966; human: Cilimbaris, 1910; Ruskell, muscle spindles in skeletal muscles have been1989, 1999; Lukas et al., 1994; Blumer et al., 1999). shown to be dependent not only on neurotrophins,This is shown in Cilimbaris’ original drawing of but also specific genetic transcription factorssheep lateral rectus in Fig. 2. It has long been (Sekiya et al., 1986; Walro and Kucera, 1999;known that MIFs are also closely associated with Fan et al., 2000; Kucera et al., 2002).muscle spindles: branches from extraocular MIFsenter the sheep muscle spindles and build nuclear Comparison of extraocular and skeletal musclebag fibers (Harker, 1972; Baker, 1974; Morgan spindlesand Proske, 1984). It is significant that the muscle The occurrence of muscles spindles in eye muscles,spindles of sheep (artiodactyls) eye muscles are an as explained above, is extremely variable betweenexception in that they are well developed, and species; this is not the case with skeletal muscles. Ahence very similar to those of skeletal muscle second difference is that in general the extraocular(Harker, 1972). muscle spindles appear poorly preserved in com- parison to those in skeletal muscle, even to theMuscle spindles in skeletal muscle point that some authors have raise the question ofIn skeletal muscles it is well established that whether or not they are functional (Ruskell, 1989,sensory information used for motor control is 1999; Blumer et al., 1999; Bruenech and Ruskell,generated by muscle spindles, and Golgi tendon 2000, 2001). A cross section of the human extra-organs. The skeletal muscle spindles contain three ocular muscle spindle is shown in Fig. 3. Mosttypes of intrafusal muscle fiber, termed nuclear muscle spindles lack an expansion of the equato-chain, nuclear bag1, and nuclear bag2 fibers (Walro rial zone. All muscle spindles contain fibers of theand Kucera, 1999). Nuclear bag1 intrafusal fibers nuclear chain type, but no nuclear bag fibers, areof muscle spindles also have the same heavy-chain present. Furthermore, extraocular muscle spindlesmyosin as the MIFs (Pedrosa-Domellof et al., also have many anomalous fibers which pass
  • 48. 84Table 1. Number of muscle spindles in human extraocular muscles (Lukas et al. 1994) Individuals Mean7standard deviationa 1 2 3 72a 83a 67a Female Female Male Right Left Right Left Right LeftMedial rectus 5b 15 19 20 17 23 18.873.0, n ¼ 5Lateral rectus 21 22 18 17 19 19 19.371.9, n ¼ 6Superior rectus 17 16 13 14 20 15 15.872.5, n ¼ 6Inferior rectus 30 36 33 31 42 32 34.074.4, n ¼ 6Superior oblique 24 22 22 21 41 34 27.378.2, n ¼ 6Inferior oblique 3 7 3 6 4 3 4.371.8, n ¼ 6Orbitc 100d 118 108 109 143 126 120.8714.4, n ¼ 5a Mean7standard deviation of counts in 6 (5b) specimens of this muscle. b Incomplete count due to technical reasons in parts of thisspecimen. c Total number of spindles in all extraocular muscles of this orbit. d Incomplete total. Fig. 1. The location of muscle spindles in human extraocular muscles (Lukas et al., 1994).through the muscle spindle capsule without any maturing at different times, and how this is coor-intrafusal modification. An exception to this is dinated with the development of sensory andseen in ungulates where the extraocular spindles motor innervation is completely unknown (Porterhave none of these differences, and they appear et al., 1995; Cheng et al., 2003, 2004). However,very similar to the skeletal spindles (Harker, 1972; one can be certain that it will vary between species.modified from Blumer et al., 2003). In the light of the multiple factors known toaffect the development of muscle spindles in skel- Palisade endingsetal muscles, it is not surprising that there is a widevariation in the presence or absence of muscle If the orbital layer uses muscle spindles to generatespindles found in extraocular muscles. The eye its sensory signals what does the global layer use?muscle has different layers (global and orbital) The global layer possesses an unusual feature
  • 49. 85Fig. 2. Drawings modified from the sketches of Cilimbaris (1910) from lateral rectus of the sheep. Note that muscle spindles (whitecircles with central black dots) lie in, or close to, the orbital layer.Fig. 3. (A) Semithin cross section through a human extraocular muscle spindle. The muscle spindle contains six nuclear chain fibers(NCF) and one anomalous fiber (AF). An associated muscle fiber (ASF) is running between the capsule (C); nerve (N); scale bar, 50 mm(Blumer et al., 1999). (B) Human extraocular muscle spindle. Ultrathin cross section through a nuclear chain fiber with a sensory nerveterminal (ST) containing mitochondria. Basal lamina (BL); scale bar, 1 mm. Inset: line drawing of the region of interest. Nuclear chainfiber (NCF) with a central nucleus (N) (modified from Blumer et al., 1999).unique to eye muscles, it has palisade endings at the Several authors have suggested that palisade end-myotendinous junctions (Dogiel, 1906; Cilimbaris, ings could be the source of sensory afferent signals1910; Ruskell, 1999). Palisade endings have been (Ruskell, 1999; Donaldson, 2000; Weir et al., 2000;found in almost all species that have been inves- Buttner-Ennever et al., 2002); but there still con- ¨tigated, including the rat (Eberhorn et al., 2005). flicting reports on the functional nature of palisade
  • 50. 86endings, whether they are sensory or motor struc- contact with the collagen fibrils, which is analogoustures, or both (Lukas et al., 2000; Konakci et al., to the nerve terminals in Golgi tendon organs2005). (Lukas et al., 2000; Konakci et al., 2005). Such Palisade endings form a cuff of nerve branches nerve terminals are arguably sensory in nature.around the muscle fiber tip, like a palisade fence; Similar results were found in monkey, cat, andbut they contact only one type of muscle fiber, the sheep.MIFs of the global layer (Mayr, 1977; Alvarado- Interestingly, a few palisade terminals madeMallart and Pincon Raymond, 1979; Richmond neuromuscular, as apposed to the more usualet al., 1984; Ruskell, 1999). The term ‘‘innervated neurotendinous, contacts, and at the point ofmyotendinous cylinders’’ is used to describe the contact with the muscle membrane they lacked apalisade endings along with their fibrous capsule. basal lamina; these structures resemble in someThe palisade terminals arise from nerve fibers that ways sensory nerve terminals on intrafusal fibers inenter the tendon from the central nerve entry zone, muscle spindles (Fig. 5A and B) (Kubota, 1988;and then turn back 1801, to contact the tip of the Ruskell, 1989; Blumer et al., 1999, 2003; Konakcimuscle fibers (Fig. 4). Detailed ultrastructural et al., 2005). A few neuromuscular junctions werestudies of palisade endings have been made in also reported by Richmond et al. (1984) in palisademonkey (Ruskell, 1978), cat (Alvarado-Mallart endings of humans.and Pincon Raymond, 1979), sheep (Blumer et al., In palisade endings of humans, Lukas et al.1998), rabbit (Blumer et al., 2001), and human (2000) have found sensory-like neurotendinous(Sodi et al., 1988; Lukas et al., 2000). In the vast contacts and motor neuromuscular contacts: andmajority of cases the palisade terminals, covered the authors daringly propose that palisade endingsby an intact basal membrane, made intimate might combine sensory and motor function. The terminals of rabbit palisade endings were unique, in that they all possessed a basal lamina, they were all neuromuscular and bound a-bungarotoxin, thereby resembling motor terminals (Blumer et al., 2001). Recently, Konakci et al. (2005) have demon- strated in cats that palisade endings are cholinergic structures. Palisade endings are supplied by nerve fibers which stain positively for choline acetyl- transferase and the palisade-ending terminals (neurotendinous and neuromuscular contacts) are choline acetyltransferase immunoreactive too. Only the sparse neuromuscular contacts are positive for a-bungarotoxin as well — a feature of motor terminals. The presence of sparse acetylcholine receptors at the myotendinous region, which bind a-bungarotoxin, has been found on singly and multiply innervated muscle fibers of frog muscle (Miledi et al., 1984). The uncertainty concerning the sensory orFig. 4. Palisade endings in an extraocular rectus muscle of a motor nature of palisade endings is compoundedcat, viewed by a confocal laser scanning microscope. Nerve fi- by the conflicting evidence on the location of theirbres (red) come in from the right pass up to the tendon, then cell somata. If the palisade endings are sensoryturn back to form palisade endings around the muscle fiber tip.Nerve fibers are labeled with antineurofilament, nerve terminals their ganglion cell body should be in the trigeminal(green) with antisynaptophysin. Muscle fibers are stained with ganglion or in the mesencephalic trigeminalphalloidin. Scale bar, 50 mm (Konakci et al., 2005). nucleus; whereas if the endings are of a motor
  • 51. 87Fig. 5. (A) A neurotendinous terminal of a palisade ending in cat extraocular muscle. A nerve terminal (NT) is making contact to thesurrounding collagen fibrils (C). The areas of the nerve terminal contacting the collagen lack a Schwann cell (S) and are indicated witharrowheads. The basal lamina (BL) is indicated by an arrow. The nerve terminal contains mitochondria and many small clear vesicles.Fibrocyte (F). Scale bar, 1 mm. (B) A neuromuscular terminal of a palisade ending in cat extraocular muscle. An ultrathin sectionthrough a nerve terminal (T) establishing contact (arrow) on the muscle fiber (MF). The synaptic cleft is free from a basal lamina (BL).Inset: line drawing of the region of interest. Scale bar, 1 mm (modified from Konakci et al., 2005).origin then they would have cell bodies associated Golgi tendon organswith the oculomotor nuclei. Tozer and Sherrington(1910) as well as Sas and Schab (1952) provided Golgi tendon organs have been reported in theevidence for their location in the oculomotor nerve tendons of extraocular eye muscles of someor nucleus, a result more compatible with either a artiodactyls such as sheep, camel, pig, and calfmotor role for the palisade endings, or perhaps an (Ruskell, 1990, 1999; Blumer et al., 2000), and veryaberrant pathway for the afferent axons (Gentle rarely in monkey (Ruskell, 1979). They exhibitand Ruskell, 1997; Ruskell, 1999). The results of structural features not seen in skeletal Golgiother studies point to the trigeminal ganglion as tendon organs, several different types have beenthe location of palisade ending soma (Billig et al., described and are shown in Fig. 6. More specifically,1997), and imply a sensory function. The function they have an enlarged capsular space and mostof palisade endings is at present not clearly Golgi tendon organs contain up to three muscleunderstood. fibers. Such intracapsular muscle fibers are one
  • 52. 88Fig. 6. Schematic drawings of different types of Golgi tendon organ found in sheep. (A) Type 1: contains exclusively collagen bundles.(B) Type 2: three muscle fibers terminate inside the tendon organ. (C) Type 3: one muscle fiber traverses the tendon organ. (D) Type 4:one muscle fiber terminates inside the tendon organ and another passes through it. C, capsule; N, nerve; COL, collagen; MF, musclefiber (modified from Blumer et al., 2000).Fig. 7. Golgi tendon organ in the eye muscle of a cow. Ultrathin section through a nerve terminal (T) among the collagen bundles. Theterminal is filled with dark mitochondria and some smaller lighter vesicles are visible. Schwann cell (S), basal lamina (arrowhead).Inset: line drawing of the region of interest (modified from Blumer et al., 2003).special type of eye muscle fiber — the MIFs — tendon organs lie in one specific layer of the eyewhich are exclusive to eye muscles, and in this case muscle, called the peripheral patch layer (Blumerserve to adjust the sensitivity of the Golgi tendon et al., 2000). The ultrastructural features of Golgiorgan (Blumer et al., 2000). Of particular interest tendon organs in eye muscles of artiodactyls arein the context of this paper, is that all the Golgi illustrated in Fig. 7.
  • 53. 89 ´Fig. 8. Drawing of the development of skeletal Golgi tendon organs, adapted from Zelena and Soukup (1977). Palisade endingsresemble immature Golgi tendon organs at development stage P3. The origin of palisade endings is unclear, but one determine whether the proprioceptors occur andexciting suggestion comes from the work of Zelena ´ persist in each layer, or not.and Soukup (1977) on the development of Golgitendon organs, and is illustrated in Fig. 8. In theirstudy of Golgi tendon organs in rat skeletal muscle, A possible role for palisade endings and the globalthey found that at the embryological stage E21 a layer MIFsnerve inserts between the aponeurosis and the at-taching muscle fibers. At the postnatal stage P5 the Whether or not all these receptors provide adevelopment of myelin around the nerve by proprioceptive input to the central nervous systemSchwann cells is accompanied by the growth of a is not known. Palisade endings are associated withfibrous capsule, the nerve terminals begin to with- the MIFs of the global layer, which insert via thedraw from the muscle fibers into the tendon, and in tendon onto the eyeball itself: thus the palisadeaddition the immature MIFs become singly inner- endings would be admirably suited to sensing eyevated with a central endplate. The Golgi tendon movements. If this is the case, and they function asorgan is fully developed at the stage of P14. a giant ‘‘inverted muscle spindle’’ to use the wordsHowever, the immature Golgi tendon organ, at of David A. Robinson, the MIF motoneuronsday P3–5, where the nerve is attached to the mul- would be the equivalent of the g-innervation of atiply innervated muscle fibers, is strikingly similar muscle spindle, regulating the baseline the morphology of palisade endings. This led The afferent signal could be used to adjust eye ´Zelena and Soukup (1977) to suggest that palisa- alignment or calibrate space (Lewis et al., 2001;de endings may represent immature Golgi tendon Buttner-Ennever et al., 2003). Ultrastructural ¨organs. studies of the eye muscles of patients with con- In summary, it seems possible that each eye muscle genital strabismus showed that the innervation oflayer has its own individual type of proprioceptors the myotendinous junction was abnormal in these(Fig. 9). If this hypothesis survives more intensive cases, and could conceivably contribute to the eyescrutiny then it will certainly simplify the under- misalignment (Domenici-Lombardo et al., 1992).standing of eye muscle proprioception. And an Given the close association of the global MIFsimportant question to answer now is what factors with the palisade endings, it is of special interest to
  • 54. 90Fig. 9. A schematic drawing of the location of sensory receptors in the extraocular eye showing that different receptors are associatedwith a different muscle layers. The muscle spindles lie in and around the orbital layer, palisade endings in the global layer and Golgitendon organs (only present in artiodactyls) in the peripheral patch layer.Fig. 10. Hypothetical proprioceptive pathways based on known connections: if proprioceptive signals are generated in the palisadeendings on multiply innervated extraocular muscle fibers (MIFs), the information may first relay in the spinal trigeminal nucleus (Sptrig. n). From here axons project to the superior colliculus tier, which is closely interconnected to the central mesencephalic reticularformation (cMRF), and the supraoculomotor area (SOA). The cMRF and SOA are direct premotor structures for the oculomotorneurons of the MIFs.understand if the MIF motoneurons function of the abducens nucleus, described in Chapter 4as g-motoneurons. Recently, experiments were (Buttner-Ennever et al., 2001). The premotor ¨conducted to determine the MIF motoneuron inputs to the global MIF motoneurons werelocation and premotor inputs. The motoneurons investigated with transsynaptic retrograde tracersof the global MIFs lie around the periphery of the that were confined to the distal MIF endplateoculomotor trochlear and abducens nuclei, not region of the muscles, distal to the central motorwithin the individual motoneuron subgroups, but endplate zone, and also distal to the termination ofin slightly separate groups, namely the C-group, the orbital layer (Buttner-Ennever et al., 2002). ¨the S-group, the trochlear cap, and the medial aspect The tracer did not pass back to the classical
  • 55. 91premotor regions for eye movement control (e.g., Referencesparamedian pontine reticular formation (PPRF)or the magnocellular vestibular nuclear neurons), Abrahams, V.C. (1979) Propioceptive influences from eye mus- cle receptors on cells of the superior colliculus. Prog. Brainbut that it was transported from the lateral rectus Res., 50: 325–334.MIF motoneurons retrogradely to vestibular areas Alvarado-Mallart, R.M., Batini, C., Buisseret, C., Gueritaud,possibly associated with gaze-holding, and to J.P. and Horcholle-Bossavit, G. (1975) Mesencephalicthe mesencephalic reticular formation and the projections of the rectus lateralis muscle afferents in thesupraoculomotor area. The latter two regions are cat. Arch. Ital. Biol., 113: 1–20.directly and intimately interconnected to the Alvarado-Mallart, R.M. and Pincon Raymond, M. (1979) The palisade endings of cat extraocular muscles: a light andsuperior colliculus (Chen and May, 2000), a electron microscope study. Tissue Cell, 11: 567– of sensorimotor interaction for eye position Ashton, J.A., Boddy, A., Dean, S.R., Milleret, C. and(Basso et al., 2000). Furthermore, the ascending Donaldson, I.M.L. (1988) Afferent signals from cat extraoc-axons of the spinal trigeminal nucleus (Fig. 10) ular muscles in the medial vestibular nucleus, the nucleusthat could carry putative proprioceptive signals praepositus hypoglossi and adjacent brainstem structures. Neuroscience, 26: 131–145.from the palisade endings, and project to the same Baker, D. (1974) The morphology of muscle receptors. In: Huntcollicular layers that project to mesencephalic C.C. (Ed.), Handbook of Sensory Physiology. Springer-reticular formation and the supraoculomotor Verlag, New York, pp. 1–190.area (Harting and Van Lieshout, 1991; Mize, Basso, M.A., Krauzlis, R.J. and Wurtz, R.H. (2000) Activation and inactivation of rostral superior colliculus neurons during1996; Waitzman et al., 2000). The possibility that smooth-pursuit eye movements in monkeys. J. Neuro-this circuit, and of course others including the physiol., 84: 892–908.cerebellum, could subserve proprioception seems Batini, C., Buisseret, P. and Buisseret-Delmas, C. (1975) Trige-possible from the neuroanatomical results, and is minal pathway of the extrinsic eye muscle afferents in cat.put forward as a hypothesis in Fig. 10. Brain Res., 85: 74–78. In conclusion, we have considered the evidence Batini, C., Buisseret, P. and Kado, R.T. (1974) Extraocular proprioceptive and trigeminal projections to the Purkinjefor sensory innervation of eye muscles and for the cells of the cerebellar cortex. Arch. Ital. Biol., 112: 1–17.central pathways that may be involved in the Billig, I., Buisseret-Delmas, C. and Buisseret, P. (1997) Iden-information processing. Some patterns in the or- tification of nerve endings in cat extraocular muscles. Anat.ganization of the muscle spindles, palisade endings, Rec., 248: 566–575. Blumer, R., Konakci, K.Z., Brugger, P.C., Blumer, M.J.F.,and Golgi tendon organs with respect to different Moser, D., Schoefer, C., Lukas, J.-R. and Streicher, J. (2003)muscle layers has been recognized, and may lead to Muscle spindles and Golgi tendon organs in bovine calfa clearer understanding of the factors involved in extraocular muscle studied by means of double-fluorescenttheir development (Buttner-Ennever et al., 2003). ¨ labeling, electron microscopy, and three-dimensionalThe morphological results are still open to different reconstruction. Exp. Eye Res., 77: 447–462.interpretations, but a sensory hypothesis fits more Blumer, R., Lukas, J.R., Aigner, M., Bittner, R., Baumgartner, I. and Mayr, M. (1999) Fine structural analysis of extraoc-easily with most physiological, clinical and neuro- ular muscle spindles of a two-year-old human infant. Invest.anatomical studies (Lewis and Zee, 1993). At Ophthalmol., 40: 55–64.present it seems that palisade endings are a more Blumer, R., Lukas, J.R., Wasicky, R. and Mayr, R. (1998)likely candidate than muscle spindles for a role in Presence and structure of innervated myotendinousproprioception, although this hypothesis is not fa- cylinders in sheep extraocular muscle. Neurosci. Lett., 248: 49–52.vored by all of the authors. But a primary goal for Blumer, R., Lukas, J.R., Wasicky, R. and Mayr, R. (2000)future experiments has to be the location of the Presence and morphological variability of golgi tendonneuronal cell bodies of the receptors, and the de- organs in the distal portion of sheep extraocular muscle.termination of the afferent pathway. Anat. Rec., 258: 359–368. Blumer, R., Wasicky, R., Hotzenecker, W. and Lukas, J.R. (2001) ¨ Presence and structure of innervated myotendinous cylinders inAcknowledgments rabbit extraocular muscle. Exp. Eye Res., 73: 787–796. 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  • 58. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 4 The extraocular motor nuclei: organization and functional neuroanatomy J.A. Buttner-Enneverà ¨ Institute of Anatomy, Ludwig-Maximilian University of Munich, Pettenkoferstrasse 11, D-80336 Munich, GermanyAbstract: The organization of the motoneuron subgroups in the brainstem controlling each extraocular eyemuscle is highly stable through the vertebrate species. The subgroups are topographically organized in theoculomotor nucleus (III) and are usually considered to form the final common pathway for eye musclecontrol. Eye muscles contain a unique type of slow non-twitch, fatigue-resistant muscle fiber, the multiplyinnervated muscle fibers (MIFs). The recent identification the MIF motoneurons shows that they too havetopographic organization, but very different from the classical singly innervated muscle fiber (SIF) moto-neurons. The MIF motoneurons lie around the periphery of the oculomotor nucleus (III), trochlear nucleus(IV), and abducens nucleus (VI), slightly separated from the SIF subgroups. The location of four differenttypes of neurons in VI are described and illustrated: (1) SIF motoneurons, (2) MIF motoneurons, (3)internuclear neurons, and (4) the paramedian tract neurons which project to the flocculus. Afferents to themotoneurons arise from the vestibular nuclei, the oculomotor and abducens internuclear neurons, themesencephalic and pontine burst neurons, the interstitial nucleus of Cajal, nucleus prepositus hypoglossi,the supraoculomotor area and the central mesencephalic reticular formation and the pretectum. The MIFand SIF motoneurons have different histochemical properties and different afferent inputs. The hypothesisthat SIFs participate in moving the eye and MIFs determine the alignment seems possible but is notcompatible with the concept of a final common pathway.Introduction identified motoneurons, or specific premotor con- nections (Horn et al., 1995; Horn and Buttner- ¨The most exciting scientific developments over the Ennever, 1998; Eberhorn et al., 2005): and thelast 10 years in the field of the extraocular motor characteristics can in turn be used as markers innuclei have encompassed both molecular and sys- the human brain to locate homologous neuronaltemic approaches. First, there is the identification groups. Alongside these advances has been theof a multitude of neurotrophins, transcription development of transsynaptic tracer techniques,factors, genetic factors, membrane receptors, and starting with lectins, then tetanus toxin, and cul-transmitters which have a specific relationship to minating in the injection of particular strainsthe extraocular motoneurons. In addition, the com- of rabies virus, whose uptake is restricted to mo-bination of histochemical and immune techniques tor terminals, but can travel over an unlimitedwith tracer tracing has permitted transmitters, or number of synapses and at the same time amplifyhistochemical characteristics, to be associated with the marker-signal (Buttner-Ennever et al., 1981; ¨ Evinger and Erichsen, 1986; Itaya, 1987; Horn andÃCorresponding author. Tel.: +49 89 5160 4851; Buttner-Ennever, 1990; Kuypers and Ugolini, ¨Fax: +49 89 5160 4857; 1990; Herzog and Kummel, 2000; Erichsen and ¨E-mail: May, 2002; Graf et al., 2002; Morcuende et al.,DOI: 10.1016/S0079-6123(05)51004-5 95
  • 59. 962002; Ugolini et al., 2005). This powerful virus McGurk, 1985; Szabo et al., 1987). For a compre-tracer technique promises to reveal major principles hensive review on this topic at both the light andupon which the oculomotor system is organized. electron microscopic level see Evinger (1988). With respect to the abducens motoneuron size, a study comparing squirrel monkey with cat foundGeneral features of motoneurons the diameter for monkey motoneurons was 20–44 mm (mean 31.773.8 mm), and four or moreExtraocular motoneurons develop within the primary dendrites per cell, compared with catsegmented neuroepithelium in a caudal rostral abducens where the size ranged from 26 to 66 mm,sequence, like the eye muscles they innervate; and averaged 37.276.2 mm, also with four or moreabducens nucleus (VI) is first, followed by trochl- dendrites per cell (Russell-Mergenthal et al., 1986;ear (IV) and finally the oculomotor neurons (III) McClung et al., 2001). Although there is a wide(Shaw and Alley, 1981; Szyszka-Mroz, 1999). The variation in the reports of abducens motoneuronthree extraocular motor nuclei develop from dif- sizes, reviewed by McClung and colleagues, thereferent brain segments: abducens neurons originate is a general consensus that those of cat are largerfrom rhombomeres 5 and 6: trochlear neurons than those in monkey (Langer et al., 1986; McCreadevelop in rhombomere 1, and the oculomotor et al., 1986; McClung et al., 2001). A comparisonnucleus (III) is derived from the most caudal mid- of the sizes of medial rectus motoneurons withbrain segment, or mesomere, just in front of the those of the lateral rectus in monkey showed thatmidbrain–hindbrain boundary (Matesz, 1990; of the three MR subgroups (see below) those of theBaker, 1992; Straka et al., 1998, 2001). These A group were indistinguishable from abducensand other reviews have dealt with the further motoneurons while those of the B-group weredevelopment of oculomotor circuitry (Glover, larger and the C-group smaller (Buttner-Ennever ¨2003). Although the IV may later merge into and Akert, 1981; Buttner-Ennever et al., 2001; ¨caudal III in some species, alone from ontogeny, McClung et al., 2001).the two nuclei must be considered as separate en-tities. The location of the three extraocular nucleiwithin the brainstem is shown in Chapter 1, Fig. 2. Oculomotor nucleusMorphometry of motoneurons Organization of motoneuron subgroupsIn homeotherms the soma-dendritic morphology of Neurons in III innervate the ipsilateral medial andthe motoneurons is constant across species; an in- inferior rectus (MR, IR), the inferior oblique (IO)creasing soma diameter leads to more, rather than and contralateral superior rectus (SR); IV controlsthicker dendrites. It is difficult to decide from which the contralateral superior oblique (SO); and VIspecies of mammal or bird a motoneuron recon- motoneurons drive the lateral rectus (LR) muscle.struction is taken (Evinger, 1988). Nevertheless The mammalian III also includes motoneuronsthere are species differences in absolute soma size; a which innervate the levator palpebrae superiorishuman has motoneurons with an average diameter (LP); they lie in a slightly separate subgroup inof approximately 50 mm, and 12–20 primary dend- caudal III, called the central caudal nucleus (seerites (Szabo et al., 1987); whereas a guinea pig has below). The precise location of the motoneuronoculomotor neurons of about 30 mm diameter, and populations is dependent on the sequence of5–6 primary dendrites. In contrast, a major change muscle and neuronal development (Baker, 1992;appears in poikilotherms, where the oculomotor Straka et al., 1998). The motoneuron subgroups inneurons look very different. They have much larger III are organized in a topographic map, and arediameter primary dendrites than homeotherms, and illustrated for a few species schematically in Fig. 1.with increasing soma diameter the dendritic diam- The individual maps of many different vertebrateeter increases (Graf and Baker, 1985; Graf and classes have been reviewed and discussed by
  • 60. 97Fig. 1. Organization of motoneuron subgroups within the oculomotor nucleus III in different species (not scaled). Note that the basicpattern is relatively constant; however, LP moves laterally in lateral-eye mammals and the MR innervation in elasmobranchs iscrossed. The avian EW (pigeon) is large and well organized. The example of the teleost is taken from the flounder, and of theelasmobranch from the skate (modified from Evinger, 1988).Evinger (1988). Here, the studies will be only 1985), rabbit (Murphy et al., 1986), rat (Glicksman,cited, since despite minor differences the general 1980).They follow, from rostral to caudal, the se-organization is similar in mammals: monkey quence of IR, MR, IO, SR (and LP) (Shaw and(Buttner-Ennever et al., 2001), cat (Miyazaki, ¨ Alley, 1981). The subgroups of LP and MR show
  • 61. 98most variation. In frontal-eyed animals, like theprimate or cat, LP motoneurons lie in a bilobedcell group on the midline (nucleus centralis cau-dalis, CCN), whereby many of the motoneuronslie contralaterally within CCN (Sun and May,1993). In lateral-eyed animals, like rabbit and rat,the LP motoneurons are situated laterally, andcontralateral (Fig. 1), but in the guinea pig theyare scattered ventrolaterally within the medial lon-gitudinal fasciculus (MLF) of the contralateralside (Evinger et al., 1987). The organization of theoculomotor nucleus in lower species has been thesubject of many studies: lampreys (Fritzsch andSonntag, 1988), chameleon (El-Hassni et al.,2000), and the weakly electric fish (Szabo et al.,1987). The basic internal organization of theoculomotor nucleus (III) is remarkably constantacross almost the entire spectrum of vertebratespecies. An exception to the basic plan of organ-ization in III is seen in elasmobranchs where theMR motoneurons lie in contralateral III (Fig. 1).It is instructive to consider the consequences of thestandard pattern of extraocular innervation. Itmeans that an excitatory premotor input to the IIIand IV of one side, results in the ipsilateral torsionof both eyes (Fig. 2), conversely a lesion of the Fig. 2. Organization of the motoneuron subgroups within IIIpremotor pathway would cause torsion to the other and IV, showing that an excitatory input to all the subnuclei onside. A good example of this seen with stimulation the left side (e.g., RIMLF) will lead to an ipsitorsional eyeand lesions of is the rostral interstitial nucleus of movement (right eye intorts, and left eye extorts).the MLF (RIMLF) see Chapter 1, Fig. 3, alsoChapter 5, and the RIMLF section of this chapter. correlated with the innervation of a specific muscle There is a prominent change in the arrangement fiber type. Recent experiments show that theof MR motoneuron subgroups in primates (Fig 1): motoneurons of the C-group innervate the multi-here there are three distinct clusters of MR ply innervated muscle fiber (MIF) motoneurons ofmotoneurons, ventral the A-group extending into both MR and IR (see section on motoneuronthe MLF, dorsolateral the large motoneurons of types) (Buttner-Ennever et al., 2001). A schematic ¨the B-group and dorsomedially at the peripheral diagram of an MIF motoneuron is shown inborder of the oculomotor nucleus the C-group, Fig. 4, and compared to a motoneuron innervatingconsisting of smaller motoneurons, see Fig. 3 a singly-innervated muscle fiber (SIF).(Buttner-Ennever and Akert, 1981). Rudimentary ¨ The MIF motoneurons of the IO and SR lieMR cell clusters, similar to some if not all of the together close to the midline, sandwiched betweenwell-defined A, B, and C subgroups in primates are the oculomotor nuclei, and hence called theseen in lower species such as cat (Miyazaki, 1985) ‘‘S-group’’ (Buttner-Ennever et al., 2001; Wasicky ¨and rat (Eberhorn, personal communication). The et al., 2004). Excitatory inputs to the S-groupA-group reaches its largest proportions in the would lead to upward deviation of the eyes; and tohuman III. It is surprising that the different func- the C-group, containing MR and IR motoneurons,tions of the A-, B-, and C-groups remain to a large a similar input would result in vergence with aextent unclear, and as yet only the C group can be downward component.
  • 62. 99 Fig. 4. Schematic diagram of an eye muscle, showing an SIF with a central endplate zone; and MIF with ‘‘en grappe’’ terminals along the whole length (in some cases one MIF is innervated by several motoneurons. Note that a tracer injection at the muscle tip, avoiding the central endplate zone, will retorgradely label only MIFs. was mainly taken up by the widely scattered ‘‘en grappe’’ terminals of the MIF muscle fibers, and labeled the MIF motoneurons (Buttner- ¨ Ennever et al., 2001). In addition, it was argued that the MIFs of the global layer rather than the orbital layer, were primarily labeled, since the or- bital layer of muscle is now known to terminate more proximally than the global layer, on Tenon’s capsule (Chapter 1, Fig. 10; and Chapter 2, Fig. 2). This argument depends heavily on the new insights into the termination of the global and orbital layers of the eye muscles (Demer et al., 2000; Oh et al., 2001; Ruskell et al., 2005). At theFig. 3. The MIF motoneurons, mainly supplying the global present time the location of the motoneurons of thelayer of muscle (black dots), lie around the periphery of III, IV, orbital MIFs is unknown (Eberhorn et al., 2005).and VI in a different pattern from the SIF motoneurons. The The S-group motoneurons in monkey (Fig. 3) canC-group contains MR and IR MIF motoneurons; the S-group be correlated with a similar cell cluster in mancontains IO and SR MIF motoneurons. The MR SIF (Horn et al., unpublished observations). This generalmotoneurons in the dorsal B-group, and ventral A-group, areindicated by open circles. region is often referred to as the nucleus of Perlia in humans (Olszewski and Baxter, 1982). The nucleus of Perlia appears to be a variable feature in adult The MIF motoneurons, shown as black dots in humans (Warwick, 1954), and the only evidence toFig. 3, were located by retrograde tracer injections suggest that it plays a role in the control of vergenceinto the distal muscle–tendon junction of the is ‘‘the time of appearance in both the species andextraocular muscles, avoiding the ‘‘en plaque’’ the embryo which coincides with the positioning ofendplate zone (Fig. 4). Therefore the tracer the eyes in the frontal plane were convergence
  • 63. 100becomes possible’’ (Adler, 1950). This may not be However, there is general agreement that twitchfar from the current hypotheses on the function of motoneuron units innervate the SIFs, and the non-the S-group MIFs (see below), but great care must twitch units innervate global MIFs (Lennerstrand,be taken since there are several cell groups on the 1975; Nelson et al., 1986). MIF (nontwitch) firingmidline between the oculomotor nuclei in human, so characteristics may be deduced from studies into define them as the nucleus of Perlia, the S-group, frog and cat, where nontwitch units were describedEdinger–Westphal nucleus or an interneuron sub- (Goldberg et al., 1981; Dieringer and Precht, 1986;group needs careful analysis (Fig. 5A) (Ishikawa Nelson et al., 1986; Shall and Goldberg, 1992). Inet al., 1990). frog, nontwitch units were shown to fire tonically at around 50 Hz (Dieringer and Precht, 1986; Straka and Dieringer, 2004).Motoneurons of singly and multiply innervated Both motoneuron types, SIFs and MIFs, aremuscle fibers cholinergic (Figs. 5A–E), but they have been shown in monkey to have different histochemicalIt has been described above how the motoneurons staining properties (Eberhorn et al., 2005). Theseof SIFs and MIFs tend to lie separate from each double-labeling experiments revealed that the MIFother in III, IV, and VI and have a completely motoneurons in the periphery of the motor nucleidifferent organization of their subgroups (Fig. 3). do not contain nonphosphorylated neurofilamentsThis permits a differential analysis of their afferent (as detected with SMI32-immunostaining), orinputs (Wasicky et al., 2004), and it shows that SIF parvalbumin, and they lack perineuronal netsand MIF motoneurons do not receive identical (Fig. 5E). In contrast, SIF motoneurons expressinputs: some afferents target both, and others all markers at high intensity (Figs. 5D, E).innervate one or the other (Figs. 7D, E). A majorinput to the MIF motoneurons of the C- andS-groups is the pretectum (Fig. 7E see section Putative role of MIF and SIF motoneurons‘‘Pretectum’’). The elegant transsynaptic retrograde It is widely accepted that the unit activity of thestudies of the premotor inputs to LR MIF moto- motoneurons specifies the movements of the eye inneurons, using rabies virus, show that the central the head under all circumstances. Furthermore,mesencephalic reticular formation (cMRF) and the discharge of all motoneurons are thought tothe supraoculomotor area (SOA) supply afferents, contribute to all types of eye movements, whetheras well as areas associated with the neural inte- saccades, VOR or vergence (Keller and Robinson,grator, like nucleus prepositus hypoglossi (PPH) 1972; Gamlin and Mays, 1992). However, severaland the parvocellular parts of the medial vestib- recent reports have demonstrated, under certainular nucleus (MVNp); however, the MIFs do not circumstances, a dissociation or uncouplingreceive direct afferents from premotor saccadic between motoneuron activity and the eye move-regions such as the paramedian pontine reticular ments, for example, during head restrained andformation (PPRF), the inhibitory burst neurons nonrestrained conditions (Ling et al., 1999). Aboutarea and the oculomotor internuclear neurons 66% of abducens motoneurons, in some condi-(OMN-INTs) (see Fig. 8, Chapter 1 and Chapter tions, fire as a result of monocular movements of5) (Buttner-Ennever et al., 2002; Ugolini et al., ¨ not only the ipsilateral, but also the contralateral2005). eye (Zhou and King, 1998). Another set of exper- The results suggest that the functional role of iments, whose results should cause a great deal ofMIF is different from that of the SIF, and thus deliberation, showed that during convergencechallenges the idea of a ‘‘final common pathway’’ there was a slight decrease rather than increase inin which it is postulated that all motoneurons par- muscle forces of MR and LR measured in mon-ticipate in all types of eye movements (Miller, keys (Miller et al., 2002). Given that we now have2003). Individual recordings from MIF motoneu- recognized the identity and location of MIF moto-rons in behaving primates have not been reported. neurons, and found them to possess very different
  • 64. 101Fig. 5. Photomicrographs of transverse sections of: (A) oculomotor nucleus, (B) trochlear nucleus, and (C) abducens nucleus, double-labeled for choline acetyltransferease (ChAT) (red) and perineuronal nets (green). All motoneurons and many EW neurons are ChATpositive (red). Only SIF motoneurons within the motor nuclei are also ensheathed by perineuronal nets (green). MIF motoneurons(arrows) lack perineuronals nets and lie close to EW. Histochemical differences between ABD-INT, SIF and MIF motoneurons areshown in the high-powered photographs of the abducens nucleus neurons in (D) double-stained for perineuronal nets (brown) andChAT (black) motoneurons, SIF motoneurons are black (ChAT-positive) surrounded by brown nets (white arrows), a putative ABD-INT (black arrow) is unstained (ChAT-negative) with brown nets: in E) shows three black (ChAT-positive) SIF motoneurons withbrown nets, and one black MIF motoneuron without brown nets. (Eberhorn et al., 2005). Calibration in (A)–(C) is 500 mm and in (D)and (E) it is 50 than the SIF motoneurons, we must the length of the eye muscle (Mayr et al., 1975),now ask what role they play in oculomotor control contract more slowly than SIFs, are fatigue resist-(Buttner-Ennever et al., 2001, 2002). The MIF ¨ ant (Morgan and Proske, 1984), and are driven bymuscle fibres of the global layer extend throughout tonically firing units (Lennerstrand, 1975; Dieringer
  • 65. 102and Precht, 1986). It is not clear how much they situation in cats, where the topography of OMN-contribute to the tension of eye muscles in natural INTs is not restricted to particular divisions of theconditions, but experimentally exposing eye III nucleus. The crossed pathway from OMN-muscle to succinylcholine causes them to contract INTs directly onto LR motoneurons is monosy-and the effect is caused by the depolarization of naptic, and was shown to target SIF (twitch) LRMIFs and not SIFs (Bach-y-Rita et al., 1977). As motoneurons exclusively, and not MIF (non-discussed in Chapter 3, MIFs are associated with twitch) LR motoneurons (Buttner-Ennever et al., ¨palisade endings at their tips at the myotendinous 2003; Ugolini et al., 2005).junction, and this combination has been compared In primates it has been shown that OMN-INTsto ‘‘an inverted muscle spindle,’’ in the words of behave in a remarkably similar way to MR moto-David A. Robinson (Steinbach, 2000). It is possible neurons during vergence and versional eye move-that this combined structure could provide a sen- ments, but OMN-INTs show vertical eye positionsory or proprioceptive feedback signal to the cen- sensitivity (Clendaniel and Mays, 1994). The iden-tral nervous system (CNS), which regulates the tified OMN-INTs display a burst-tonic pattern ofmuscle activity (see Chapter 3, Fig. 9). It is still too activity during adducting saccades (Clendaniel andearly to decide what role MIF motoneurons play Mays, 1994). The OMN-INT pathway is predom-in the control of eye movements, but currently inantly, if not entirely, excitatory, since microstim-evidence supports the idea that the SIF or twitch ulation of the oculomotor nucleus, where bothmotoneurons primarily drive the eye movements, MR motoneurons an OMN-INTs are located,whereas the MIF or nontwitch motoneurons induces, in addition to large adduction of theparticipate in determining the tonic muscle activity, ipsilateral eye (MR motoneuron activation), aas in gaze-holding, vergence and eye alignment smaller abduction of the contralateral eye (LR(Buttner-Ennever et al., 2001, 2002). ¨ motoneuron): moreover, reversible inactivation with lidocaine at the same III site results in hypometric and slowed abducting saccades in the contralateralOculomotor interneurons eye (Clendaniel and Mays, 1994). Therefore, OMN-INTs send an excitatory signal to the cont-Several populations of internuclear neurons with ralateral LR motoneurons, appropriate for hori-diverse projection targets, such as the spinal cord, zontal conjugate eye movements during saccades.the cerebellum, the abducens nucleus have been Although the reciprocal connectivity between LRidentified within and around the oculomotor nu- and MR motoneurons by OMN-INTs and the re-cleus (Phipps et al., 1983; Maciewicz et al., 1984; ciprocal pathway from VI to III, by the abducensChung et al., 1987; Clendaniel and Mays, 1994). In internuclear neurons (ABD-INTs, see below) bothlampreys, there is evidence for GABA-immunore- might serve to coordinate LR and contralateralactive neurons within the extraocular motor nuclei MR their action may not be exactly equivalent.(Melendez-Ferro et al., 2000). The best investigat- The OMN-INTs behave exactly like MR moto-ed of these interneurons are the oculomotor inter- neurons, presumably because they receive axonnuclear neurons (OMN-INT) lying within within collaterals of MR motoneurons, at least in catsthe III and in the supraoculomotor area, which (Spencer et al., 1982). By contrast, ABD-INTs doproject bilaterally to the abducens nucleus. These not behave entirely like LR motoneurons and dohave been demonstrated in the cat (Maciewicz not receive collateral input from LR motoneuronset al., 1975b; Maciewicz and Phipps, 1983; May (cat: Highstein et al., 1982; squirrel monkey:et al., 1987) and monkey in retrograde labeling McCrea et al., 1986).experiments and with antidromic activation from In addition to their burst-tonic pattern of activitythe abducens nucleus. In primates, most OMN- during conjugate eye movements, most OMN-INTsINTs are confined to the contralateral MR subdi- show an increase of tonic discharge for vergencevisions (Buttner-Ennever and Akert, 1981; Langer ¨ (Nakao et al., 1986; Zhang et al., 1991, 1992;et al., 1986; Ugolini et al., 2005), contrary to the Clendaniel and Mays, 1994). Most LR motoneurons
  • 66. 103and ABD-INTs decrease their activity during con- immunoreactivity, indicating glycinergic afferentsvergence (Gamlin et al., 1989b). Since the OMN- (Horn, personal observations).INTs within the MR subgroups are excitatory, The LP raises the upper eye lid and of necessitythey cannot be the source of the appropriate in- must be closely coordinated with the vertical eyehibitory vergence signal to LR motoneurons: their movements. It develops embryologically from theinput is inappropriate. However, their tonic activ- SR muscle and in some ways the neural activity ofity during vergence might explain why LR moto- its motoneurons is very similar to SR, increasingneurons do not decrease their activity as much for with upward eye movement; but during blinks thevergence as for conjugate eye movements of sim- LP activity ceases, while SR motoneurons give ailar amplitude (Gamlin et al., 1989b), implying burst of activity (Evinger et al., 1984; Buttner- ¨that some co-contraction of LR and MR muscles Ennever and Horn, 2004). In the primate the CCNoccurs during convergence. was shown to receive afferents from the interstitial In the cat, OMN-INTs constitute a nonuniform nucleus of Cajal, the nucleus of the posterior com-population, showing low percentages of immuno- missure (May et al., 2002) and from a small,staining for various calcium-binding proteins, recently identified cell group, medial to the rostralespecially calbindin (De la Cruz et al., 1998). Of interstitial nucleus of the MLF (RIMLF), whichthe OMN-INTs labeled retrogradely from the ab- was called ‘‘M-group’’ and considered to helpducens nucleus, none are serotoninergic (May coordinate the activity of LP with eye movementset al., 1987) or glycinergic (Spencer et al., 1989) (see Chapter 5; Horn et al., 2000; Chen and May,and only a small percentage (20%) is GABAergic 2002). Studies in rabbit and monkeys revealed(De la Cruz et al., 1992). The functional role of projections from neurons at the rostral borderthese GABAergic OMN-INTs is not clear. of the principal and spinal trigeminal nucleus (pars oralis) to CCN, which presumably provide the inhibition during blinks (May et al., 2002;Central caudal nucleus Morcuende et al., 2002; Buttner-Ennever and ¨ Horn, 2004).In primates, the levator palpebrae (LP) motoneu-rons lie in the central caudal nucleus (CCN) acompact unpaired subgroup situated dorsal to the Edinger– Westphal nucleuscaudal pole of the oculomotor nucleus in human,and usually considered as part of III (Schmidtke In addition to controlling the extraocular musclesand Buttner-Ennever, 1992). Within the CCN, the ¨ the oculomotor complex also sends efferents in themotoneurons of both eyelids appear intermixed, oculomotor nerve (III) to the ipsilateral ciliaryand recent experiments show that even in primates ganglion in the orbit, whose neurons control thethe LP motoneurons lie mainly contralateral (Sun smooth muscle of the iris and of the lens. Theand May, 1993; Buttner-Ennever et al., 2001). ¨ name Edinger–Westphal nucleus (EW) is oftenThere are conflicting reports as to whether some loosely given to this group of neurons. Currently itLP motoneurons innervate the muscles of both is generally accepted in medical circles that thesides (Sekiya et al., 1992; Van der Werf et al., cholinergic parasympathetic preganglionic neu-1997), or whether each motoneuron innervates rons of EW carry signals to the ciliary ganglion,only the levator palpebrae of one side (Porter and mediate accommodation of the lens throughet al., 1989). The CCN motoneurons are smaller the ciliary muscles, as well as constriction of thecompared to those of the extraocular eye muscles pupil through the contraction of the constrictor, orand are more easily visualized with parvalbumin sphincter muscles of the iris. A more specificimmunostaining than the other motoneurons of nomenclature of these neurons arising from studiesIII. They receive a strong supply of GABA- of the monkey, groups the neurons together as theimmunoreactive terminals and they are very spe- visceral nuclei. These are composed of two cellcifically associated with glycine transporter groups the EW and the anteromedian nucleus
  • 67. 104(AM). The cholinergic cells of EW are shown in in birds the characterization of the preganglionicFig. 5A; it forms two slender columns of small neurons of EW is superb. The caudal-lateral sub-cells, one each side of the midline, and dorsal to division of EW projects to the ciliary ganglion cellsthe rostral three-fifths of the somatic III; in trans- controlling the iris; those in the medial EW inner-verse section of mid III each column divides into vate the ganglion cells controlling the choroidtwo smaller columns, but rostrally they merge to a capillaries, and the rostral–lateral EW neuronssingle cell group. The AM extends further rostral control the accommodation ganglion cells inner-than the motoneurons of III, and is continuous vating the ciliary muscles (Reiner et al., 1983,with the rostral pole of EW, but this junction is not 1991; Gamlin et al., 1984). A less well organized,distinctive. The location of the preganglionic neu- but similar topography can be demonstrated in catrons is a subject of some confusion, because in (Erichsen and May, 2002).some species they lie scattered beyond the cytoar- A further complication in the assessment of EWchitectural boundaries of the visceral nuclei. The is that some reports suggest that some neurons oflocation of the preganglionic neurons has been EW bypass the ciliary ganglion and innervate thestudied in primates (Akert et al., 1980; Burde and iris or ciliary body directly (Jaeger and Benevento,Loewy, 1980; Clarke et al., 1985) in nonprimates 1980; Burde, 1988; Klooster et al., 1993). In ad-(Sugimoto et al., 1977; Loewy et al., 1978; Strassman dition, several studies show with tracer injectionset al., 1987; Sun and May, 1993). In monkey the that neurons in the EW area project not only topreganglionic neurons are largely confined to EW the ciliary ganglion but also to the lower brain-and AM (Akert et al., 1980; Burde and Loewy, stem, the cerebellum, and the spinal cord (Loewy1980; Ishikawa et al., 1990; May et al., 1992; Sun and Saper, 1978; Loewy et al., 1978; Sugimotoand May, 1993), but some reports found cells lat- et al., 1978; Roste, 1990; Klooster et al., 1993). Theeral to EW in the lateral visceral cell columns of difficulty of distinguishing between the severalthe ventrolateral PAG (Burde and Williams, groups of neurons lying close together on the mid-1989). Unfortunately the results of the primate line of III, has been already mentioned. The sameexperiments are confused by the use of different difficulty applies to an assessment of the efferentssets of terminology where EW is sometimes re- and afferents of the ‘‘EW region,’’ for example,ferred to as the dorsal visceral cell column (Pierson from the vestibular nuclei (Balaban, 2003), fromand Carpenter, 1974) and other times as the medial the pretectum (Buttner-Ennever et al., 1996b; ¨visceral cell column (Carpenter et al., 1970). Most Clarke et al., 2003) and the accessory optic nucleineurons of the dorsomedial EW are larger than the (see Chapter 13; Clarke et al., 2003). Likewise, thesurrounding cells, Gamlin and colleagues showed reports of EW degeneration in Alzheimer diseasethat preganglionic neurons subserving accommo- must also be critically assessed since the exactdation of the lens, and projecting to the ciliary location of the preganglionic cells in humans areganglion, were confined to this cell group, and unknown (Scinto et al., 1999, 2001).were not found further laterally in lateral visceral Functional considerations of the EW mustcell columns (Gamlin et al., 1994). It is important include an analysis of the ‘‘near response’’to remember that the location of EW in human as or ‘‘near triad’’ (Leigh and Zee, 1999). Lensput forward by Olszewski and Baxter (1982) is accommodation is one part, pupillary constrictionbased on cytoarchitectural features alone. is a second and vergence is the third component. In cat and rabbit the preganglionic neurons are The first two functions are controlled by EW neu-in a completely different location from primates: rons around the midline of the III, whose location isneither EW nor AM contain significant numbers hardly distinguishable from the C- and S-groupof preganglionic neurons; instead they lie dorsal to MIF motoneurons (Fig. 5A). If the MIF motoneu-III in the periaqueductal gray substance and in the rons are involved in control of eye muscles before,tegmental area ventral to III (Sugimoto et al., during or after vergence, then the neuroanatomy of1977; Loewy et al., 1978; Strassman et al., 1987; the midline III region is well suited for the synkineseErichsen and May, 2002). In contrast to mammals, of these three functions.
  • 68. 105Trochlear nucleusThe trochlear nucleus (IV) lies in the midbrainventral to the aquaeduct. In humans, it has beenobserved to consist of one large group ‘sunken’into the MLF; and several smaller groups ofmotoneurons further caudally (Olszewski andBaxter, 1982). It contains only motoneurons ofthe contralateral superior oblique muscle; howeverthe contribution of SO motor unit activity duringsome types of eye movements such as convergence(Mays et al., 1991), counterrolling during static tilt(Sasaki et al., 1991) is still not well understood.The motoneurons innervating the MIF, or slownontwitch muscle fibers, lie in a tight cluster in thethe dorsal cap of the nucleus, see Fig. 5B (Buttner- ¨Ennever et al., 2001). In all mammals where thetrochlear nucleus has been studied (rabbit, rat, Fig. 6. Diagram illustrating four different types of neuronhamster, guinea pig, cat, and ferret) the percentage within the abducens nucleus and their targets.of ipsilaterally projecting neurons, usually of smallsize, was approximately 2–4% (Murphy et al., comparison across species, see Evinger (1988). In1986); and in lamprey was estimated as 16% primate, it contains at least four functional cell(Fritzsch and Sonntag, 1988). groups (Fig. 6): (1) motoneurons innervating the SIF (or twitch) muscle fibers of the lateral rectus muscle; (2) motoneurons innervatingTensor tympani motoneurons nontwitch muscle fibers of the lateral rectus mus- cle; (3) abducens internuclear neurons (ABD-A small number of neurons around the dorsal cap INT); and (4) floccular-projecting neurons in theof the trochlear nucleus were retrogradely filled rostral cap, which belong to the paramedian tractfrom the ipsilateral tensor tympani muscle (Shaw neurons (see Chapter 5). The motoneuronsand Baker, 1983). The motoneurons were small controlling the SIF and MIF muscle fibres areand appeared very similar in both type and loca- scattered throughout the motor nucleus (Fig. 7A),tion to the SO MIF motoneurons. The tensor but those controlling the MIF fibers are arrangedtympani muscle and the EOM are both innervated around the periphery of the nucleus in monkey, seeby the trigeminal nerve (by motor and sensory Fig. 7B (Buttner-Ennever et al., 2001). The organ- ¨nerves, respectively), and are the only muscles in ization of the MIF motoneurons in VI is not somammals known to contain MIFs (Morgan and clear as in III and IV (Figs. 3 and 5), but theProske, 1984), so we consider the fact that their histochemical differences to SIFs remain identicalmotoneurons are intermingled to be highly signif- as described above: the abducens MIF motoneu-icant. No labeled cells in the trochlear nucleus rons lack perineuronal nets (Fig. 5E), and do notwere found by Murphy et al. (1986) in the rabbit have nonphosphorylated neurofilaments (Eberhornfollowing tensor tympani muscle injections. et al., 2005). In teleosts the abducens is clearly divided into a rostral and caudal division (Sterling,Abducens nucleus 1977), but inspite of a clear size-difference between the motoneuron of the two divisions, no differencesThe abducens nucleus (VI) lies in the pontomed- in the physiological properties could be foundullary brainstem beneath the floor of the fourth (Sterling, 1977; Pastor et al., 1991; Cabrera et al.,ventricle as a round nucleus adjacent to the: for a 1992).
  • 69. 106Fig. 7. (A)–(C) show the differential distribution of cell groups in abducens nucleus (VI) of monkey: (A) retrograde tracer filling of SIFand MIF abducens motoneurons with a large injection of cholera-toxin subunit B into the belly of LR; (B) retrograde tracer filling ofabducens MIF motoneurons with a small injection of rabies virus into the distal tip of LR; (C) retrograde tracer filling of abducensinternuclear neurons with an injection of WGA.HRP into III of the contralateral side. (D) and (E) demonstrate different inputs to SIFand MIF motoneurons of III: (D) fine silver grain anterograde labeling of the A- and C-groups of MR motoneurons after a [3H]leucine injection into the right VI; (E) fine silver grain anterograde labeling of the C- and S-groups after an injection into the pretectum,right side. Note that the SIF motoneurons of III remain mostly unlabeled, although fibers of passage are present. Calibration in(A)–(C) is 500 mm and in (D) and (E) it is 500 mm.Abducens internuclear neurons Ennever and Akert, 1981). The ABD-INTs tend to lie lateral the rootlets of the VI in primates (Fig. 7C),The internuclear neurons of the abducens nucleus and in cat they are present throughout the VI, more(ABD-INT) project to the motoneurons of the prevalent rostrally, but intermixed with motoneu-medial rectus muscle in the contralateral oculo- rons in the ratio of about 1:2, respectively (Steigermotor nucleus, thereby forming the anatomical and Buttner-Ennever, 1978). This correlates with ¨basis for conjugate eye movements (Buttner- ¨ the report of Spencer and Sterling (1977) in cat,
  • 70. 107and also in rabbit (Labandeira-Garcia et al., 1989) The PMT cell groups receive afferents from eitherwhere ABD-INTs comprised 25% of abducens vertical premotor cell groups, such as INC and thecells in the most successful experiments, and ABD- Y-group, or from horizontal premotor structuresINTs were slightly smaller than motoneurons. like PPRF or oculomotor internuclear neurons.Single cell reconstructions of motor and internu- We have recently found both vertical and hori-clear neurons revealed minor differences in the zontal PMT cell groups close to or within VI. Thesoma-dendritic morphology, but their axons dif- location of two PMT groups are seen in Fig. 7Cfered in that motoneurons had no collaterals, and (arrows) where the light gray (WGA.HRP)the crossed axon of the ABD-INT gave off collat- anterograde labeling from OMN-INT afferentserals as it entered the MLF (Highstein et al., 1982). marks (1) the dorsomedial abducens, and (2) theABD-INTs have been examined in both frog supragenual region (Langer et al., 1985). The PMT(Straka and Dieringer, 1991) and goldfish (Cabrera groups could provide the flocculus and ventralet al., 1992). para-flocculus of the cerebellum with a copy of the Motoneurons and internuclear neurons exhibit oculomotor input signal. Damage could lead to athe same burst-tonic firing pattern during eye disturbance in gaze-holding, see also Chapters 1movements (Fuchs et al., 1988), and while the and 5 (Buttner et al., 1995). ¨motoneurons activate the LR, the ascending axonsof the ABD-INT cross the midline, enter the MLF,terminate in MR motoneuron subgroups of the IIIand drive the contralateral eye in a conjugate Accessory abducens nucleusmovement. Hence, damage to the MLF (internu-clear ophthalmoplegia, INO) causes paresis of the In addition to the extraocular eye muscles rotatingMR. Only MR motoneurons, and not the inter- the eye, most land-dwelling animals have a set ofnuclear neurons, carry vergence-related signals, muscles controlling the nictitating membrane orand therefore in INO vergence remains intact but third eyelid (Chapter 2). The accessory abducensconjugate eye movements are disrupted (Delgado- nucleus (AC-VI) innervates these muscles via theGarcia et al., 1986a and b; Zhou and King, 1998). abducens nerve (NVI). The AC-VI lies in the ven- tral pons just above the superior olive and near the spinal trigeminal nucleus from which it receivesA cell group of the paramedian tracts plentiful afferents (see below). The motoneurons in amphibian and mammalian AC-VI innervate theThe paramedian tract (PMT) cell groups have ipsilateral retractor bulbi muscles (RBMs) (Grantbeen brought to the attention of oculomotor et al., 1979; Spencer et al., 1980; Spencer andneuroanatomists on account of their projection Porter, 1981; Murphy et al., 1986; Evinger et al.,to the flocculus and ventral paraflocculus region, 1987; Barbas-Henry and Lohman, 1988). Retrac-demonstrated in experimental tract tracing exper- tor bulbi contraction pulls the eye back into theiments (Blanks et al., 1983; Sato et al., 1983; orbit, which in turn squeezes the nictitatingLanger et al., 1985; Buttner-Ennever and Buttner, ¨ ¨ membrane out of the orbit, up over the front of1988; Blanks, 1990). It is well known that the the eye. In birds, the AC-VI supplies the quadratevestibular nuclei project to the floccular region, and pyramidalis muscles, which replace the RBMbut it is less well known that probably even more (Isomura, 1981; Labandeira-Garcia et al., 1987).floccular-projecting neurons lie scattered among Since the nictitating membrane is a tendon ofthe fascicles of the MLF in the pons and medulla. the pyramidalis muscle, contraction causes theThese neuronal groups have been called various nictitating membrane to sweep across the front ofnames, but are collectively referred to here as PMT the eye, without retracting or rotating the globe. Incell groups. There are at least six relatively sepa- species without a movable nicitating membranerate ‘‘PMT groups’’ scattered in the MLF, rostral, the retractor bulbi and its innervation is poorlycaudal, and even within, the abducens nucleus. developed, as for example in the guinea pig where
  • 71. 108less than 20 AC-VI motoneurons supply the thin INC, SVN, and the Y-group send a small numbersheet of retractor bulbi (Evinger et al., 1987). of projections to LR motoneurons (Graf et al., The AC-VI lies about 0.6 mm ventral to the 2002; Ugolini et al., 2005). This has been inter-abducens nucleus in rabbit. It contains about 250 preted as a necessity for spatial coordination of eyemotoneurons and almost all are labeled by tracer movement coordinates, and adaptive plasticityinjections into the four slips of RBM (Murphy (Graf et al., 1993). Some afferents to the oculo-et al., 1986). The RBM in rabbit, cat, and rat is motor nuclei are found only in certain species; formade up of four slips of muscle which insert prox- example, the accessory optic nuclei in the pigeonimal to the equator of the globe. Gross dissection are reported to project to III (Brecha and Karten,showed that branches of both the oculomotor and 1979; Brecha et al., 1980).abducens nerves entered the RBM, but never fromthe trochlear nerve (Murphy et al., 1986). There Vestibular afferentswas usually leakage from the RBM injections, so itis difficult to estimate how many neurons in ab- The projections from the vestibular nuclei to theducens and the OMN also supplied the RBM. oculomotor nuclei are formed by several parallelHowever, both anatomical and physiological ex- pathways, subserving compensatory and pursuitperiments confirm that abducens and oculomotor eye movements. The best studied pathway is theneurons also innervate the RBM (Crandall et al., three neuron arc involving the primary canal1981; Meredith et al., 1981). In primates, neurons afferents projecting to the secondary vestibularjust ventral to, and in, the VI innervate the acces- neurons, which in turn send axons to the moto-sory lateral rectus muscle which is a vestigial form neurons in VI, IV, and III (Tarlov, 1970; Graybielof the retractor bulbi (Chapter 2; Spencer and and Hartwieg, 1974; Gacek, 1977; Carpenter andPorter, 1981; Schnyder, 1984). In squirrel monkey Cowie, 1985; Epema et al., 1990).it was estimated that there are 1418 abducens neu-rons, and roughly 75% motoneurons were labelledfrom R and 50% from retractor bulbi in rabbit Secondary vestibulo-ocular neurons(Murphy et al., 1986). But different numbers were Careful intra-axonal staining reconstructions ofpublished for the rabbit: 400 abducens neurons, secondary vestibular neurons receiving canal36% motoneurons were labelled from LR, and afferents demonstrated ascending axons that do72% from retractor bulbi (Gray et al., 1981). not just excite or inhibit the motoneurons of one eye muscle, but project to the extraocular moto- neuron pools of yoked muscle pairs, e.g., SO-IR;Afferent pathways SR-IO, and generate a particular conjugate eye movement, such as upward, downward, torsional,Many neural networks converge on the extraocu- or horizontal movements. Many studies were usedlar motoneurons to drive the various different to compile the scheme of connections shown intypes of eye movement and to maintain the correct Fig. 8, and also in Chapter 1, Fig. 7 (Highstein,alignment of the eyes (Fig. 9A). The relative inde- 1973; Cohen, 1974; King et al., 1978; Andersonpendence of saccadic circuits from vestibular net- et al., 1979; Precht, 1979; McCrea et al., 1980,works, or of vertical saccade premotor regions, 1987a, b; Graf et al., 1983; Isu and Yokota, 1983;from horizontal saccade premotor areas, is usually Mitsacos et al., 1983; Hirai and Uchino, 1984b;emphasized to simplify the neuroanatomical pic- Graf and Ezure, 1986; Isu et al., 1988; Ohgakiture (Buttner-Ennever and Horn, 2004). However, ¨ et al., 1988a, b; Buttner-Ennever, 2000). These sec- ¨it is well to remember that all six eye muscles par- ond-order vestibular cells tend to lie in the centralticipate in all types of eye movements. The highly magnocellular regions of the vestibular complexsensitive transsynaptic tracing with rabies indicates (MVNm and SVNm). The magnocellular regionsthat there is a cross-activation between vertical are considered to provide the main output path-and horizontal systems, whereby the RIMLF, ways of the vestibular complex, and in some
  • 72. 109Fig. 8. Basic circuitry of the direct vestibulo-ocular reflex pathways by which horizontal and vertical canals activate functionallyorganized eye muscles pairs, and inhibit their antagonist pair. Note that inhibitory pathways ascend ipsilaterally in MLF, andexcitatory pathways in crossed MLF. The secondary anterior canal neurons in SVN form an additional ascending pathway (gray), thecrossed ventral tegmental tract (CVT); (int), abducens internuclear is referred to as zone 1 (Buttner-Ennever, ¨ Non-second-order vestibulo-ocular neurons1992, 2000). The secondary vestibular neurons Many non-second-order vestibular neurons,have a dominant canal input, and project to the including the NO-producing neurons describedmotoneurons via the MLF. Ipsilateral pathways below, also project to the oculomotor nuclei, butare inhibitory and contralateral pathways excita- there is less information on these pathways. Theytory; whereby the inhibitory transmitter for hor- lie in the rostral MVNp, marginal zone adjacent toizontal VOR is glycine, that for the vertical VOR is PPH, SVN and the dorsal Y-group, for review seeGABA, and both use glutamate and/or aspartate Chapter 6 (Buttner-Ennever, 1992, 2000). Those in ¨as their excitatory transmitter (Spencer et al., 1989, the rostral MVNp become very numerous in2003; McElligott and Spencer, 2000). Some oculo- primate, compared to cat (Langer et al., 1986;motor afferents from the SVN in rabbit may as- Highstein and McCrea, 1988). The marginal zonecend via the brachium conjuctivum and cross with cells lie slightly further caudal; many are inhibitoryit in the caudal mesencephalon (Yamamoto et al., neurons using glycine as their transmitter, and1978). A second, parallel pathway running further with axons that cross the midline and terminate inventrally and crossing at roughly the same level the abducens nucleus (Langer et al., 1986; Spencer(just rostral to nucleus reticularis tegmenti pontis) et al., 1989; McFarland and Fuchs, 1992). Theyhas been described, and called the ‘‘crossing ven- are also particularly prominent in primates andtral tegmental tract’’ (CVT) (Fig. 8). It carries sec- may play a role in pursuit eye movements. Neuronsondary anterior canal afferents from SVN to the in the dorsal division of the Y-group, also called themotoneurons in III of the upward moving eye infracerebellar nucleus, are floccular target neuronsmuscles, SR and IO (Stanton, 1980; Sato et al., which are active during upward optokinetic and1984; Hirai and Uchino, 1984b; Uchino and Hirai, smooth pursuit eye movements, also in vestibulo-1984; Uchino et al., 1994), and also carries affer- ocular suppression but not in pure vestibular com-ents from the floccular target neurons in the dorsal pensatory eye movements (e.g., in dark) (ChubbY-group (Sato et al., 1984; Carpenter and Cowie, and Fuchs, 1982; Plazquez et al., 2000). They have1985). Further experiments are needed to exclude a strong excitatory monosynaptic connection tothe possibility that the CVT has not been mistaken upward motoneurons in III which utilizes the CVTfor the brachium conjunctivum in some cases (Fig. 8) or the brachium conjuctivum (Sato et al.,(Sato et al., 1984). 1984; Yamamoto et al., 1986; Sato and Kawasaki,
  • 73. 110 The otolith projections to the oculomotor nuclei follow a completely different pattern from those of the canals; for a review, see Buttner-Ennever ¨ (1999). Primary afferents from the sacculus and utricle terminate mainly in the LVN, DVN, caudal SVN, and nodulus (Ishizuka et al., 1980; Imagawa et al., 1995). In the vestibular nuclei there is some convergence of canal and otolith signals onto the secondary neurons (Uchino et al., 2005). Utricular information can reach the abducens motoneurons and ABD-INTs via monosynaptic (Imagawa et al., 1995), disynaptic (Uchino et al., 1997), and mul- tisynaptic routes (Uchino and Isu, 1996). Saccular afferents probably only use multisynaptic path- ways to extraocular motoneurons. It is interesting in this respect that there is no strong eye move- ment response to a loud click on the mastoid bone, which activates the underlying sacculus relatively specifically. In contrast, there is overwhelming evidence for powerful projections of the utricle and sacculus to neck muscle motoneurons (Uchino et al., 2005). Ascending tract of DeitersFig. 9. (A) Summary diagram of the inputs to all extraocular The medial rectus subgroup in the oculomotormotoneurons. The accessory optic nuclei are only proved in nucleus receives vestibular activation via ABD-avian species. (B) The main inputs to the MIF motoneurons of INTs, and in addition a noteworthy set of directLR are limited to areas involved in gaze-holding, or tonic afferents from secondary vestibular neurons infunctions. The faint gray arrows indicate the other regions MVN. Their axons travel in the lateral wing of theshown in (A) which possibly contribute a weak input (seeUgolini et al., 2005). MLF and are called the ‘‘ascending tract of Deiters’’ (ATD), see Fig. 8 (for a review, see Buttner-Ennever and Gerrits, 2004). It is often ¨1987), and also an inhibitory pathway to the hard to see these ascending fibers in tract tracingtrochlear and inferior rectus motoneurons, which experiments presumably because they are scat-may serve to inhibit the neurons during pursuit eye tered. Single cell reconstructions of three ATDmovements (Partsalis and Highstein, 1996). cells in MVN revealed terminals over the A- and Vestibulo-oculo-collic neurons are widely B-groups of MR motoneurons but none over thespread over MVN and DVN, and possess bifur- MIF motoneurons of the C-group (McCrea et al.,cating axons which project both to the oculomotor 1987b). This finding should be substantiated. Thenuclei and to the spinal cord (Minor et al., 1990). ATD neurons transmit a PVP signal (position-Their axons travel rostrally in the MLF, and cau- vestibular-pause activity, see Chapter 1) to the MRdally mainly in the contralateral MVST. This type motoneurons along with head velocity (Reisineof neuron is not modulated by floccular influences, and Highstein, 1979). More recently, an excitingand therefore plays no role in the floccular adap- study has shown that ATD neurons carry atation the vestibulo-ocular reflex (Hirai and utricular signal combined with a horizontal canalUchino, 1984a; Stanton, 2001). activity, which generated vergence during linear
  • 74. 111acceleration. The size of the utricular signal Rostral interstitial nucleus of the MLFdepended on the viewing distance, implying theexistence of a neural multiplier in the vestibular The burst neurons for vertical and torsional sac-nuclei, and not just a simple disynaptic utricle- cades, which make up all of the medium-sizedoculomotor relay (Chen-Huang and McCrea, neurons within the rostral interstitial nucleus of1998). the MLF (RIMLF), project monosynaptically to the motoneurons of the vertical pulling extraocu- lar eye muscle pairs in the oculomotor and trochl- ear nuclei, see also Chapter 5 (Moschovakis et al.,Paramedian pontine reticular formation 1991a, b; Horn and Buttner-Ennever, 1998). In ¨ very exacting studies three types of burst neuronsThe excitatory burst neurons (EBNs) for horizon- have been found in RIMLF and their terminalstal saccades lie in the nucleus reticularis pontis reconstructed: (1) upward EBNs which fire withcaudalis, and form a cluster of neurons under the upward eye movements, and terminate on the IOMLF just rostal to the abducens nucleus in the and SR motoneurons of III, (2) upward IBNspontine reticular formation (PRF). The neurons which fire with upward eye movements, andare essential for the generation of a horizontal terminate on IR and SO; these may producesaccade (Fuchs et al., 1985; Moschovakis et al., inhibition of these motoneurons in upward gaze,1996). They project monosynaptically onto the and (3) downward EBNs which fire with down-abducens motoneurons, and internuclear neurons, ward saccades, and terminate on IR and SOsee Chapter 5 (Igusa et al., 1980; Langer et al., (Moschovakis et al., 1991a, b). The projections1986; McCrea et al., 1986; Strassman et al., 1986a; from RIMLF to III are mainly ipsilateral, there-Horn et al., 1995). These burst neurons have been fore for conjugate upward saccades, the concom-well characterized anatomically as medium-sized itant activation of the contralateral upwardand parvalbumin-positive both in monkey and muscles, probably takes place via axons crossinghumans (Horn et al., 1995). The cluster of premo- the midline in III (Moschovakis et al., 1996), andtor neurons projecting monosynaptically onto thereby providing an anatomical substrate formotoneurons extend as far rostrally as nucleus Herings law of equal innervation (Moschovakis,reticularis tegmenti pontis (NRTP), where a small 1995).group of premotor neurons form a nest in theNRTP itself (Chapter 5, Fig. 3E, arrow). Theevidence from single cell recordings in PPRF are Interstitial nucleus of Cajalless easy to interpret, they were found to carry amonocular signal to the motoneurons, and often The interstitial nucleus of Cajal (INC) lies imme-the activity was correlated with the activity in the diately adjacent and caudal to RIMLF, further-contralateral LR (Zhou and King, 1998). An more this cytoarchitectural boundary is indistinctexciting finding using transsynaptic tract tracing (Chapter 5). For this reason the studies of Hornshowed that the EBNs overwhelmingly targeted and colleagues, in which histological stainsSIF motoneurons, implying that the MIF moto- are used to differentiate between the two regions,neurons, with slow-tonic characteristics, do not are useful (Horn and Buttner-Ennever, 1998). The ¨directly participate in saccadic eye movements two areas are interrelated in function, both con-(Buttner-Ennever et al., 2002; Ugolini et al., 2005). ¨ trolling the vertical eye position: RIMLF for ver-The same was true for the inhibitory burst neurons tical saccades and INC for vertical gaze-holding,(IBNs), which lie caudal to the EBNs in the dorsal (Fukushima, 1987; Fukushima et al., 1992). Theparagigantocellular nucleus, and innervate mainly INC receives axon collaterals from all secondarythe contralateral VI SIF motoneurons (Langer vestibular neurons that supply III (McCrea et al.,et al., 1986; Strassman et al., 1986b; Scudder et al., 1987a). Descending projections from INC through1988; Robinson et al., 1994; Horn et al., 1995). MLF innervate the ipsilateral oculomotor and
  • 75. 112trochlear nucleus (Kokkoroyannis et al., 1996); spinal cord vestibular ganglion or thalamus: thishowever, the inhomogeneous character of INC rather dramatic result was interpreted to meanleaves doubt as to exactly what type of informa- that there is a specific population of oculomotor-tion is relayed to III or IV (see Chapter 5). projecting NO producing cells in the vestibular nuclei (Kevetter et al., 2000).Nucleus prepositus hypoglossi Supraoculomotor areaAll areas that project to the abducens nucleus alsoproject to the nucleus prepositus hypoglossi (PPH) The term supraoculomotor area (SOA) describes(Belknap and McCrea, 1988; McCrea, 1988). The the part of the periaqueductal gray substancesPPH and the adjacent marginal zone of the medial located immediately above the caudal two-thirdsvestibular nucleus are widely belived to be an of the oculomotor nucleus: laterally it is continu-essential part of the neural integrator for horizontal ous with the mesencephalic reticular formation.eye movements (see Chapters 1 and 7) (McFarland The EW nucleus lies within, or adjacent, to theand Fuchs, 1992; Fukushima and Kaneko, 1995). SOA and the region is closely associated with theThe larger (principal) cells in PPH give rise to control of the near-response (May et al., 1992).widespread projections to the oculomotor cell The afferent inputs to the SOA come from thegroups, including bilateral afferents to the abduc- superior colliculus (Edwards and Henkel, 1978),ens nuclei and the MR subgroups of III (Belknap the deep cerebellar nuclei (May et al., 1992),and McCrea, 1988; McCrea, 1988). The monosy- the pretectum (Buttner-Ennever et al., 1996b), and ¨naptic nature of the PPH input to extraocular the accessory optic nuclei (Blanks et al., 1995).motoneurons has been verified with transsynaptic Direct projections from the frontal and supple-tract tracing, and demonstrates that they contact mentary eye fields to the SOA have also beenMIF, and perhaps SIF, motoneurons (Buttner- ¨ traced (Stanton et al., 1988; Shook et al., 1990), asEnnever et al., 2002; Ugolini et al., 2005). The well as two regions of the cerebral cortex wheremarginal zone is thought to provide the major vergence responses have been recorded (Gamlinoutput of the horizontal integrator, and sends a and Yoon, 2000; Fukushima et al., 2005).massive pathway to the contralateral VI nucleus Premotor neurons encoding vergence have been(Langer et al., 1986; McCrea et al., 1987b). These recorded in the SOA, and laterally in the adjacentefferents are glycinergic (Spencer et al., 1989). MRF, from behaving monkeys (Mays and Porter, Nitric oxide (NO) is a freely diffusible gaseous 1984; Judge and Cumming, 1986; Zhang et al.,molecule that has recently been found to be pro- 1992). The premotor vergence neurons were shownduced in the central nervous system. The localiza- to be a source of the monosynaptic excitatorytion of NO-positive neurons and neuropile mainly drive to MR motoneurons in III during conver-to MVN and PPH suggests pivotal role of this gence (Zhang et al., 1991), and the connection wasregion, since NO has a very short half-life it prob- verified anatomically (Graf et al., 2002). In addi-ably has very local effects. Interestingly, the mar- tion, the SOA projects bilaterally to VI, andginal zone between MVN and PPH in cat, is has been discussed above as OMN-INTs (cat:devoid of NO-releasing neurons but contains Maciewicz et al., 1975a; Maciewicz and Phipps,numerous NO-sensitive neurons (Moreno-Lopez 1983; May et al., 1987; monkey: Langer et al.,et al., 2001). In a series of double-labeling exper- 1986). Recent transsynaptic tracing studies usingiments to determine which functional group of rabies virus have verified the SOA input as mo-vestibular neurons are the NO-producing cells nosynaptic onto abducens motoneurons as well,Kevetter and colleagues showed that virtually all and shown that they have a direct monosynapticcells in the NO-producing cells in caudal MVN input onto the MIF (nontwitch) motoneurons.and DVN could be retrogradely filled from the In primates, both abducens motoneurons andoculomotor nucleus, but not from the cerebellum, internuclear neurons decrease their firing rate
  • 76. 113during convergence (Mays and Porter, 1984; been investigated with several techniques: two re-Gamlin et al., 1989a). Some SOA neurons are gions have been recognized, one lying rostrally andGABAergic and could participate in the inhibition associated with vertical saccades, and a caudal(De la Cruz et al., 1992). A decrease in firing rate MRF area participating in horizontal saccadesof the excitatory ABD-INTs is ‘‘inappropriate,’’ (Waitzman et al., 2000a, b; 2002). The result ofbecause alone it would lead to decreased discharge single unit recordings, electrical stimulation andof MR motoneurons. Therefore, it must be com- inactivation experiments indicate an involvementpensated by a powerful (excitatory) vergence input in combined eye and head movements in the stab-to MR motoneurons. It is possible that the SOA ilization of gaze, the determination of primarymay provide this excitatory signal (Mays and position and saccadic metrics. Anatomically thePorter, 1984). It has been long recognized that MRF is very closely associated with the superiorinternuclear ophthalmoplegia, characterized by colliculus (Cohen and Buttner-Ennever, 1984; Chen ¨damage of the MLF which interrupts the ABD- and May, 2000; Buttner-Ennever et al., 2002) and ¨INT excitatory pathway, is characterized by loss of also to PPRF, NRTP, and the omnipause neuronsconjugate adduction on the side of the lesion, but (Edwards, 1975; personal observation).adduction for vergence is spared. By contrast,certain midbrain lesions lead to vergence deficits,but spare conjugate eye movements (reviewed by PretectumLeigh and Zee, 1999). The connectivity of SOAand its neural activity are indicative of an The nuclei of the pretectum that are associatedimportant, and often underestimated, premotor with oculomotor function are: (1) the nucleus ofrole in vergence. the optic tract (NOT) and (2) the pretectal olive (PON) (see Chapter 12). Unlike lower vertebrates, PON is embedded within NOT in primates. ThisCentral mesencephalic reticular formation region has the connectivity to influence many dif- ferent premotor networks of the oculomotor sys-This region of the reticular formation is part of tem (Chapter 12, Fig. 6) (Buttner-Ennever et al., ¨nucleus cuneiformis (see Chapter 5), and lies 1996a). With respect to direct connections tolateral to III and IV, and medially adjoining the ocular motoneurons, tracer injections into theSOA, has assumed new functional significance pretectum labelled efferent axons crossing in therecently. Rabies virus transsynaptic tracer exper- posterior commissure, and terminating over EWiments have shown somewhat unexpectedly that and the MIF motoneurons of the oculomotor andcMRF has monosynaptic connections to abducens trochlear nuclei (Fig. 7E), but not over the SIFMIF motoneurons (Buttner-Ennever et al., 2002; ¨ motoneurons (Buttner-Ennever et al., 1996b). The ¨Ugolini et al., 2005). As a result a new and exciting projections were verified with transsynaptic tracerspremotor functional role for cMRF is opened up, (tetanus toxin BIIb) injected into medial rectus.a possible contribution to proprioceptive feedback The efferents to the oculomotor complex werecircuits is fully discussed in Chapter 3 (see also Fig. found to arise from the dorsomedial NOT and10 in Chapter 3). Projections of the cMRF to PON. In addition these neuroanatomic experi-MIFs in III have not yet been investigated, but ments confirmed the monosynaptic character ofMRF and the adjacent SOA (see above) are the pretectal projection to MIF motoneurons. Upknown to contain premotor neurons encoding to now the pretectal afferents to the MIF moto-vergence, which have monosynaptic contacts to neurons appears to be their strongest single input.medial rectus motoneurons (Zhang et al., 1991; The function of the pretectal premotor pathway isGraf et al., 2002). The cMRF was orginially unknown; but since vergence premotor neuronsdefined by Cohen et al. (1986) as an area from have been located in the pretectum and MIFwhich horizontal saccades could be evoked by motoneurons tend to be associated with tonicelectrical stimulation. Since then the region has oculomotor functions, the results fit with the
  • 77. 114suggestion that PON and NOT may play a role in The contralateral excitatory afferents fromsome aspects of the near-response, i.e., vergence or secondary vestibulo-ocular neurons in MVN andeye alignment. SVN probably use glutamate and aspartate as transmitter (Dememes and Raymond, 1982), whereas the afferents from the ATD use only glutamate as a transmitter (Nguyen and Spencer,Histochemistry of motoneurons 1999).Transmitters in oculomotor and trochlear nuclei Transmitters in abducens nucleusThe motoneurons in the oculomotor, trochlearand abducens nuclei are cholinergic, as are some In the abducens nucleus identified, abducensneurons in EW nucleus (see Fig. 4 and Chapter 5) internuclear neurons have been shown not to be(Spencer and Wang, 1996; Kus et al., 2003). The cholinergic (Fig. 5D) (Spencer and Baker, 1986;motoneurons of vertical-pulling eye muscles in the Carpenter et al., 1992), but appear to use gluta-oculomotor and trochlear nuclei receive a strong mate and aspartate as transmitters (Nguyen andGABAergic, but a rather weak glycinergic input, Spencer, 1999). The PMT cell groups (see Chapterin contrast to the abducens nucleus which receive a 5) can be identified by the intense choline acetyl-strong glycinergic input from the vestibular nuclei transferase and cytochrome oxidase staining of(De la Cruz et al., 1992). These results have led to their neuropile. We have found the PMT neuronsthe concept that inhibition in horizontal eye move- in primate to be noncholinergic, but there is somement pathways is provided by glycine, while those conflicting reports from studies in rats (Rodellafor vertical eye movement pathways utilize GABA. et al., 1996). In cat, serotonin-immunoreactiveGABAergic afferents to the oculomotor and synaptic contacts were disclosed on the dendritestrochlear nucleus originate from inhibitory sec- of abducens neurons, but the serotoninergic dorsalondary vestibulo-ocular neurons in the ipsilateral raphe nucleus lying above the caudal oculomotorsuperior vestibular nucleus (rabbit: Wentzel et al., nucleus was shown not to be the source of these1995; cat: De la Cruz et al., 1992) and, at least in afferents (May et al., 1987). The abducens nucleusthe cat, from the RIMLF, however, this was not receives a strong supply of glycinergic inhibitorythe case in monkey (Horn et al., 2003). afferents, which originate from IBNs in the cont- In contrast to RIMLF, the medium-sized and ralateral PGD, the PPH and the ipsilateral mediallarge neurons in INC provided crossed GABA- vestibular nucleus (Spencer et al., 1989). Anatom-ergic projections to the downward moving eye ical studies revealed a rather weak GABAergicmuscles SO and IR (Horn et al., 2003). There are input to the abducens nucleus with a slight tenden-conflicting reports about a strong GABAergic cy of motoneurons being more heavily contactedinput to medial rectus motoneurons mediating than internuclear neurons (De la Cruz et al., 1992).horizontal eye movements: some authors did not Nitric oxide (NO) has been discussed abovesee an obvious difference in GABA terminal den- in relation to PPH. Through a known set ofsity between different motoneuron subgroups in interactions it can affect ion channels, also inrabbit and cat (De la Cruz et al., 1992; Wentzel the vestibular complex (Kevetter et al., 2000). Aet al., 1996), whereas a much weaker innervation pharmacological study in the alert cat revealedby GABAergic terminals over MR was observed that the balanced production of NO by PPHin cat and monkey (Spencer and Baker, 1992; is necessary for the correct performance of eyeHorn, personal observation). A possible source for movements (Moreno-Lopez et al., 1996). NO-pro-GABAergic afferents to MR-motoneurons are ducing neurons are prevalent in MVN/DVN, andsmall GABAergic interneurons scattered in and surprisingly are found to be particularly importantabove the oculomotor nucleus in the supraoculo- in vestibulo-ocular pathways (Kevetter et al., 2000;motor area (SOA) (De la Cruz et al., 1992). Saxon and Beitz, 2000). The interplay between NO
  • 78. 115mechanisms in MVN and PPH, including the system is exciting but at present is very difficultmarginal zone, was worked out by Moreno-Lopez to evaluate. For example, some neurotrophinset al. (2001). were found to specifically target extraocular moto- neurons: in the adult cat there is extensive neu- ronal co-expression of neurotrophin receptors, TrkCalcium-binding proteins A, B, and C, in the neurons of the III, IV, and VI nuclei. In all three nuclei, TrkB expression pre-The analysis of different brain regions suggests dominated but the degree of expression varied be-that calcium-binding proteins, such as calbindin tween the three nuclei (Benitez-Temino, 2004). An ˜D-28k, calretinin, or parvalbumin are involved in interesting finding was that abducens internuclearregulating calcium pools critical for synaptic neurons have the same Trk expression pattern asplasticity (Schwaller et al., 2002). Systems using abducens motoneurons, though the two popula-calretinin have been rather well preserved during tions have different targets (Benitez-Temino, ˜vertebrate evolution, and are found in oculomotor 2004). Since both neuron types have similar affer-neurons in bony fish (Diaz-Regueira and Anadon, ent inputs, the authors pointed out, that the2000). Motoneurons in III, IV, and VI express afferents could be a factor that determined theparvalbumin immunoreactivity (De la Cruz et al., expression of Trk receptors and not the target cells1998). In internuclear neurons at least 80% con- — the theory favored by most at present. Thetain a different calcium-binding protein, calretinin, results are in line with other findings, wherewhich could serve as a histological marker for specific GDNF factors were selective for specificinternuclear neurons in cat, but this may be muscle motoneuron circuits, for example, gfralpha1different in other species (De la Cruz et al., 1998). and gfralpha2 were only expressed in III and IV but Parvalbumin first appears in rats at embryonic not in the abducens nucleus (Mikaels et al., 2000).day 13 in the oculomotor (III, IV, VI), vestibular However, there is contrasting evidence indicatingand the trigeminal system and the sensory system that the target cells can regulate the Trk expression:of the spinal cord, and develops rapidly during the the trophic support from brain-derived neurotrophinfollowing days. In these locations the expression of factor (BDNF) for the oculomotor and trochlearparvalbumin was found to coincide with the neurons was shown to be derived from their targetsbeginning of physiological activity in nerve cells (Steljes et al., 1999).(Solbach and Celio, 1991). In the cerebral cortex In contrast to developing neurons (Chen et al.,and hippocampus, as well as in the Purkinje cells 2003), mature motoneurons do not depend onof the cerebellum, parvalbumin only appeared neurotrophins as survival factors, but rather aspostnatally. Although it has been suggested that regulators of multiple functional properties, suchcalcium-binding proteins could act as major as membrane excitability (Gonzalez and Collins,endogenous neuroprotectants, the hypothesis has 1997; Yamuy et al., 1999), synaptic inputnot been generally supported (Schwaller et al., 2002). (Novikov et al., 2000), and plasticity (McAllisterHowever, a disruption of the calcium-signaling et al., 1999). Since the co-expression of multiplecascade in mutant mice leads to severe deficits in neurotrophin receptors in the same neuronal typesynaptic transmission and in cerebellar motor is not limited to oculomotor neurons but presentcontrol (Barski et al., 2003). in various brain regions (e.g., in the trigeminal system; see Jacobs and Miller, 1999), this indicatesOther factors (neurotrophins, membrane receptors, a role, broader than oculomotor function. Oneetc.) possibility raised by these findings is that each neurotrophin receptor regulates independently, orThe screening of the brainstem for specific growth in concert with each other, multiple aspects ofor transcription factors has lead to a wealth of neuronal physiology.detailed properties of the extraocular motoneurons. Other studies report a particular associationTheir significance with regard to the oculomotor between extraocular motoneurons and specific
  • 79. 116membrane properties: for example, the Slack EOM extraocular musclespotassium channel (Bhattacharjee et al., 2002), or HC horizontal canalthe membrane proteins cadherins, important for IBN inhibitory burst neuronsadhesive mechanisms (Heyers et al., 2004). A INC interstitial nucleus of Cajaldifferential distribution was reported for the INO internuclear ophthalmoplegiaexpression of synaptosomal-associated protein IO inferior oblique muscleSNAP 25 involved in the molecular regulation of LP levator palpebrae superiorisneurotransmitter release, where two isoforms, LR lateral rectus musdeSNAP 25a and SNAP 25b, were demonstrated in Med RF medullary reticular formationEW and III, respectively (Jacobsson et al., 1999). MIF multiply innervated muscle fiberFinally, the use of transgenic mice as models for (nontwitch)the effects of diseases, such as progressive motor MLF medial longitudinal fasciculusneuropathy or ALS, on extraocular motoneurons MR medial rectus muscleare highly promising (Haenggeli and Kato, 2002). MVNm medial vestibular nucleus parsThe above section highlights only a few of the magnocellularcurrent studies, but from these it is clear that the MVNp medial vestibular nucleus parsbehavior of motoneurons in the oculomotor nuclei parvocellularis influenced by many more factors than premotor NOT nucleus of the optic tractinnervation alone. NRTP nucleus reticularis tegmenti In conclusion, the rapid advances in our knowl- pontisedge of extraocular motoneurons has enabled NIII oculomotor nervedifferent types of motoneurons to be identified, NVI abducens nerveMIFs and SIFs. Their premotor inputs clearly OMN-INT oculomotor internuclear neurondiffer, but the function of MIF motoneurons is PC posterior canalnot yet clear. A role of MIF motoneurons in gaze- PMT paramedian tract (cell groups)holding or eye alignment, their dysfunction in PON pretectal olivary nucleuscases of strabismus or, together with palisade PPH nucleus prepositus hypoglossiendings, a role in proprioception are all possibil- PPRF paramedian pontine reticularities that can be tested in the future. formation PRF pontine reticular formationAbbreviations RBM retractor bulbi muscles RIMLF rostral interstitial nucleus of theIII oculomotor nucleus MLFIV trochlear nucleus SIF singly innervated muscle fiberVI abducens nucleus (twitch)ABD-INT abducens internuclear neurons SO superior oblique muscleAC anterior canal SOA supraoculomotor areaAC-VI accessory abducens nucleus SR superior rectus muscleAM anteromedian nucleus SVNm superior vestibular nucleus, parsATD ascending tract of Deiters parvocellularisCCN central caudal nucleus of IIICVT crossing ventral tegmental tractcMRF central mesencephalic reticular formationDPG dorsal paragigantocellular Acknowledgments reticular formation (IBNs)EBN excitatory burst neuron This study is supported by a grant from theEW Edinger–Westphal nucleus Deutsche Forschungsgemeinschaft (Ho 1639/4-1).
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  • 89. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 5 The reticular formation Anja K.E. Hornà Institute of Anatomy, Ludwig-Maximilian University of Munich, Pettenkoferstrasse 11, 80336 Munich, GermanyAbstract: The reticular formation of the brainstem contains functional cell groups that are important forthe control of eye, head, or lid movements. The mesencephalic reticular formation is primarily involved inthe control of vertical gaze, the paramedian pontine reticular formation in horizontal gaze, and the med-ullary pontine reticular formation in head movements and gaze holding. In this chapter, the locations,connections, and histochemical properties of the functional cell groups are reviewed and correlated withspecific subdivisions of the reticular formation.Introduction The medial tegmental field contains the premotor circuitry for eye and head movements, and givesThe reticular formation has no distinct cytoarchi- rise to descending pathways involved in posturaltectural boundaries and forms the central core of orientation. In this chapter, only the brainstemthe brainstem extending from the mesencephalon nuclei involved in the generation of eye and headthrough the pons to the medulla oblongata (Fig. 1). movements and gaze holding and together withOther brainstem nuclei, with clearly outlined cyto- their functional neuroanatomy are described.architectural boundaries, such as the red nucleus Over the last years much progress has been(RN) or nucleus reticularis tegmenti pontis made in the identification and characterization of(NRTP) are embedded in this core. There are eye and head movement-related functional cellsubtle regional differences in the brainstem reticular groups within the reticular formation. Their con-formation cytoarchitecture, leading Jerzy Olszewski nectivity has been studied by single cell recordingand his colleagues to subdivide it into nuclei, in behaving animals and with tract tracing tech-which are still useful today (Olszewski and Baxter, niques. Five main categories of functional neurons1982). The reticular formation of the pons and associated with eye or head movements are iden-medulla can be divided into lateral and medial tified in the reticular formation. An extensivetegmental fields (Holstege, 1991). The lateral description of the physiology of eye-/or head-tegmental field contains smaller cells that are in- movement-related neurons is given in Chapter 1.terneurons, or premotor neurons, for the trigemi-nal, facial, vagal, and hypoglossal motor nuclei 1. Short-lead burst neurons: Burst neuronsand involve control of limbic functions. In addi- deliver high-frequency bursts of activitytion, it houses the premotor neurons with long shortly before and during saccadic eye move-descending axons to motor neurons of the spinal ments, but are otherwise silent during fixationcord involved in respiration, abdominal pressure, and slow eye movements (for review, seemicturition, and blood pressure (Holstege, 1991). Scudder and Kaneko, 2002). Based on their preferred saccade directions they can be di- vided into horizontal, upward, and down-ÃCorresponding author. Tel.: +49 89 5160 4880; ward burst neurons. Furthermore, theseE-mail: groups are subdivided into excitatory (EBN)DOI: 10.1016/S0079-6123(05)51005-7 127
  • 90. 128Fig. 1. Sagittal view of a monkey brainstem showing the localization of oculomotor-related nuclei within the reticular formation. Theshaded regions are subregions containing premotor neurons for vertical eye movements the rostral interstitial nucleus of the mediallongitudinal fascicle (RIMLF) and the interstitial nucleus of Cajal (INC) and the pontine paramedian reticular formation (PPRF) forhorizontal eye movements. The numbered lines indicate the planes of transversal sections shown in Figs. 2–5. and inhibitory (IBN) burst neurons 3. Omnipause neurons (OPNs): Saccadic OPNs (Moschovakis et al., 1996). The IBNs show act as triggers for the initiation of saccadic the same activity pattern as the EBNs eye movements in all directions (Luschei and (Hikosaka et al., 1978; Yoshida et al., 1982; Fuchs, 1972; Evinger et al., 1982; Strassman Strassman et al., 1986b). Premotor EBNs and et al., 1987; Moschovakis et al., 1996; IBNs for upward and downward saccades are Scudder and Kaneko, 2002). During fixation located in the mesencephalic reticular forma- and slow eye movements, the OPNs discharge tion and those for horizontal saccades in the at high firing rates exerting a tonic inhibition pontine reticular formation. on premotor burst neurons, IBNs, and EBNs 2. Long-lead burst neurons (LLBNs): LLBNs (Figs. 6 and 7) (Nakao et al., 1989, 1991; include an additional group of saccade-related Ohgaki et al., 1989). Only shortly before and burst neurons. They are characterized by a during a saccade are the OPNs inhibited, longer latency between the onset of the sac- thereby releasing the inhibition from premo- cade and the saccade-related burst, which is tor burst neurons and enabling an activation often preceded by an irregular, low-frequency of the extraocular motoneurons to perform a activity (Hepp et al., 1989; Moschovakis et al., saccade (for review, see Moschovakis and 1996). On the basis of their location, projec- Highstein, 1994; Scudder and Kaneko, 2002). tion targets, and postsynaptic action, several 4. Burst-tonic neurons: Burst-tonic neurons are subclasses of LLBNs have been described, represented, for example, by the motoneurons e.g., pontine LLBNs, medullary LLBNs, of extraocular muscles (see Chapter 4). They burster driving neurons, reticulo-spinal neu- exhibit high-frequency bursts that are rons (RSNs), reticulo-tectal LLBNs, precere- proportional to the amplitude of the saccade bellar LLBNs, tectal LLBNs (Moschovakis in their on-direction, and a tonic activity et al., 1996). Those in other regions are not whose frequency is related to the new considered here. eye-position.
  • 91. 129 5. Tonic neurons: Tonic neurons discharge with physiological experiments indicate that premotor a frequency related to an eye position. These up- and down-burst neurons within each RIMLF units are thought to mediate the integration are intermingled (Buttner et al., 1977; Crawford ¨ of eye velocity signals from burst neurons to and Vilis, 1992; Horn and Buttner-Ennever, ¨ eye position signals in extraocular motoneu- 1998b). In cats, the RIMLF may also be involved rons (Moschovakis et al., 1996). They are in the coordination of eye and head movements found, for example, in the nucleus prepositus (Isa et al., 1992b). hypoglossi (PH) (see Chapter 7) and intersti- The RIMLF lies in the mesencephalic reticular tial nucleus of Cajal (INC), both nuclei formation and forms the medial part of the H known to participate in integrator function fields of Forel (Figs. 1 and 2A and B). In trans- (Fukushima et al., 1992). verse sections, it forms a wing-shaped nucleus ventromedial to the third ventricle and borders the Attempts have been made to characterize the parvocellular portion of the red nucleus (RN)functional cell groups of the oculomotor system dorsomedially (Fig. 2A). The RIMLF adjoinshistochemically in the monkey (Horn et al., 1994, directly the rostral end of the INC from which it1995, 2000; Horn and Buttner-Ennever, 1998b). ¨ is separated by the traversing fibers of the fa-Based on their location, cytoarchitecture, and sciculus retroflexus (TR). Its rostral end is roughlyhistochemical properties, e.g., cytochrome oxidase demarcated by the traversing fibers of theactivity, acetylcholine esterase activity, expression mamillo-thalamic tract (MT) (Buttner-Ennever ¨of calcium-binding proteins, their homologous cell and Buttner, 1988b). In transverse sections, the ¨groups could be identified in humans as well posterior thalamo-subthalamic artery (star) serves(Paxinos and Huang, 1995; Buttner-Ennever and ¨ as a helpful landmark, which borders the RIMLFHorn, 2004; Koutcherov et al., 2004). dorsomedially like an eyebrow (Fig. 2B) (Buttner- ¨ An overview of the current knowledge on the Ennever et al., 1982). The RIMLF is composed oflocation, connections, and histochemical proper- several morphological cell types, enclosing small-ties of functional cell groups of the eye and head to medium-sized neurons, which are embedded inmovement system and their association with the fibers of the medial longitudinal fasciculuscertain reticular brain nuclei will be given in the (MLF), resulting in its reticulated appearancefollowing sections. (Crossland et al., 1994).Mesencephalic reticular formation Connections. The burst neurons of the RIMLF were shown to project monosynaptically to theBrainstem regions motoneurons of the vertical pulling extraocular eye muscles in the oculomotor and trochlear nucleiRostral interstitial nucleus of the medial longitudinal predominantly of the ipsilateral side (Moschovakisfascicle et al., 1991a, b; Wang and Spencer, 1996b; HornThe rostral interstitial nucleus of the medial and Buttner-Ennever, 1998b). Single-cell studies in ¨longitudinal fasciculus (RIMLF) contains the pre- the squirrel monkey propose a bilateral projectionmotor burst neurons, which are essential for the of upward burst neurons to the INC, the adjacentgeneration of vertical and torsional saccades mesencephalic reticular formation, and the oculo-(Buttner et al., 1977; Vilis et al., 1989; Crawford ¨ motor nucleus (Moschovakis et al., 1991a). Aand Vilis, 1992). From recording studies in the purely ipsilateral projection arises from downwardmonkey the current concept is put forward: the burst neurons in the RIMLF to the INC andright RIMLF contains up- and down-burst oculomotor and trochlear nucleus (Fig. 6)neurons with a clockwise torsional component, (Moschovakis et al., 1991b). Additional targetsand the left RIMLF up- and down-burst neurons are the RIMLF of the contralateral side, the para-with a counterclockwise torsional component median tract (PMT) neurons (see below), and(Crawford and Vilis, 1992). Anatomical and sparsely the spinal cord (Holstege and Cowie,
  • 92. 130Fig. 2. Drawings of transverse sections through the mesencephalic reticular formation taken from the levels indicated in Fig. 1A andG. The rectangles indicate the area shown in the magnifications seen on the right side in B and H. Parvalbumin (PV)-immunolabelinghighlights the RIMLF and the adjacent M-group within the mesencephalic reticular formation (B). A detailed view of PV labeledneurons revealed that those in the RIMLF are elongated (D), whereas those in the M-group are round (C). Neighboring semithinsections of presumed premotor burst neurons in the RIMLF, showing a strong input by GABAergic (E) and glycinergic (F) afferents(arrows). PV-labeling delineates the interstitial nucleus of Cajal (INC) from the adjacent nucleus Darkschewitsch (ND) and nucleusBechterew (NB). High-power photographs of a medium-sized neuron in INC containing PV (I) and a smaller neuron expressingglutamate decarboxylase (GAD) as a marker for GABA (K). Scale bars: A, G: 2 mm; B, H: 500 mm; C–F, I, K: 20 mm.
  • 93. 1311989; Moschovakis et al., 1991a, b; Wang and tracing studies revealed that it in addition projectsSpencer, 1996b). From anatomical and recording strongly to the motoneurons of the levator palpe-studies, the saccadic premotor burst neurons in the brae muscle, which elevates the upper eyelidmacaque monkey are considered all excitatory (see (Porter et al., 1989; Horn et al., 2000). In the pri-below), unlike in cats, where a considerable pop- mate, the M-group lies immediately medial to theulation of inhibitory premotor neurons is found in caudal third of the RIMLF as part of the centralthe RIMLF (see below) (Spencer and Wang, gray of the third ventricle (Fig. 2A and B), whereas1996). Only in squirrel monkey were a few in cats the homolog premotor neurons were foundup-burst neurons in the RIMLF identified as within the medial RIMLF (Chen and May, 2002).inhibitory, based on their projection targets in the Unlike the RIMLF, the M-group of the primate isoculomotor and trochlear nuclei, the motoneurons composed of densely packed round cells, which areof the inferior rectus (IR), and superior oblique indistinguishable from the cells of the central gray(SO) muscles (Moschovakis et al., 1991a, 1996). In in Nissl-stained sections (Fig. 2C; Horn et al.,contrast to the excitatory up-burst neurons in the 2000). Till date no systematic recording studiesRIMLF, these presumed inhibitory up-burst have been performed on these neurons, but basedneurons have recurrent collaterals supplying the on its connections (see below) a role in eye–lidRIMLF. coordination during upgaze is most likely (Horn The burst neurons in the RIMLF receive a et al., 2000; Horn and Buttner-Ennever, 2002). ¨strong input from the inhibitory, glycinergic OPNsfrom the nucleus raphe interpositus (RIP) within Connections. Anterograde tract-tracing experi-the pontine reticular formation (Horn et al., 1994), ments revealed that the M-group projects notwhich prevents the burst neurons from firing dur- only to the levator palpebrae motoneurons in theing fixation and slow eye movements. In addition, central caudal nucleus, but also to the ipsilateralthe RIMLF receives afferents from the INC and motoneurons of the superior rectus (SR) andthe deep layers of the superior colliculus (SC) inferior oblique muscle (10), which elevate the(Moschovakis et al., 1988b; Nakao et al., 1990; eye (see Chapter 4; Porter et al., 1989). In addition,Kokkoroyannis et al., 1996). A minor projection a weak projection to the motoneurons of thefrom the medial vestibular (MV) nucleus targets frontalis muscle in the dorsal part of the facialmainly the mediocaudal part of the RIMLF (Fig. nucleus was noted, which also participates in ex-6) (Buttner-Ennever and Lang, 1981; Matsuo ¨ treme upgaze (Welt and Abbs, 1990). Parvalbuminet al., 1994; Horn and Buttner-Ennever, 1998a). ¨ (PV) immunoreactive fibers running between the In cats, the RIMLF and the area ventral to it RIMLF and the M-group indicate a connectioncontains premotor neurons with projections to the between both nuclei, and it is suggested that themotoneurons of dorsal neck muscles (RSNs), M-group receives a copy of the burst signal fromwhich may participate in the control of eye–head the upward burst neurons of the adjacent RIMLFor only head movements in this species (Isa et al., via (PV immunoreactive) collaterals and carries it1992a, b; Isa and Sasaki, 2002). In the monkey, to the motoneurons of the levator palpebrae mus-spinal projecting neurons were only found in the cles thereby coupling the lid movements to upwardadjacent mesencephalic reticular formation, but eye movements (Sibony and Evinger, 1998; Hornnot within the RIMLF (Robinson et al., 1994). et al., 2000). Like the adjacent RIMLF, the M- group receives afferent projections from the medial part of the deep layers of the SC, which encodeM-group upward saccades (see Chapter 11) (Robinson,Only recently was a small cell group of premotor 1972; Moschovakis, 1996), from the INC and fromneurons identified in the rostral mesencephalon of the MV nuclei. Unlike the RIMLF, the M-groupthe monkey by retrograde transsynaptic tracing does not receive afferents from the lateral part of thefrom extraocular eye muscles, which was termed SC, which encodes downward saccades, and theM-group (M) (Horn et al., 2000). Anterograde saccadic OPNs (Horn and Buttner-Ennever, 1998a). ¨
  • 94. 132Interstitial nucleus of cajal of small- to medium-sized neurons with few large-The INC participates in vertical and torsional eye sized multipolar cells intermingled (Carpenter andmovements similar to RIMLF, but the INC serves Peter, 1970; Bianchi and Gioia, 1991) and lies justan integrator function for vertical and torsional beneath the nucleus of Darkschewitsch (ND),eye movements contributing more to vertical gaze which contains more densely packed elongatedholding rather than the generation of eye move- spindle-shaped strongly Nissl-stained cellsments (see Chapter 1) (Fukushima et al., 1992). In (Olszewski and Baxter, 1982; Bianchi and Gioia,monkeys and humans a role in head coordination 1990). Unlike earlier assumptions the ND is nothas been shown (Fukushima, 1987), but this role is directly involved in eye-movement pathways, butquestioned by Robinson et al. (1994), since the is more closely related to the inferior olive,INC does not project strongly to motoneurons substantia nigra, and zona incerta (ZI) (Spenceof the neck muscles (Robinson et al., 1994; and Saint-Cyr, 1988; Ondodera and Hicks, 1998).Kokkoroyannis et al., 1996). There are reportsfavoring the rostral part of the central mesence-phalic reticular formation (CMRF) adjacent to the Connections. There are three main efferent pro-INC as integrator for head movements, because jection systems leaving the INC (Kokkoroyannisof its extensive projections to the spinal cord et al., 1996): the ascending system has strong pro-(Robinson et al., 1994; Kokkoroyannis et al., jections to the ipsilateral mesencephalic reticular1996). The INC contains several functional cell formation including the RIMLF and ZI, whichgroups related to eye movements: burst-tonic, tonic, was shown to contain saccade-related pause neu-saccade-related burst neurons, burster-driving rons (Ma, 1997). Weaker projections were foundneurons (BDNs), and vestibular neurons reflected to the ipsilateral centromedian and parafascicularin variable cytoarchitecture, large cells caudally thalamic nuclei and bilateral to the mediodorsal,and smaller cells rostrally (for review, see Fukushima central medial, and lateral nuclei of the thalamus.and Fukushima, 1992; Helmchen et al., 1996b): Second, the descending system projects throughburst-tonic and tonic neurons encode the eye the MLF and innervates the ipsilateral oculomotorposition and they are involved in the vertical in- and trochlear nucleus, the ipsilateral paramediantegrator function (for review, see Fukushima et al., pontine reticular formation (PPRF), medullary1992). At least one-third of eye-movement-related midline cell groups that belong to the PMT groupsneurons within the INC are saccade-related burst (see below; Buttner-Ennever et al., 1989; Buttner- ¨ ¨neurons (Helmchen et al., 1996b). Unlike tonic Ennever and Horn, 1996). Further, descendingand burst-tonic neurons, they do not project to projections terminate in the vestibular nuclei, themotoneurons of extraocular muscles, but are prepositus hypoglossal nucleus, the gigantocellularthought to relay an inhibitory feedback signal to portion (NRG) of the medullary reticular forma-the RIMLF (Moschovakis et al., 1991b, 1996). In tion, which mediates head movements (Cowie et al.,the INC and the adjacent reticular formation lat- 1994; Cowie and Robinson, 1994), the inferioreral to it in cats BDNs were identified (Fukushima olive, and the ventral horn of C1–C4 (Holstege,et al., 1991). Other neurons apparently participate 1988; Holstege and Cowie, 1989). The commis-in eye–head movements in the vertical and sural fibers of the INC project via the posteriortorsional planes, since stimulation of the INC commissure (PC) to the nucleus of the posteriorresults in an ipsilateral ocular tilt reaction consist- commissure (NPC), the contralateral INC, and theing of an ipsilateral head tilt, with compensatory contralateral oculomotor and trochlear nuclei toeye movements (Westheimer and Blair 1975; innervate only the motoneurons of vertical pullingFukushima et al., 1986; Lueck et al., 1991). eye muscles (Kokkoroyannis et al., 1996). In The INC lies within the MLF as a rather well- addition, the INC receives inputs from premotorcircumscribed nucleus in the mesencephalic reticular neurons that encode eye or head velocity signals,formation lateral to the rostral pole of the e.g., from secondary vestibulo-ocular neuronsoculomotor nucleus (Fig. 2G and H). It consists (Iwamoto et al., 1990) and from the Y-group of
  • 95. 133the vestibular nuclei (for review, see Leigh and Buttner-Ennever, 1984; Chen and May, 2000), with ¨Zee, 1999). reciprocal connections back to the SC (Moschovakis et al., 1988a, b; Chen and May, 2000). Intracellular and bulk tracing studies revealed descendingCentral mesencephalic reticular formation projections to areas referred to as the nucleusA specific area of the mesencephalic reticular for- raphe pontis (RP) and obscurus, the paramedianmation lateral to the oculomotor nucleus has been reticular nucleus, and the intermediate interstitialdistinguished on account of its involvement in the nucleus of the MLF, which all must be considered ascontrol of saccades, and was designated as CMRF PMT neurons (see below) (Buttner-Ennever, 1992). ¨(for review, see Cohen et al., 1986). Stimulation in Afferents also targeted the nucleus raphethis region induces contralateral saccadic eye interpositus (RIP), the paragigantocellular nucleusmovements, whereby small saccades are induced (PGD), the prepositus nucleus (PH), the nucleusfrom stimulation dorsally, and gradually larger reticularis gigantocellularis (NRG), and the spinalsaccades more ventrally (Cohen et al., 1986). These cord (Robinson et al., 1994; Scudder et al., 1996a).different CMRF areas receive afferents from cor- Recent transsynaptic tracing studies in monkeysresponding small and large saccade areas of the SC revealed direct projections exclusively from the(Cohen and Buttner-Ennever, 1984). Recording ¨ horizontal-saccade-related caudal CMRF to ab-studies in the mesencephalic reticular formation ducens motoneurons innervating multiply inner-revealed two subregions containing neurons with a vated presumed nontwitch fibers of the laterallow-frequency, long-latency discharge before sac- rectus muscle (Buttner-Ennever et al., 2001). ¨cades (Waitzman et al., 2000a, b) that may in part Additional afferents to CMRF arise from thebe identical with the reticulo-tectal LLBNs PPRF (Buttner-Ennever and Henn, 1976), and in ¨described by Moschovakis et al. (1988b, 1996): a the light of more recent research CMRF efferentsventrocaudal region lateral to the oculomotor are seen to project to the OPNs in RIP (Buttner- ¨nucleus corresponding to the CMRF proper Ennever, personal observation). Independent trac-(CMRF) or nucleus subcuneiformis contains er experiments showed that the CMRF containsneurons that discharge before saccades with a neurons that project to the oculomotor nucleuscontraversive horizontal or downward oblique and the cervical spinal cord (C2), although it wascomponent (Fig. 2G). Neurons in a more rostral not shown whether these were the same neuronssubregion (CMRF-r) lateral to the INC were most (Robinson et al., 1994).sensitive to contraversive oblique and verticalsaccades (Fig. 3A and C) (Scudder et al., 1996a;Handel and Glimcher, 1997). The functional role Nucleus of the posterior commissureof CMRF in gaze control is not clear, but three The NPC lies rostrally to the deep layers of thedifferent hypotheses have been put forward: colliculus superior and is closely associated with(1) saccade triggering; (2) a feedback system the fibers of the PC (Fig. 3A and B). Based on theinforming the SC about dynamic changes in gaze; cytoarchitecture and relationship to the fibers ofand (3) a feedforward system from the SC to the PC, five different cell groups were identified inpontine gaze centers. A role as integrator for head the NPC of monkeys and humans (Kuhlenbeckmovements is also suggested (Robinson et al., and Miller, 1949; Carpenter and Peter, 1970): the1994) and it is possible that the BDNs lateral to INC principal part, the medially adjacent magnocellu-are located within the rostral CMRF (Fukushima lar part, which borders on the periaqueductal gray,et al., 1991). It may well be that there are multiple and the rostral, the subcommissural, and thefunctions connecting this region with cell popula- infracommissural parts, which all lie within thetions supporting several different functions. periaqueductal gray. Usually, in the oculomotor literature NPC refers to the two largest groups, theConnections. The CMRF has been shown to be magnocellular and principle parts. All partsa major target for SC output (Cohen and consist of small- and medium-sized neurons; only
  • 96. 134Fig. 3. Drawings of transverse sections through the midbrain taken from the levels indicated in Fig. 1A and D. The rectangles indicatethe area shown in the magnifications seen on the right side (B, C, E). Parvalbumin (PV)-labeling delineates the nucleus of the posteriorcommissure (NPC). Numerous small and large multipolar PV-positive neurons are embedded in a strongly stained neuropil (B). Agroup of PV-positive neurons is located lateral to the oculomotor nucleus (III) and dorsal to the red nucleus (RN), which correspondsto the central mescencephalic reticular formation (CMRF). Detailed view of the NRTP in a Nissl-stained section demonstrating itscytoarchitecture (E). The open arrow points to the region where tracer-labeled premotor neurons were found (F). The small arrows inE point to an area where floccular-projecting neurons are found that are included in the paramedian tract neurons. In addition, thesePMT neurons express cytochrome oxidase (G; arrows). Scale bars: A, E: 2 mm; B, C, E, G: 500 mm; F: 20 mm.
  • 97. 135in the magnocellular part large cells are of the monkeys and humans (Fig. 2D) (Horn andpredominant type (Bianchi and Gioia, 1993). Buttner-Ennever, 1998b; Horn et al., 2003a). ¨ Recording experiments in the macaque monkey Anatomical studies in the RIMLF of the catrevealed neurons in the NPC that fire with upward revealed the presence of GABA-immunoreactivesaccades. Unlike the burst neurons in the RIMLF neurons within the dorsomedial part, which projectthese saccade-related NPC neurons do not project to the oculomotor nucleus (Spencer and Wang,to motoneurons of extraocular eye muscles, but 1996). In contrast, the RIMLF of the monkeytarget neurons in the contralateral NPC, the INC, contains only few small GABA-immunoreactivethe RIMLF, and intralaminar thalamic nuclei. neurons that are not premotor burst neuronsThey are thought to play a role in modulating the (Carpenter et al., 1992; Horn et al., 2003b). Invertical gaze integrator (Moschovakis et al., 1996). addition, the RIMLF is devoid of glycine-positive neurons (Horn, personal observations) implyingConnections. Fibers of the magnocellular part of that in the primate the RIMLF does not containthe NPC project through the ventral part of the any premotor inhibitory burst neurons (IBNs).PC to the contralateral INC, the magno- Presumed premotor burst neurons in the RIMLFcellular part of the NPC, the RIMLF, and the receive a strong innervation by GABA- and glycine-supraoculomotor area, the region immediately immunoreactive terminals (Fig. 2E and F), the latterdorsal to the oculomotor nucleus (Carpenter possibly derived from the OPNs in the RIP (Hornet al., 1970; Buttner-Ennever and Buttner, 1988b; ¨ ¨ et al., 1994). GABAergic afferents could arise fromGrantyn, 1988). In addition, descending fibers saccade-related burst neurons in the INC, whichterminate in the PPRF, but sparsely in the spinal do not project to eye muscle motoneurons (Fig. 6)cord at cervical levels (Benevento et al., 1977; (Helmchen et al., 1996b; Moschovakis et al.,Holstege, 1988; Satoda et al., 2002). The NPC has 1996).reciprocal connections with the SC, and receives a The M-group can be outlined by its high contentstrong input from the frontal eye fields of the of COX and PV, mainly in the neuropil (Fig. 2B)cortex and the dentate nucleus of the cerebellum (Horn et al., 2000). Prominent PV immunoreactive(Leichnetz, 1982; Sugimoto et al., 1982; Grantyn, fibers running between the M-group and RIMLF1988; Stanton et al., 1988). imply a connection between both nuclei. As the adjacent RIMLF, the M-group does not contain GABAergic neurons, but unlike the RIMLF, theHistochemistry of the mesencephalic reticular neurons of the M-group are not ensheathed byformation perineuronal nets (Horn, personal observations). The INC is outlined by its high PV content orRecent work in monkeys and humans showed that COX activity, and thereby sharply separated fromthe RIMLF is delineated within the mesencephalic the dorsally adjacent ND, which exhibits much lessreticular formation by its strong cytochrome oxidase PV immunoreactivity (Fig. 2H) (Horn and(COX) activity and parvalbumin (PV) expression Buttner-Ennever, 1998b). The PV expression is ¨(Fig. 2B) (Horn and Buttner-Ennever, 1998b; Horn ¨ confined to medium- and large-sized neurons in theet al., 2000). Combined anterograde tracing and INC (Fig. 2I), some of which are projection neu-immunocytochemical methods indicate that the pre- rons to the motoneurons of vertical extraocular eyemotor burst neurons in the RIMLF use aspartate or muscles, presumed premotor burst-tonic neuronsglutamate as transmitter (Fig. 6) (Spencer and (Horn and Buttner-Ennever, 1998b). With in situ ¨Wang, 1996). In addition, most, if not all, premo- hybridization methods and immunocytochemistrytor neurons contain the calcium-binding proteins a considerable number of small- and medium-sizedPV and calretinin, and they are ensheathed by GABAergic neurons were found in the INC ofprominent perineuronal nets as revealed by Wisteria monkeys (Fig. 2K (Horn et al., 2003b). Combinedfloribunda agglutinin-binding and chondroitin tracing experiments revealed that motoneuronssulfate proteoglycan-immunohistochemistry in of at least the IR muscle in the oculomotor
  • 98. 136nucleus receive a projection from medium-sized 1996a). Bilateral RIMLF lesions result in a com-GABAergic neurons of the contralateral INC, and plete vertical gaze paralysis, but vertical gaze hold-a non-GABAergic projection from smaller neu- ing, vestibular eye movements and pursuit arerons in the ipsilateral INC (Horn et al., 2003b). preserved, as are horizontal saccades (for review,Some GABAergic neurons in the INC may repre- see Kompf et al., 1979; Suzuki et al., 1995; Leigh ¨sent nonpremotor saccade-related burst neurons, and Zee, 1999). In patients, a rare pure isolatedwhich would provide an inhibitory feedback signal downgaze paralysis can be observed only afterto the RIMLF (see Fig. 6) (Helmchen et al., 1996b; discrete bilateral lesions of the RIMLF, whereas aMoschovakis et al., 1996). In addition, the INC combined up- and downgaze paralysis is seen aftercontains many GABA-immunoreactive terminals, unilateral RIMLF lesions, often but not alwayssome of which could arise form collaterals of the involving lesions of the PC (Christoff, 1974;inhibitory secondary vestibulo-oculomotor projec- Cogan, 1974; Trojanowski and Lafontaine, 1981;tions from the ipsilateral superior vestibular Buttner-Ennever et al., 1982; Pierrot-Deseilligny ¨nucleus, which were shown to be GABAergic et al., 1982; Ranalli et al., 1988; Helmchen et al.,(Fig. 6) (De la Cruz et al., 1992). 1996a; Riordan-Eva et al., 1996). The neuroana- The CMRF lacks distinctive boundaries, but the tomical basis for up- and downgaze paralysis issaccade-related region lies caudal and ventral to still not understood. Whereas in cats premotorthe PC and overlaps the rostral portion of nucleus upgaze neurons tend to lie more caudally andsubcuneiformis in monkeys (Waitzmann et al., downgaze neurons rostrally (Wang and Spencer,1996). With PV immunostaining an area lateral to 1996b), the premotor burst neurons for up- andthe INC is outlined by its presence of immuno- downgaze are intermingled within the RIMLF ofstained neurons, which corresponds to the location the monkey (Buttner et al., 1977; Moschovakis ¨of the CMRF (Fig. 3C). There is evidence sup- et al., 1991a, b; Horn and Buttner-Ennever, ¨porting the GABAergic nature of some neurons 1998b). Based on their anatomical work in catswithin CMRF (Chen and May, 2000). showing that both excitatory and inhibitory inputs The NPC has a moderate acetylcholine esterase arise from an RIMLF region and establishactivity (Paxinos and Huang, 1995). The high PV monosynaptic connections with the same moto-content of numerous medium-sized neurons and neuron subgroups ipsilaterally, the intermingling ofthe neuropil delineates the NPC from the deep premotor burst neurons was assigned to theirlayers of the SC (Fig. 3B). It contains GABAergic different postsynaptic actions (Spencer and Wang,neurons that project to the SC in the cat (Appell 1996; Wang and Spencer, 1996a). Since in monkeysand Behan, 1990). there is no evidence for inhibitory premotor burst neurons within the RIMLF (Horn et al., 2003b), a separation of the output pathways for upward andLesions — clinical data downward saccades must be considered as cause for the dichotomy of a vertical gaze palsy inA general feature of lesions within the rostral primates (Pierrot-Deseilligny et al., 1982).mesencephalon is the impairment of vertical eye A lesion of the M-group should lead to amovements partially combined with impairment of dissociation of lid and eye movements manifestinghead or lid movements. Based on experimental as pseudoptosis on attempted downgaze or lid lagand clinical data, several hypotheses are put for- during vertical gaze, as reported in a patient with award for the control of vertical gaze (for review, lesion including the M-group (Galetta et al., 1996).see Leigh and Zee, 1999; Bhidayasiri et al., 2000). The postmortem analysis of a clinical case with Unilateral experimental lesions of the RIMLF downgaze paralysis and ptosis revealed a lesion ofin monkeys lead to a tonic ocular torsion, deficits parts of the RIMLF and the adjacent M-group.of torsional saccades, and produce a spontaneous The patient’s ability to perform upward saccadescontralesional torsional nystagmus (Crawford and demonstrates that the M-group does not act as aVilis, 1992; Suzuki et al., 1995; Helmchen et al., pure upgaze center (Buttner-Ennever et al., 1996). ¨
  • 99. 137 Unilateral lesions of the INC lead to a contra- Averbuch-Heller, 1997). The reanalysis of clinico-lateral head tilt with torsion of the eyes to the pathological cases with a vertical gaze paralysiscontralateral side but a torsional nystagmus to the and lid retraction showed that the common le-ipsilateral side, a criterion that helps to distinguish sioned area involved the PC and the NPC, whereasan INC lesion from a RIMLF lesion resulting in the lesions in cases with only vertical gaze paralysisan contralesional torsional nystagmus (Halmagyi and no lid retraction spared the nuclei and theet al., 1994; Ohashi et al., 1998; Leigh and Zee, fibers of the PC (Schmidtke and Buttner-Ennever, ¨1999). While the deficits after an RIMLF lesion 1992).are thought to result from an imbalance ofthe saccade generator, a vestibular imbalanceprobably causes the deficits after an INC lesion Proposed circuitry for the generation of vertical(Rambold et al., 2000; Buttner and Helmchen, ¨ saccades2002). Bilateral lesions of the INC result in an up-beat nystagmus and neck retroflexion (Fukushima, Although conclusive correlative studies for all1987; Helmchen et al., 1998), clinical signs functional cell groups within the premotor net-characteristic of progressive supranuclear palsy work for vertical saccades and their connectivity(Fukushima-Kudo et al., 1987). After bilateral are still incomplete, a simplified circuitry basedmuscimol injections in the INC downward sacca- on current physiological, anatomical, and histo-des are lost possibly due to the lesion of downward chemical data is shown in Fig. 6 (Schwindt et al.,BDNs (Fukushima and Fukushima, 1992). A 1974; Moschovakis et al., 1996; Horn et al.,lesion of the PC, which contains the crossing 2003b): An excitatory signal from the deep layersfibers of the burst-tonic and tonic neurons, leads to of SC encoding vertical saccades (see Chapter 11;the inability to hold eccentric gaze after vertical Robinson 1972) would activate premotor EBNssaccades (Partsalis et al., 1994). in the RIMLF and at the same time mediate an In monkey, lesions of the CMRF cause transient inhibition to saccadic OPNs in the RIP —deficits in contralateral gaze shifts. A pharmaco- presumably via pontine LLBNs — therebylogical lesion (muscimol injection) of the CMRF releasing the OPN inhibition from burst neuronsproper caused contraversive, upward saccade, in the RIMLF. An activated premotor down EBNhypermetria, and destabilization of gaze fixation in the RIMLF monosynaptically activates the IRand head tilts (Waitzman et al., 2000a). An and SO motoneurons in the ipsilateral motorinactivation of the rostral mesencephalic reticular nuclei (III and IV), and presumably via collateralssubregion lateral to the INC caused hypometria of premotor down burst-tonic neurons in the ipsi-vertical saccades (Waitzman et al., 2000b). A lateral INC (Moschovakis et al., 1991b). Duringhypothesis about the role of the CMRF in upward saccades the IR and SO motoneuronsproprioception is put forward in Chapter 3. would be inhibited by commissural fibers from Till date the role of the NPC in vertical gaze is GABAergic upward IBNs in the contralateralnot fully understood. On the basis of experimental INC, which, in turn, would be driven by premo-lesions and clinical observations, the NPC has long tor up-burst EBNs in the contralateral RIMLF.been suspected as being involved in the generation A GABAergic commissural projection from pre-of upward eye movements, since a damage of the sumably up burst-tonic neurons could theoreticallyNPC resulted in upward gaze paralysis. These also inhibit contralateral INC neurons with down-clinical syndromes are also known as dorsal mid- ward directions (Fig. 6, dashed line) (Chimotobrain syndrome, Parinaud’s syndrome, or pretectal et al., 1999). The presence of GABAergic andsyndrome (Pasik et al., 1969; Carpenter et al., non-GABAergic commissural INC projections1970; Christoff, 1974; Leigh and Zee, 1999). The could, in addition, or alternatively, activate orfrequently observed accompanying lid-retraction turn off their contralateral counterparts duringindicates a role in the premotor control of the up- upward eye movements (Fig. 6; solid commissuralper eyelid (Schmidtke and Buttner-Ennever, 1992; ¨ line). Some GABAergic neurons in the INC may
  • 100. 138represent non-premotor saccade-related burst Nucleus reticularis pontis caudalisneurons, which are thought to project back to The NRPC houses the EBNs for horizontalthe RIMLF, thereby contributing to a local feed- saccades (Grantyn et al., 1980; Igusa et al., 1980;back loop according to the eye displacement Sasaki and Shimazu, 1981; Strassman et al., 1986a;model (Moschovakis et al., 1991a, b; Helmchen Hepp et al., 1989). The NRPC adjoins the NRPO et al., 1996b). rostrally and extends to the rostral end of the abducens nucleus caudally (Fig. 4A). Similar to the NRPO, the NRPC consists of small- toParamedian pontine reticular formation medium-sized cells. Additionally, a few large cells, presumably reticulospinal neurons, are scatteredOriginally the term ‘‘paramedian pontine within the NRPC. Tract-tracing experimentsreticular formation’’ was introduced in macaque in the monkey have shown that the EBNs formonkeys defining the brainstem site where lesions horizontal saccades lie as a compact group withinproduce horizontal gaze palsy (Fig. 1) (Cohen a circumscribed area underneath the MLF.and Komatsuzaki, 1972). The PPRF extends Medially the EBN area is bordered by the dorsalfrom the level of the abducens nucleus to the nucleus of RP and the interfascicular nucleus oftrochlear nucleus rostrally. Anatomically it is the preabducens area (IFPA), which are both partcomposed of the oral pontine reticular nucleus, of the PMT cell groups (see below) (Fig. 4A, B, E,the caudal pontine reticular nucleus (NRPC), F) (Langer et al., 1986; Strassman et al., 1986a;the NRTP, and corresponding midline areas Belknap and McCrea, 1988; Horn et al., 1995).including the RIP. In rostrocaudal dimensions, the EBN area starts immediately dorsal and rostral to the saccadic OPNs in the RIP and extends approximatelyBrainstem regions 2 mm rostrally (Fig. 4A and E). The horizontal EBNs form a homogeneous population of mainlyNucleus reticularis pontis oralis medium-sized neurons with four to six primaryThe most rostral nucleus of the PPRF is the dendrites, which can extend close to the midline,nucleus reticularis pontis oralis (NRPO), which but do never cross to the contralateral sidelies ventral to the trochlear nucleus and is adjoined (Fig. 4D) (Moschovakis et al., 1996).by the NRPC caudally. The rostral NRPO is bor-dered by the NRTP ventrally and the brachiumconjunctivum (BC) dorsally (Fig. 3D). The NRPO Connections. Horizontal EBNs project toconsists of small to medium-sized neurons, but is the motoneurons and internuclear neurons withincharacterized by a more cellular appearance in the ipsilateral abducens nucleus, the IBN area onNissl-stained sections and the presence of plump the same side, and perihypoglossal complex andneurons (Olszewski and Baxter, 1982). medial part of the MV nucleus (Langer et al., 1986; The NRPO contains saccadic LLBNs (Hepp Strassman et al., 1986a; Horn et al., 1995). Recentand Henn, 1983; Scudder et al., 1996b). Single-cell studies applying retrograde transsynaptic tracingreconstructions of horseradish peroxidase-filled, with rabies virus from the lateral rectus muscleelectrophysiologcially identified saccadic LLBN in revealed that horizontal EBNs and IBNs projectthe NRPO of the monkey revealed projections to only to motoneurons supplying singly innervatedthe dorsomedial part of the NRPC and the PGD, muscle fibers, confirming the notion that mainlywhich correspond to the EBN and IBN areas, these ‘‘twitch’’ motoneurons participate in saccaderespectively, the NRTP and the NRG, which generation, and not the ‘‘nontwitch’’ motoneuronscontains premotor neurons for head movements lying around the periphery of VI and innervating(Cowie et al., 1994; Scudder et al., 1996b). In ad- multiply innervated muscle fibers. These ‘‘non-dition, the NRPO is one target of saccade-related twitch’’ motoneurons play a less direct role intecto-reticulo neurons (Scudder et al., 1996a). saccades, but are presumably involved in eye
  • 101. 139Fig. 4. Drawings of transverse sections through the pontine reticular formation taken from the levels indicated in Fig. 1A and E. Therectangles indicate the area shown in the magnifications seen on the right side (B, F, G). PV immunostaining highlights the areacontaining excitatory burst neurons (EBNs) for horizontal saccades within the nucleus reticularis pontis caudalis (NRPC; dotted line)underneath the medial longitudinal fascicle (MLF) (B). The arrow underneath the MLF indicates a PMT neuron area. High-powerphotographs of the EBNs demonstrate their morphology (D) and their PV expression (C). Acetylcholine esterase histochemistry labelsthe interfascicular nucleus of the preabducens area (IFPA) and is considered as one PMT group (F). A detailed view is given of thenucleus raphe interpositus (RIP) that contains saccadic omnipause neurons. The neurons in RIP are ensheathed by prominentperineurons nets (G) and contain nonphosphorylated neurofilaments (NP-NF) that outline their morphology (H). Scale bars: A, E:2 mm; B, F: 500 mm; C, D: 50 mm; G: 200 mm; H: 50 mm.
  • 102. 140alignment and gaze holding (Chapter 4; Buttner- ¨ immediately dorsal to NRTP around the midline,Ennever et al., 2001). and at this level the cells are difficult to distinguish Within the NRPC and in the vicinity of the from each other (Fig. 3E) (Chapter 10).abducens nucleus, a class of LLBN, the RSNs, wasfirst described in cats. In the NRPC they were Connections. The NRTP has extensive projec-found intermingled with EBNs (Grantyn et al., tions to the cerebellum (Chapter 10; Voogd, 2004).1987). The RSNs are activated during eye move- The medial, dorsomedial, and the extreme lateralments and neck muscle activity during gaze shifts divisions (processus tegmentosis lateralis) projectto the ipsilateral side and they are thought to par- heavily to the flocculus (Langer et al., 1985b).ticipate in the coordination of head and eye during These subdivisions are targeted by afferents fromgaze shifts to direct the eye accurately in space the SC (see Chapter 11). Immediately ventral to(Grantyn and Berthoz, 1987; Grantyn et al., 1992). the NRTP at the midline, a group of floccularThe RSNs have large cell bodies with extensive projection neurons was identified, which may bedendritic branches and project via the medial part of the continuum of scattered PMT neuronsreticulospinal tract to the spinal cord and give off (Fig. 3E and G) (Langer et al., 1985a).collaterals to the abducens nucleus providing A group of premotor neurons is present withindense termination fields, to EBNs in the NRPC the dorsal margin of the ipsilateral NRTP as alsomainly contralateral, the NRPO, the IBNs in the indicated by retrograde transsynaptic tracing fromPGD, the OPNs, the NRTP, and the NRG con- the lateral rectus muscle (Fig. 3E and F) (Langertaining head-movement-related neurons (Grantyn et al., 1986; Horn et al., 1995), but their function iset al., 1987). In the monkey, RSNs were identified not known. Until recently the NRTP was thoughtand characterized by single-cell studies (Scudder to be mainly associated with the saccadic systemet al., 1996b). As in cats, they lie near the abducens on account of its connections with the SC and thenucleus and project to the spinal cord in the frontal eye fields or the optokinetic system (Kellerreticulospinal tract just lateral and ventral to the and Crandall, 1983; Crandall and Keller, 1985)MLF giving off collaterals to the IBNs, the PH, (see Chapter 11). More recent data suggest anand ventral and dorsal subdivisions of the para- additional involvement in vergence and accommo-median reticular nuclei. Unlike in cats, these RSNs dation (Gamlin and Clarke, 1995) and smooth-do not project to motoneurons of the abducens pursuit-like eye movements (Yamada et al., 1996;nucleus (Scudder et al., 1996b). These findings Suzuki et al., 1999).support the view that eye and head movements —activated by a gaze command from the SC and/orfrontal eye fields — may be controlled more inde- Nucleus raphe interposituspendently in primates than in animals with Combined physiological and anatomical experi-coupled eye and head movements and would be ments showed that the saccadic OPNs lie within aexchangeable as suggested by clinical observations distinct nucleus at the ventrocaudal border of the(Gaymard et al., 2000). nucleus RP and dorsal to the nucleus raphe magnus (RM), and was termed nucleus raphe interpositus (RIP) (Fig. 4A, E, G) (Buttner- ¨Nucleus reticularis tegmenti pontis Ennever et al., 1988). In monkeys, the RIP formsThe NRTP adjoins the pontine nuclei dorsally. two vertical columns adjacent to the midline, con-The cells are similar to those of the reticular sisting of medium-sized neurons that are horizon-formation, but they are far more densely packed tally oriented and have prominent dendrites(Fig. 3D and E). The lateral regions, including reaching across the midline and thereby forming aprocessus tegmentosis lateralis and ventral parts, dense fiber plexus (Fig. 4H). Recording experimentscontain small cells, while larger diameter neurons in monkeys indicated that virtually all neurons with-tend to cluster near the midline (Brodal and in the RIP are OPNs (Langer and Kaneko, 1990).Brodal, 1971). The rostral end of nucleus RP lies In all species studied so far, including humans, the
  • 103. 141RIP lies at the level where the traversing fibers of inhibitory input to OPNs presumably involvingthe abducens nerve (NVI) rootlets appear (Fig. 5E inter-relayed inhibitory neurons, thereby generat-and G) (Buttner-Ennever et al., 1988; Horn et al., ¨ ing a saccade (Buttner-Ennever et al., 1999; ¨1994; Buttner-Ennever and Horn, 2004). ¨ Yoshida and Yoshida et al., 2001). Possible can- Saccadic OPNs act as a trigger for the initiation didates for these inhibitory neurons are LLBNs inof saccadic eye movements in all directions and the NRPC (Scudder et al., 1996b) or LLBNs in thewere described in cats and monkeys (Luschei and dorsomedial NRTP (Langer and Kaneko, 1990),Fuchs, 1972; Keller, 1974; Evinger et al., 1982; all of which were shown to receive afferents fromStrassman et al., 1987). Recent research suggests a the SC and project to the OPNs. It is also possiblemore global role of OPNs in the control of eye that local interneurons in the vicinity of the RIPmovements: OPNs modulate their firing rate with provide the inhibition to OPNs, which could ex-smooth pursuit (Missal and Keller, 2002; Keller plain terminations around RIP from collicularand Missal, 2003) and during vergence, but do not neurons (Scudder et al., 1996a, b; Buttner-Ennever ¨pause as seen with saccades (Busettini and Mays, et al., 1999). In addition, OPNs receive afferents2003). In cats, OPNs do not only trigger saccadic from the cortical frontal eye fields (Stanton et al.,eye movements, but participate in gaze control, 1988) and the supplementary eye fields (Shooki.e., combined eye and head movements (Pare and et al., 1988) — from where vergence-related infor-Guitton, 1990, 1998). However, in the primate mation could arise (Gamlin and Yoon, 2000).the OPNs apparently control only that portion ofgaze movement that involves the eye movement(Phillips et al., 1999). In addition, OPNs may form Histochemistry of the pontine reticular formationa link to the premotor circuit of the blink system,since stimulation of the OPNs suppresses reflex Within the NRPC, the dorsomedial part containingblinks and OPNs cease firing during blinks the EBNs for horizontal saccades is delineated by(Evinger et al., 1994; Mays and Morisse, 1995; its strong PV labeling (Fig. 4B), which was used toSibony and Evinger, 1998). identify the homolog area in the NRPC in humans as well (Horn et al., 1995, 1996; Buttner-Ennever ¨Connections. The axons of the majority of OPNs and Horn, 2004). Double-labeling experiments incross the midline and project directly to the ver- monkeys demonstrated that the EBNs themselvestical burst neurons in the RIMLF, the horizontal express PV and that they are part of the medium-burst neurons (EBN) in the dorso-medial NRPC, sized cell population within the NRPC (Fig. 4C),and the IBNs in the dorsal PGD (Figs. 6 and 7) presumably using glutamate as a transmitter.(Strassman et al., 1987; Ohgaki et al., 1989 Unlike the adjacent raphe nuclei the RIP doesMoschovakis et al., 1996). Only few neurons not contain 5-HT-immunoreactive neuronswithin the OPN region project to the spinal cord (Buttner-Ennever et al., 1988; Horn et al., 1994; ¨(Robinson et al., 1994). Hornung, 2003). Histochemical methods in mon- Physiological and anatomical studies in cats and keys revealed that the neurons of the RIP aremonkeys provide evidence that two categories of glycinergic, and that they receive a similar stronginput reach the OPNs from the SC (Fig. 7): A supply of glycine- and GABA-immunoreactivedirect excitatory projection arises from the ‘‘fixa- terminals on their somata and proximal dendrites,tion cells’’ or ‘‘tectal pause neurons’’ in the rostral whereas glutamatergic afferents are confined to theSC, which inhibits the generation of a saccade (cat: dendrites (Horn et al., 1994). Although embeddedMunoz and Guitton, 1991; monkey: Munoz and in a network of 5-HT and catecholaminergicWurtz, 1993; Everling et al., 1998; Buttner-Ennever ¨ fibers, only few immunostained varicosities areet al., 1999). Saccade-related neurons in the associated with RIP neurons (Horn et al., 1994). Indeep layers of the caudal SC encoding large addition, the RIP shows positive staining foramplitude saccades were shown to project to acetylcholine esterase activity, and can be deline-premotor burst neuron areas, but provide an ated by its strong COX and PV content or
  • 104. 142Fig. 5. Drawings of transverse sections through the pontine reticular formation midbrain taken from the levels indicated in Fig. 1A, E,H. The rectangles indicate the area shown in the magnifications seen on the right side (D, F, G, I, K). Dorsal to the abducens nucleus(VI) adjacent to the genu of the facial nerve (NVII) the nucleus supragenualis (SG) and a continuous area ventrally (arrows) ishighlighted by cytochrome oxidase staining and must be considered as a paramedian tract (PMT) cell group (B). PV immunostainingdelineates a triangular area within the dorsal paragigantocellular nucleus (PGD) representing the location of inhibitory burst neurons(IBN) for horizontal saccades (D). The high-power magnification of retrogradely labeled IBNs demonstrates the morphology of theseneurons (C). Sections at corresponding cutting planes stained for acetylcholine esterase (ACHE) (F, I) and for Nissl (G, K) dem-onstrates the location and appearance of the nucleus pararaphales (PRA) (F, G) and intrafascicular nucleus of the medial longitudinalfascicle (IFM) (I, K), respectively. Scale bars: A, E, H: 2 mm; B: 500 mm, C: 50 mm, D: 500 mm, F, G, I, K: 500 mm.
  • 105. 143Fig. 6. Simplified diagram summarizing the pathways for the generation of vertical saccades and their presumed transmitters. Forfixation, the rostral colliculus superior (SC) activates directly the omnipause neurons (OPN) in the nucleus raphe interpositus (RIP),thereby inhibiting the burst neurons in the rostral interstitial nucleus of the medial longitudinal fascicle (RIMLF) via glycine (GLY).For a saccade, the more caudal regions of the SC activate the burst neurons in RIMLF and intermediate, presumably long-lead burstneurons (LLBN), which may inhibit the OPNs by GABA or glycine. ‘‘Down’’ neurons are shown on the left side, ‘‘up’’ neurons on theright side. Excitatory neurons are indicated by open circles, inhibitory by filled circles. The RIMLF provides excitatory projections todown motoneurons (IR and SO) (left side) in the oculomotor (III) and trochlear nucleus (IV), and to the ipsilateral interstitial nucleusof Cajal (INC), which projects to the motoneurons by itself. Further, the down motoneurons receive inhibitory GABAergic projectionsfrom the contralateral INC. These neurons could be activated by premotor ‘‘up’’ neurons in the contralateral RIMLF, therebyinhibiting the SO and IR motoneurons during upward saccades. From experimental data it is not clear whether the GABAergiccommissural projections arise from collaterals of premotor neurons (dashed line, question mark) or by independent connections (solidline). Non-premotor saccade-related burst neurons in the INC may provide inhibitory projections back to the RIMLF. In addition, theINC receives input from collaterals of secondary vestibular neurons, and a weak input targets the medial part of the RIMLF.mmunoreactivity for nonphosphorylated neuro Lesion studies — clinical datafilaments (NP-NF) (Fig. 4H) (Buttner-Ennever ¨et al., 1988; Horn et al., 1994). Furthermore, the A general feature of lesions within the PPRF is anneurons of RIP are ensheathed by prominent impairment of eye movement in the horizontalperineuronal nets (Fig. 4G) (Horn et al., 2003a). plane (for review, see Leigh and Zee, 1999).
  • 106. 144 the contralateral side in the dark and a contralat- eral gaze-evoked nystagmus in the light (Henn et al., 1984; Hepp et al., 1989; Zee, 1998). Selective experimental and pharmacological lesions of the OPNs in monkeys resulted in slowed, but other- wise normal saccades (Kaneko, 1992, 1996; Soetedjo et al., 2002) and not in oscillations as hypothesized earlier (Zee and Robinson, 1979; Ashe et al., 1991; Kaneko, 1992, 1996; Soetedjo et al., 2002). From clinicopathological studies in humans, it is not clear whether the slowing of sac- cades is due to lesions of the OPNs or the adjacent EBNs (Hanson et al., 1986; Johnston et al., 1993; Kato et al., 1994). Theoretically, it is also possible that restricted lesions of the OPNs may result in oscillations (ocular flutter and opsoclonus) (Leigh and Zee, 1999; Schon et al., 2001). On the other hand, the analysis of cases with opsoclonus in patients did not reveal any severe deficits of OPNs (Buttner-Ennever and Horn, 1994; Wong et al., ¨ 2001). However, degenerated OPNs were noted in a patient suffering from spinocerebellar ataxia type 3 (SCA3), who had slowed horizontal saccades, but no oscillations (Rub et al., 2003). ¨ Proposed circuitry for the generation of horizontal saccades A highly simplified diagram showing the immedi- ate premotor circuitry for the generation ofFig. 7. Simplified diagram summarizing the pathways for the horizontal saccades is shown in Fig. 7. For ageneration of horizontal saccades and the presumed transmit- horizontal saccade an excitatory signal from theters. For fixation, the rostral colliculus superior (SC) activates deep layers of the SC encoding horizontal saccadesdirectly the omnipause neurons (OPN) in the nucleus raphe would activate the premotor circuitry within theinterpositus (RIP), thereby inhibiting the excitatory burst neu-rons (EBN) in the PPRF and inhibitory burst neurons (IBN) in PPRF (see Chapter 11; Robinson, 1972, Keller,the dorsal paragigantocellular nucleus (PGD). For a saccade, 1974; Leigh and Zee, 1999; Scudder and Kaneko,the more caudal regions of the SC activate the burst neurons in 2002): EBNs excite the motoneurons and internu-the PPRF and PGD. Interrelayed inhibitory neurons, presum- clear neurons in the ipsilateral abducens nucleus,ably long-lead burst neurons (LLBN), may inhibit the OPNs by thereby also activating the medial rectus (MR)GABA or glycine. The EBNs project directly to the motoneu-rons and internuclear neurons in the abducens nucleus (VI) and motoneurons in the contralateral oculomotorto the IBNs of the same side, thereby providing the neuroan- nucleus, which results in a saccade to the ipsilat-atomical basis for conjugate horizontal saccades. eral side (Fig. 7; Strassman et al., 1986a). At the same time, IBNs are driven by the EBNs, and they Experimental unilateral lesions of the saccadic inhibit the motoneurons in the contralateralburst neuron region in the pontine reticular for- abducens nucleus in order to evoke a conjugatemation result in an ipsilateral gaze paralysis with a saccade (Strassman et al., 1986a, b). Saccade-spontaneous nystagmus with quick phases toward related LLBNs may relay the inhibition to the
  • 107. 145OPN in order to generate a saccade (see above; for gaze shifts, the NRG may control exclusively headreview, see Moschovakis et al., 1996; Leigh and movements.Zee, 1999; Scudder and Kaneko, 2002). The NRG lies within the medial medullary reticular formation between the caudal aspect of the abducens nucleus rostrally and the rostral thirdMedullary reticular formation of the hypoglossal nucleus caudally. Dorsally the NRG is bordered by the PGD, which contains theBrainstem regions IBNs for horizontal saccades (Scudder et al., 1988; Horn et al., 1995), medially by the tectospinal tractNucleus paragigantocellularis dorsalis (TST) with the raphe nuclei, laterally by the dia-In monkeys, the dorsal PGD, a triangular area just gonally directed margin of the parvocellular re-caudal and ventral to the abducens nucleus, was ticular nucleus, and ventrally by the inferior oliveshown to contain the premotor IBNs for horizontal (Fig. 5A and E) (Cowie and Robinson, 1994). Thesaccades (Fig. 5A and D) (Strassman et al., 1986b; main feature of the NRG is the presence of manyScudder et al., 1988). Alternatively, this area dispersed large-sized neurons (Olszewski andhad been termed nucleus supragigantocellularis Baxter, 1982).(Langer et al., 1986). IBNs have four to nineprimary dendrites, which can enter the abducens or Connections. Efferent fibers from the NRGPH, but do not cross the midline (Fig. 5C) project via two pathways to the caudal medulla(Strassman et al., 1986b). and cervical spinal cord: One descends in the anterolateral funiculus of the ipsilateral spinalConnections. The axons of IBNs target moto- cord and terminates in the ventral horn; the otherneurons and internuclear neurons in the contra- descends bilaterally in the MLF to the anteriorlateral abducens nucleus (VI), the rostral pole of funiculi and medial portions of the spinal graythe MV and PMT cell groups (Yoshida et al., matter. The projection pattern of the latter path-1982; Scudder et al., 1988; Horn et al., 1995). way within the various motoneuron pools in theDuring saccades the IBNs are driven by EBNs, cervical spinal cord reflects the topographicaland they monosynaptivally inhibit the motoneu- order of head movement upon stimulation inrons of the contralateral lateral rectus muscle in different NRG areas (Cowie et al., 1994; Peterson,order to enable a conjugate horizontal eye move- 2004). In addition, the NRG projects rostrally toment. The IBNs show the same activity pattern as the INC, caudal RIMLF, the PPRF, and caudalthe EBNs (Hikosaka et al., 1978; Yoshida et al., vestibular nuclei. Projections to the trigeminal,1982; Strassman et al., 1986b). facial, and hypoglossal nuclei were noted, but no connections were found with the oculomotor nuclei (Cowie et al., 1994). In monkeys, neuronsNucleus reticularis gigantocellularis of the NRG were found to project to the cervicalA systematic stimulation study in the ponto- spinal cord (C2), but not to extraocular motonuclei,medullary reticular formation in monkeys from as the dorsally located IBNs in the PGD, and there-which isolated, predominantly ipsilateral head fore assumed to be related only to head movements.movements could be evoked outlined a region Reticulospinal neurons in the NRPC and NRGcorresponding to the gigantocellular reticular nu- in cats receive monosynaptic excitation from thecleus (NRG) (Cowie and Robinson, 1994; Cowie contralateral SC (Iwamoto and Sasaki, 1990; Isaet al., 1994). Whereas head movement-related ar- and Sasaki, 2002). Thereby it was shown thateas in the PPRF rostral to the abducens nucleus single RSNs project onto different groups of neck(Vidal et al., 1983), CMRF (Cohen et al., 1985), motoneurons that work in synergy (Chapter 17;and periabducens area dorso-rostral to the NRG Shinoda et al., 1996). In cats, RSNs in the NRPC(Whittington et al., 1984) seem to be related to the differ from those more caudal in the NRG by theircoordination of head and eye movements during collateral projections. The latter provides only few
  • 108. 146collaterals in the medullary reticular formation, for the individual groups proposed by Langer andwhereas those in the NRPC project to the ab- colleagues for the primate is used here (Langerducens nucleus, PH, and vestibular nucleus et al., 1985b). The most rostral PMT cell group lies(Grantyn et al., 1987). These projection patterns just ventral to the nucleus reticularis pontissuggest that RSNs in the NRPC are involved in (NRTP) and was called dorsal midline pontinecombined eye and head movements, whereas group (Fig. 3D, E, G). Further caudally theRSNs in the NRG may control only head move- intrafascicular nucleus of the preabducens areaments (Grantyn et al., 1992). (IFPA), a cell group scattered between the fibers of In the PH and the underlying medullary the MLF, is evident (Fig. 4E and F). They arereticular formation of cat BDNs were identified, continuous with a small region just dorsal to RP,whose discharge pattern correlates with quick beneath the fiber bundle of the MLF, which wasphases of nystagmus accompanying contraversive termed the dorsal subnucleus of the nucleus raphehorizontal head rotations (Chapter 7; Ohki et al., pontis (arrow Fig. 4A and B). It corresponds to the1988; Kitama et al., 1992). The axons of the BDNs nucleus ‘‘L’’ in the atlas of Paxinos et al. (2000).cross the midline and terminate presumably via A further PMT-cell group of round, medium-sizedexcitatory synapses within the contralateral NRTP neurons forms the rostral cap of the abducensand the EBN and IBN areas (Ohki et al., 1988). nucleus. As motoneurons and internuclear neurons within the abducens nucleus, the PMT neurons are ensheathed by perineuronal nets, but unlike moto-PMT cell groups neurons, they are not cholinergic (Eberhorn et al.,PMT neurons were defined as groups of neurons 2004). The neurons of the nucleus supragenualisthat lie around the midline fiber bundles of the (SG) are strongly labeled after a floccular tracerpons and medulla and project to the flocculus and injection defining them as PMT cell groups, but areventral paraflocculus (Blanks et al., 1983; Langer considered anatomically as part of the perihypglos-et al., 1985b; Buttner-Ennever and Buttner, 1988a; ¨ ¨ sal complex by Brodal (1983) (Fig. 5B). PMT neu-Akaogi et al., 1994). Later, it was shown that all rons are represented by the nucleus pararaphalesthese cell groups receive afferents from oculomotor (PRA) at the midline of the medulla ventral to thepremotor neurons (Buttner-Ennever et al., 1989; ¨ caudal PH (Fig. 5E–G). The cells of the medullaryButtner-Ennever and Horn, 1996). The PMT cell ¨ interfascicular nucleus (IFM), which is divided intogroups lie close to the raphe nuclei, RP, RM, dorsal and ventral parts (Brodal and Brodal, 1983;raphe dorsalis, and raphe obscurus, and have Langer et al., 1985b), lie as compact cell clusterstherefore been mistaken for them in earlier liter- within the PMTs ventromedial to the rostral end ofature (McCrea et al., 1987a, b). But some criteria the hypoglossus nucleus (XII) (Fig. 5H, I, K).may help to distinguish between both neuronalgroups: PMT cell groups tend to lie slightly lateral Connections. By definition, the PMT cells projectwithin the fibers of the paramedian tracts, whereas to the flocculus and ventral paraflocculus. Otherneurons of the RM and raphe obscurus lie vent- projection targets may include the vermal lobules VIrally to the PMT neurons, immediate at the mid- and VII (Brodal and Brodal, 1983; Yamada andline. Unlike a major portion of the raphe nuclei Noda, 1987). Afferent projections from severalneurons, the PMT neurons are not serotoninergic. premotor brainstem regions have been found There are at least six relatively separate ‘‘PMT (Buttner-Ennever and Buttner, 1988a): these include ¨ ¨groups’’ scattered in the MLF, extending from the the internuclear neurons in the abducens nucleuslevel of the hypoglossal nucleus to the pontine (McCrea et al., 1986), the horizontal EBNs in theplane. In cats, rats, and monkeys, they have been dorsomedial NRPC, and the IBNs in the PGDgiven different names by different investigators (Strassman et al., 1986a, b). Projections were foundreviewed by Buttner-Ennever (1992). Because of ¨ from secondary vestibular neurons of vertical andthe similarity of the nomenclature of some PMT cell horizontal canals (McCrea et al., 1987a, b) and fromgroups with the RIMLF and INC, the nomenclature the INC and RIMLF (Buttner-Ennever et al., 1989). ¨
  • 109. 147 Floccular projecting neurons in the IFPA — a clinical analyses of brainstem nystagmus. Pharma-presumed PMT cell group — showed a burst-tonic cological lesions of the NRG in cats abolish spon-firing pattern (Nakao et al., 1980). Theoretically, taneous head movements (Suzuki et al., 1989).the PMT cell groups are thought to contribute togaze holding by carrying a motor-like feedbacksignal to the flocculus (for a review, see Buttner- ¨ AbbreviationsEnnever and Horn, 1996). III oculomotor nucleus IV trochlear nucleusHistochemistry of the medullary reticular formation Vm motor trigeminal nucleus VI abducens nucleusWith PV immunolabeling the triangular area VII facial nucleuscontaining IBNs is outlined within the PGD and XII hypglossus nucleuswas identified in humans as well (Horn et al., 1995; ACHE acetylcholine esteraseButtner-Ennever and Horn, 2004). The IBNs ¨ CMRF central mesencephalic reticularthemselves express a strong PV immunoreactivity formation(Fig. 5C and D), and use glycine as a transmitter, COX cytochrome oxidasethereby exerting an inhibition onto the neurons in CTB cholera toxin subunit Bthe abducens nucleus (Spencer et al., 1989). DV descending vestibular nucleus The PMT groups contain high levels of COX EBN excitatory burst neuronand acetylcholine esterase activity, which can GLY glycinebe used to delineate these cell groups by their H Hfields of Forelpronounced neuropil labeling within the reticular HB nucleus habenularisformation (Figs. 4G and 5B, F, I). The transmitter IBN inhibitory burst neuronof PMT neurons is unknown. There is one report IC inferior colliculuson floccular projecting neurons in the abducens IFM intrafascicular nucleus of thenucleus of the rat that uses acetylcholine as a MLFtransmitter (Rodella et al., 1996), but this is not IFPA intrafascicular nucleus of theconfirmed in the monkey (Eberhorn et al., 2004). preabducens areaUnlike the adjacent raphe nuclei at the midline, the INC interstitial nucleus of CajalPMT cell groups do not contain serotonin as a IO inferior oblique muscletransmitter. From immunocytochemical staining IR inferior musclethere is evidence that all PMT cell groups receive a LD lateral dorsal nucleusstrong innervation from GABAergic terminals LGN lateral geniculate nucleus(Horn, personal observation). LLBN long-lead burst neuron LR Lateral rectus muscleLesions — clinical data LV lateral vestibular nucleus M M-groupIn clinical cases, lesions of the midline brainstem MB mammillar bodyoften cause nystagmus, and the usual hypothesis MGN medial geniculate nucleusput forward is ‘‘lesions of vestibular structures,’’ ML medial lemniscusbut in some cases it is likely to be due to lesions of MLF medial longitudinal fasciculusthe PMT neurons (Buttner et al., 1995). A recent ¨ MR medial rectus musclestudy showed that reversible chemical lesions to MT mamillo-thalamic tractPMT cell groups in cats caused a nystagmus, sup- MV medial vestibular nucleusporting the above hypothesis (Nakamagoe et al., NB nucleus of Bechterew2000). These studies demonstrate that PMT cell ND nucleus of Darkschewitschgroups should be taken more into account in future NIV trochlear nerve
  • 110. 148NPC nucleus of the posterior Acknowledgments commissureNP-NF non-phosphorylated This work was supported by the Deutsche neurofilaments Forschungsgemeinschaft (Ho 1639/4-1).NRG nucleus reticularis gigantocellularisNRPC nucleus reticularis pontis caudalis ReferencesNRPO nucleus reticularis pontis oralisNRTP nucleus reticularis tegmenti Akaogi, K., Sato, Y., Ikarashi, K. and Kawasaki, T. (1994) pontis Mossy fiber projections from the brain stem to the nodulus in the cat — an experimental study comparing the nodulus, theNV trigeminal nerve uvula and the flocculus. Brain Res., 638: 12–20.NVI abducens nerve Appell, P.P. and Behan, M. (1990) Sources of subcorticalOI oliva inferior GABAergic projections to the superior colliculus in the cat.OPN omnipause neuron J. Comp. Neurol., 302: 143–158.PC posterior commissure Ashe, J., Hain, T.C., Zee, D.S. and Schatz, N.J. (1991) Micro- saccadic flutter. Brain, 114: 461–472.PF nucleus parafascicularis Averbuch-Heller, L. (1997) Neurology of the eyelids. Curr.PGD neucleus paragigantocellularis Opin. Ophthalmol., 8: 27–34. dorsalis Belknap, D.B. and McCrea, R.A. (1988) Anatomical connec-PH prepositus hypoglossus nucleus tions of the prepositus and abducens nuclei in the squirrel monkey. J. Comp. Neurol., 268: 13–28.PM paramedian nucleus Benevento, L.A., Rezak, M. and Santos-Anderson, R. (1977)PMT paramedian tract An autoradiographic study of the projections of the pre-PN pontine nuclei tectum in the rhesus monkey (Macaca mulatta): evidence forPPRF paramedian pontine reticular sensorimotor links to the thalamus and oculomotor nuclei. formation Brain Res., 127: 197–218.PRA nucleus pararaphales Bhidayasiri, R., Plant, G.T. and Leigh, R.H. (2000) A hypo- thetical scheme for the brainstem control of vertical gaze.PV parvalbumin Neurology, 54: 1985–1993.RB restiform body Bianchi, R. and Gioia, M. (1990) Accessory oculomotor nucleiRIMLF rostral interstitial nucleus of the of man. 1. The nucleus of Darkschewitsch: a Nissl and Golgi medial longitudinal fascicle study. Acta Anat., 139: 349–356.RIP nucleus raphe interpositus Bianchi, R. and Gioia, M. (1991) Accessory oculomotor nuclei of man. 2. The interstitial nucleus of Cajal — a Nissl andRM nucleus raphe magnus Golgi study. Acta Anat., 142: 357–365.RN red nucleus Bianchi, R. and Gioia, M. (1993) Accessory oculomotor nucleiRO nucleus Roller of man. 3. The nuclear complex of the posterior commissureRP nucleus raphe pontis — a Nissl and Golgi study. Acta Anat., 146: 53–61. Blanks, R.H.I., Precht, W. and Torigoe, Y. (1983) AfferentRSN reticulo-spinal neuron projections to the cerebellar flocculus in the pigmented ratSC superior colliculus demonstrated by retrograde transport of horseradishSG nucleus supragenualis peroxidase. Exp. Brain Res., 52: 293–306.SN substantia nigra Brodal, A. (1983) The perihypoglossal nuclei in the macaqueSO superior olive monkey and the chimpanzee. J. Comp. Neurol., 218:SOL nucleus tractus solitarius 257–269. Brodal, A. and Brodal, P. (1971) The organization of theST nucleus subthalamicus nucleus reticularis tegmenti pontis in the cat in the light ofSV superior vestibular nucleus experimental anatomical studies of its cerebral cortical affer-TR tractus retroflexus ents. Exp. Brain Res., 13: 90–110.TST tectospinal tract Brodal, A. and Brodal, P. (1983) Observations on the projec- tion from the perihypoglossal nuclei onto the cerebellum inVPM nucleus ventralis posterior medialis the macaque monkey. Arch. Ital. Biol., 121: 151–166.WFA wisteria floribunda agglutinin Busettini, C. and Mays, L.E. (2003) Pontine omnipause activityY Y-group during conjugate and disconjugate eye movements inZI Zona incerta Macaques. J. Neurophysiol., 90: 3838–3853.
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  • 118. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 6 The Anatomy of the vestibular nuclei Stephen M. Highstein1,Ã and Gay R. Holstein2 1 Washington University School of Medicine, Box 8115, 4566 Scott Avenue, St. Louis, MO 63110, USA 2 Mount Sinai School of Medicine, Box 1140, One Gustave Levy Place, New York, NY 10029, USAAbstract: The vestibular portion of the eighth cranial nerve informs the brain about the linear and angularmovements of the head in space and the position of the head with respect to gravity. The termination sitesof these eighth nerve afferents define the territory of the vestibular nuclei in the brainstem. (There is also asubset of afferents that project directly to the cerebellum.) This chapter reviews the anatomical organizationof the vestibular nuclei, and the anatomy of the pathways from the nuclei to various target areas in thebrain. The cytoarchitectonics of the vestibular brainstem are discussed, since these features have been usedto distinguish the individual nuclei. The neurochemical phenotype of vestibular neurons and pathways arealso summarized because the chemical anatomy of the system contributes to its signal-processing capa-bilities. Similarly, the morphologic features of short-axon local circuit neurons and long-axon cells withextrinsic projections are described in detail, since these structural attributes of the neurons are critical totheir functional potential. Finally, the composition and hodology of the afferent and efferent pathways ofthe vestibular nuclei are discussed. In sum, this chapter reviews the morphology, chemoanatomy, con-nectivity, and synaptology of the vestibular nuclei.Anatomy principal sensory trigeminal nucleus and caudal- ly with the dorsal portion of Deiters’ nucleusLocation of the vestibular nuclei in the brainstem (see below). The caudalmost extension of SVN is formed by cells of the MVN. The LVN orThe vestibular nuclei are located within the medulla Deiters’ nucleus is bordered rostrally and dorsallyand pons of the brainstem (Brodal and Pompeiano, by the SVN, medially by the MVN, and caudally1957; Brodal et al., 1962) (Fig. 1). Classically, four by the head of the DVN. Its lateral border ismajor cell groups have been distinguished: the formed by incoming fibers of the eighth nerve. Thesuperior, medial, lateral and descending vestibular MVN is bounded dorsally by the fourth ventricle,nuclei (SVN, MVN, LVN, and DVN, respective- although dorsolaterally the MVN fuses with thely). The SVN or nucleus of Bechterew is an elon- SVN. The DVN forms the lateral border of MVNgated elliptical region with the long axis oriented throughout its rostro-caudal extent, as it descendsrostrocaudally (Fig. 1A–E). For most of its extent, caudally toward the dorsal motor vagal nucleusthe nucleus is bounded dorsally by the superior and the hypoglossal nucleus. Medial cell strandscerebellar peduncle, medially by the fourth ventri- interconnect the MVN with the nucleus preposituscle, and laterally by the LVN. The ventral border hypoglossi (nPH), and the MVN merges ventrallyis indistinct, merging rostrally with cells of the with the reticular formation. The DVN abuts the LVN rostrally, reaches the floor of the fourth ven-ÃCorresponding author. Tel.: +1 314 362 1012; tricle dorsally, borders the MVN medially, andFax: +1 314 535 3740; E-mail: merges with the reticular formation ventrally.DOI: 10.1016/S0079-6123(05)51006-9 157
  • 119. 158Fig. 1. A series of eight Nissl-stained coronal sections from rostral (A) to caudal (H) through the vestibular nuclear complex of thesquirrel monkey. Abbreviations as described in the text. Scale bar in D is for all figures and represents 0.5 mm.Other regions receiving direct innervation from the to the cerebellar floccular complex, these projec-vestibular branch of the eighth nerve tions have never been convincingly demonstrated in mammals. Conservatively, it is clear that vest-As indicated above, eighth nerve fibers also reach ibular projections to the floccular complex arisethe nodulus and uvula of the cerebellum, ending as from the vestibular nuclei via a class of vestibularmossy fibers in the cerebellar cortex. While there cells called flocculus projecting neurons (FPNs)have been reports of direct vestibular nerve input (Langer et al., 1985a).
  • 120. 159Cytoarchitectural subdivisions; morphology of VOR and non-VOR neurons in SVN, adaptedintrinsic neurons from Mitsacos et al. (1983a, b). The branching pattern of most VOR neurons (Fig. 3, upper panel)Superior vestibular nuclei is isodendritic (Ramon-Moliner and Nauta, 1966).Peripheral and central. In the squirrel monkey That is, most of the dendrites follow a straight(illustrated in Fig. 1) as in most mammals, the course and branch such that the primary dendriticSVN lies at the head of the vestibular nuclear segments are shorter than the secondary ones,complex (VNC), extending from the caudal por- which, in turn, are shorter than the tertiarytions of the trigeminal motor and principal sensory branchlets.nuclei to slightly caudal to the abducens nucleus. Physiologically unidentified (non-VOR) neuronsIn primates, the SVN has a cup-shaped center are located predominantly, but not exclusively, in(open end up) composed of medium-sized the periphery of the SVN. This cell population,(30–40 mm diameter) multipolar somata surround- subsequently identified by the course of the initialed on three sides by smaller neurons. However, cell portions of their axons, is comprised of neuronsbody size distinctions are less pronounced in the that project to the cerebellum or the dorsal pontineprimate than in rabbit (Epema et al., 1988) and cat reticular formations, others that contribute axons(Gacek, 1969). to the brachium conjunctivum (superior cerebellar peduncle), and those that project to the ipsi- orSomatodendritic morphology of SVN neurons. contralateral VNC. The somal shapes of theseSVN cells send projections rostrally to the oculo- non-VOR neurons also vary. Their dendritic fieldsmotor nuclei, thalamus and reticular formations, are largely confined to the cellular boundaries ofdorsally to the cerebellum, and have both ipsilat- SVN, and the dendritic trees demonstrate the sameeral and contralateral terminations within the rostrocaudal orientation preference as observedVNC. Mitsacos et al. (1983a, b) conducted a with the VOR-SVN neurons. While on averagedetailed study of SVN neurons in the squirrel only 16% of VOR neuronal dendrites exhibit anmonkey, and found that the somatodendritic mor- allodendritic branching pattern (daughter branch-phology of the cells correlates at least partially es shorter than parents, resulting in dendritic ar-with the termination sites of their axons. In this borizations that are denser toward the periphery ofstudy, all cells were monosynaptically activated by the dendritic tree), 25% of the non-VOR neuronsstimulation of the ipsilateral eighth nerve, and show this pattern of ramification (Fig. 3, lowerwere either antidromically identified as cells with panel). Neurons projecting to the cerebellum ex-projections to the oculomotor nuclear complex hibit a particularly high degree of allodendritic(so-called vestibulo-ocular reflex or VOR neurons) branching. The VOR and cerebellar-projectingor were electrophysiologically unidentified. The SVN neurons in the squirrel monkey are morpho-cells were then injected with tracer molecules for logically similar to those described in the catneuronal reconstructions. In agreement with find- (Highstein et al., 1987), although the dendritic ar-ings obtained using retrograde tracers, this study borizations of primate SVN neurons tend to re-demonstrated that VOR-SVN neurons are pre- spect the cellular boundaries of the nucleus,dominantly, but not exclusively located within the whereas those of the cat often traverse these bor-central portion of the SVN. These neurons have a ders. Fig. 4 illustrates five cerebellar projectingmean somal diameter of 25–50 mm and vary in neurons in the SVN of the squirrel monkeyshape from pyramidal or multipolar to elliptical (Highstein et al., 1987), all with the characteristicor fusiform. Most neurons exhibit the greatest allodendritic branching pattern.dendritic spread along the rostrocaudal axis and The LVN has been subdivided into dorsal andthe shortest extent in the coronal plane. In general, ventral regions on the bases of cytoarchitectonics,the dendrites of these cells remain within the the differential topography of afferents from cere-cytoarchitectonically defined boundaries of the bellar cortex, and the different axonal projectionsSVN. Fig. 2 is a composite drawing illustrating of the intrinsic neurons.
  • 121. 160Fig. 2. A composite drawing illustrating the dendritic architecture of 12 superior vestibular nucleus neurons shown in a coronal view throughthe right SVN in squirrel monkey. The emerging axon of each neuron is designated by a small arrow. Dorsal (D) and medial (M) aspects areindicated by directional arrows at lower left. BC: brachium conjunctivum; RB: restiform body. Adapted from Mitsacos et al. (1983a).Dorsal LVN (dLVN; Deiters’ nucleus). Deiters’ by fiber bundles containing axons that travel tonucleus was originally defined as the portion of the and from the cerebellum and to the spinal cord,LVN in which cells undergo chromatolysis follow- imparting a reticular appearance to the lesions of the rostral spinal cord (Brodal and Primary afferents in squirrel monkey project pre-Pompeiano, 1957). This has become accepted no- dominantly to the ventral and rostral portions of themenclature for the dorsal portion of the LVN LVN (Carleton and Carpenter, 1984). Numerous(dLVN), co-extensive with the region containing anatomical studies utilizing several techniques for‘‘giant’’ neurons and distinct from the ventral part bulk label or whole nerve degeneration (Lorenteof the nucleus (vLVN), which contains smaller ´ de No, 1933a; Walberg et al., 1958; Hauglie-cells. The dLVN extends rostrocaudally from Hanssen, 1968; Gacek, 1969; Stein and Carpenter,the middle of the SVN to an area just caudal 1976; Kotchabhakdi and Walberg, 1978; Korte,to the abducens nucleus. It is bordered medially by 1979) have reported that there are no primarythe MVN, laterally by the incoming eighth nerve afferent terminals on neurons in the dorsal androot, caudally by the head of the DVN, and ventrally caudal LVN, the regions known to contain giantit merges imperceptibly with vLVN. Although the cells. However, these anatomical observations aresignal feature of the dLVN is the population of at variance with physiological findings that stim-giant, 40–70 mm diameter cell bodies, the region ulation of the vestibular nerve results in monosy-contains medium- and small-sized somata as well naptic activation of ipsilateral dorsal Deiters’(Fig. 5) (Highstein et al., 1987). The caudal portion neurons. Estimates ranging from 12% (Wilsonof the dLVN and the entire DVN are traversed and Melville-Jones, 1979) to 29% (Ito, 1969; Ito
  • 122. 161Fig. 3. Superior vestibular nucleus neuronal reconstructions. The upper panel illustrates the soma and dendritic tree of a VOR-SVNneuron in the cat. The curved arrow indicates a terminal dendritic ramification. The lower drawing illustrates a non-VOR-SVN neuronwith projections to the cerebellum. Arrowheads indicate dendritic segments with allodendritic branching patterns. Abbreviations arefor wavy dendrites (w), dendritic processes (p), spines (s) and axons (a). Scale bars in both figures represent 100 mm, with the arrowpointing toward the midline. The vestibular cells are from Mitsacos et al. (1983a, b).et al., 1969a, b; Kawai et al., 1969) have been the squirrel monkey (Highstein et al., 1987). Inprovided for dLVN neurons that can be monosy- addition, intracellular injections of anatomical trac-naptically activated by vestibular nerve stimula- ers into primary otolith afferents have revealed thattion. Moreover, monosynaptic EPSPs have been saccular afferents in particular innervate dorsalrecorded from neurons of this region with axons Deiters’ cells (Imagawa et al., 1998; Newlands andin the lateral vestibulospinal tract (LVST) fol- Perachio, 2003, Newlands et al., 2003), at least in thelowing ipsilateral eighth nerve stimulation in gerbil. Additionally or alternatively, dendrites of
  • 123. 162Fig. 4. A composite reconstruction of five cerebellar-projecting SVN neurons. The arrows indicate axonal bifurcations within thecerebellar white matter of the three more dorsally located cells into branches supplying the cerebellar flocculus (FL) and more medialparts of the cerebellum. The arrowhead indicates the origin within the SVN of a thin varicose collateral from the axon of one of thesecells; the collateral exits the dorsal border of the SVN to course dorsally and medially within the cerebellar white matter. The axons ofthe two ventrally located cells each bifurcate within the restiform body and give rise to two collaterals projecting to the cerebellarcortex of the flocculus. Abbreviations as above, with the medial (m) and lateral (L) divisions of SVN distinguished. Modified fromHighstein et al. (1987).dorsal Deiters’ neurons may extend beyond the bor- the largest ones are similar to the large neuronsders of this nuclear subdivision into territories that found between the fiber bundles of the spinal ves-are known to receive primary afferent terminals. tibular nucleus, and differ clearly from the typical Deiters’ neurons lying further laterally, which usu- ally have an eccentric nucleus. This border regionVentral LVN. The vLVN extends rostrally as a between LVN and MVN provides the main outputtongue of neurons ventral to the SVN. The nucleus pathways of the nucleus, projecting, for example,is bounded laterally by incoming eighth nerve fib- directly to the oculomotor neurons, and formingers and the inferior cerebellar peduncle and medi- the second neuron of the three-neuron VOR path-ally by the dorsal acoustic stria. Caudally the way (for review, see Buttner-Ennever, 1992). ¨nucleus abuts the DVN. The location of the vLVNis illustrated in Fig. 1. This area is often referred toas the magnocellular or ventrolateral subdivision Medial vestibular nucleusof the MVN (Epema et al., 1988). It contains neu- The MVN is also called the triangular nucleus orrons of various diameters; most are medium sized; nucleus of Schwalbe (Brodal and Pompeiano,
  • 124. 163 surface of VNC cells (Mannen, 1965), and spines are plentiful on both the dendrites and somata (Mugnaini et al., 1967a, b). On the basis of cyto- architectonics, the MVN can be subdivided into three parts: a parvocellular division adjacent to the fourth ventricle, a more ventrolaterally situated magnocellular area, and a caudal region (Epema et al., 1988). Golgi impregnations in kittens (Hauglie-Hanssen, 1968) have revealed three types of terminal fibers in MVN. Type 1 fibers are thin (3–9 mm) and provide small (2 mm diameter) round-oval or pear-shaped terminal boutons. Type 2 fibers, in addition, support round-fusiform boutons en passage. Type 3 fibers are small, with minute boutons en passage, and apparently orig- inate in the cerebellar fastigial nuclei. Afferents to monkey MVN take origin ipsilat- erally from the semicircular canals, otolith organs, and interstitial nucleus of Cajal (IC); contralater- ally from the spinal cord; and bilaterally from the vestibular nuclei, nPH, and the dorsal medullary and pontine reticular formations. Primary affer- ents are distributed to the entire extent of theFig. 5. A reconstruction of three dLVN neurons whose axons MVN (Carleton and Carpenter, 1984). In additionjoin the LVST. Abbreviations as in Fig. 4, with the facial nu- to afferents from the cerebral cortex (see below),cleus (VII) and inferior olive (IO) also indicated. Modified from cerebellar inputs are derived from the ipsilateralHighstein et al. (1987). flocculus, paraflocculus, nodulus and uvula, and possibly a small projection from the contralateral1957; Brodal et al., 1962). It borders on the SVN fastigial nucleus. Efferents from MVN are directedsuperiorly and tractus solitarius inferiorly. to the spinal cord, cerebellum and thalamus, asThroughout most of its extent, the MVN is bound- well as to the abducens, oculomotor and trochleared dorsally by the floor of the fourth ventricle nuclei. Projections to the abducens nuclei contain(Fig. 1). The caudal half of MVN is bordered inhibitory ipsilateral as well as excitatory contra-laterally by the DVN, whereas rostral MVN lateral components (Brodal, 1984; Langer et al.,is bounded laterally by the LVN. Similarly, the 1986; McCrea et al., 1987b). In rat and cat, mostmedial border of MVN is formed by nPH caudally of these efferent axons course ventromedially orand the abducens nucleus rostrally. The ventral dorsolaterally, often without issuing local collat-aspect of the MVN is separated from the reticular erals. Some of the smaller neurons, however, haveformations by a dense plexus of transversely ori- axons that divide near the soma, providing collat-ented fibers. In general, the MVN is comprised eral branches in the region of the parent cell.of small- and medium-sized neurons of triangular, There is some suggestion of a topographic orga-pear, or round shape. The dendritic processes nization in MVN. Neurons in the rostrolateralof these cells tend to be long and slender, with no region tend to be larger in size (hence the nameobvious pattern of radiation and restricted but ‘‘magnocellular area’’), receive afferents from theoverlapping dendritic fields, although many ex- semicircular canals and the flocculus, send projec-ceptions to this overall description can be found tions to the extraocular motor nuclei and the IC,(Hauglie-Hanssen, 1968). Overall, dendritic ele- and to be functionally related to VOR arcs (Epemaments constitute more than 80% of the neuronal et al., 1988; Buttner-Ennever, 1992). In contrast, ¨
  • 125. 164neurons in caudomedial MVN (the parvocellular The y-group (Fuse, 1912; Brodal and Pompeiano,region) tend to be of smaller diameter, receive in- 1957) is one of these subnuclei, and is function-puts from the otolith organs, spinal cord, nodulus, ally prominent because of its projections to theuvula, and possibly the fastigial nucleus, and send oculomotor and contralateral vestibular nucleiefferents primarily to the cerebellum and spinal (Highstein, 1973a; Pompeiano et al., 1978; Stanton,cord, the two subregions with which it is more 1980). The nucleus has a limited rostrocaudal ex-functionally related. Projections to the thalamus tent in the cat, but is much larger in the primate,appear to arise from neurons throughout the where the caudalmost cells can be found at thenucleus (Pompeiano and Brodal, 1957a; Brodal, cerebello–medullary junction. The y-group is bor-1984; Langer et al., 1985b; Scudder and Fuchs, dered ventrally by the restiform body and dorsally1992). contributes to the cell bridges with the dentate nucleus of the cerebellum.Marginal subnucleus. The region between the On cytoarchitectural grounds, the nucleus cannPH and the MVN has been designated the mar- be parsed into dorsal and ventral subdivisions. Theginal subnucleus (MS) by Langer et al. (1986). The ventral subdivision is composed of tightly packedMS provides a cellular link between the nPH and fusiform neurons that hug the dorsal aspect of thethe MVN over much of their shared area of extent. inferior cerebellar peduncle, while the dorsal divi-Thus it appears to be a subdivision of the nPH sion extends more posteriorly and is composed ofcaudally and of the MVN rostrally (Langer et al., loosely packed, scattered, multipolar neurons ex-1986). MS neurons are intermediate to large in tending from the middle of the nucleus dorsally tosize, uniform in shape, densely packed and receive the cerebellar dentate nucleus. Lorente de No ´inputs from the vestibular nuclei. (1933b) reported that eighth nerve fibers from the saccule terminate in the center of the guinea pig nucleus cerebellovestibularis, the homologDescending vestibular nucleus of the y-group in cat and monkey (Highstein andThe rostral DVN is present immediately caudal Reisine, 1979). This projection has been confirmedand ventral to the LVN, where the caudal vestib- in gerbils and squirrel monkeys (Carleton andular root fibers enter the VNC. Both the MVN and Carpenter, 1984; Kevetter and Perachio, 1984).the DVN extend caudally almost to the obex. Thecaudal aspect of the DVN reaches the floor of the e-group. The e-group is the efferent vestibularfourth ventricle dorsally and the reticular forma- nucleus, containing neurons whose axons leave thetion ventrally. The DVN is innervated unevenly by central nervous system to innervate the peripheralprimary afferents from the otolith organs as well vestibular endorgans. Most of the efferent cellsas the semicircular canals (Buttner-Ennever, 1992, ¨ are found in a circumscribed, dense column situ-1999). Tracers placed in the eighth nerve are dis- ated dorsal to the seventh nerve, and interposedtributed more prominently in the dorsal than ven- between the abducens nucleus and the SVNtral DVN (Carleton and Carpenter, 1984), and (Goldberg and Fernandez, 1980). A smaller groupclusters of terminal boutons are present rostrally of efferent neurons are present bilaterally, medialand caudally, but the central area of the nucleus ´ to the abducens nuclei near the midline raphe. Theappears relatively free of such afferent terminals. cells are predominantly ovoid in shape withAs noted above, the entire DVN has a fasciculated a mean diameter of about 15 mm. They do not ap-appearance due to a significant complement of pear to receive primary vestibular afferent input.fibers of passage. Interstitial nucleus of the vestibular nerve. ThisOther vestibular nuclei nucleus is comprised primarily of medium sizedy-group. There are numerous small satellite cell fusiform cells distributed within the rootlets of thegroups of vestibular nuclei that can be delineated incoming eighth nerve fibers, dorsal to the spinalcytoarchitectonically in a variety of species. trigeminal nucleus and tract. The interstitial nucleus
  • 126. 165receives primary vestibular afferent innervation VOR were identified as small- and medium-sized(Gacek, 1969), and projects to the flocculus cells located in the lateral crescents of rostral(Langer et al., 1985a). It is generally considered MVN. The cells have large nuclei with deepto be a displaced part of the dLVN because it indentations and relatively little cytoplasm thatusually contains some giant cells. contains loose strands of endoplasmic reticulum and occasional cisterns and vacuoles. It is likelyGroup x. This small cell group is wedged between that two different types of commissural neuronsthe caudal half of the DVN and the rostral exter- participate in the velocity storage network, sincenal cuneate nucleus. Group x does not receive pri- two distinct morphologic types of dendrites andmary vestibular afferent input, but receives spinal two types of axon terminals were observed. Somevestibular fibers, and sends projections to the cere- dendrites of this pathway contain numerous roundbellum and ascending medial longitudinal fasi- or tubular mitochondria in a pale cytoplasmicculus (MLF). matrix with few other organelles, while others had few mitochondria but many cisterns and vacuolesGroup z. Group z is located immediately rostral in dense granular cytoplasm. Similarly, someto the rostral end of nucleus gracilis. Group z does boutons contained a moderate density of largenot receive primary vestibular afferent input, but spherical synaptic vesicles, and others displayeddoes receive spinal afferent input. It does not pleomorphic, primarily ellipsoid synaptic vesicles.project to the cerebellum. Distribution of putative neurotransmitters and otherUltrastructure of vestibular neurons chemical markersThere have been remarkably few studies of the Excitatory amino acidsultrastructure of central vestibular neurons. Transmitters. Glutamate, or a closely relatedExperimental lesion studies in the cat SVN have amino acid, is widely accepted as the major exci-identified the vertical VOR neurons as medium tatory neurotransmitter of the central vestibularsize with round, unindented nuclei and indirectly system (Dememes et al., 1984; Raymond et al.,suggested that cells with commissural projections 1984; Monaghan and Cotman, 1985; Kaneko et al.,are distinguished by indented cell nuclei (Gacek 1989) (Fig. 6). Early studies demonstrated thatet al., 1988, 1989, 1991). Although two neuronal bath application of glutamate, aspartate, kainatetypes have also been distinguished ultrastructural- or quisqualate evoked pronounced depolarizationly in the border zone between MVN and DVN of of central vestibular neurons in vitro (Cochran et al.,the rat (Schwarz et al., 1977), their features are 1987; Knopfel, 1987; Lewis et al., 1989). Moresomewhat different from those of the SVN. One recently, neurons containing transmitter levels oftype are small cells with large nuclei but little cyto- glutamate or aspartate were identified by quanti-plasm, which receive many axosomatic synapses; tative (Walberg et al., 1990) and qualitative (Kumoithe other are larger cells identical to medium-size et al., 1987; Yingcharoen et al., 1989; Kevetterneurons described in primates (Brodal, 1984), and Coffey, 1991; Kevetter and Hoffman, 1991;which have organelle-rich cytoplasm but do not Zhongqi et al., 1991) immunocytochemistry inreceive direct axosomatic contacts. Both cell types all four vestibular nuclei and nPH in a varietydisplay nuclear indentations. Two similar neuronal of species. In general, these cells have small- totypes have been described in the normal cat SVN medium-size somata, although giant Deiters’ neu-(Korte and Friedrich, 1979), but as in the lesion rons were also immunolabeled. In addition, therestudy, only the smaller cells display nuclear inden- are two main glutamatergic inputs to the vestib-tations. In an experimental lesion study in pri- ular nuclei: eighth nerve afferents (Dememes et al.,mates (Holstein et al., 1999c), commissural neurons 1984; Lewis et al., 1989; Kinney et al., 1994) andrelated to the velocity storage pathway of the commissural fibers carrying intra-VNC projections
  • 127. 166Fig. 6. Glutamate immunostaining in the vestibular nuclei of the squirrel monkey obtained using a monoclonal antibody described in(Holstein et al., 2004). (A) Small glutamatergic neurons in the DVN. An intense fiber plexus can also be seen in nPH. Larger glutamate-immunoreactive cells are present in the MVN (B) and vLVN (C). Labeled fusiform neurons embedded in a dense plexus of glut-amatergic fibers are apparent in the dorsal y-group (D). Scale bars: (A) 500 mm; (B–D) 100 mm.(Cochran et al., 1987; Knopfel, 1987; Lewis et al., studies have provided visualization of kainate re-1989; Doi et al., 1990; Kinney et al., 1994) (see ceptor subunits (KA1 and GluR6-7) (Petraliabelow). These afferents contribute to the dense et al., 1994a), AMPA subunits (GluR1, 2/3, 4)glutamate-related immunoreactivity observed in (Petralia and Wenthold, 1992), and NMDA sub-fibers of varying caliber and in puncta throughout units (NR1, NR2A, NR2B) in VNC neuronsthe VNC. (Raymond et al., 1984; Monaghan and Cotman, 1985; Petralia et al., 1994b; Chen et al., 2000), in-Receptors. All types of excitatory amino acid re- cluding those receiving utricular input (Chen et al.,ceptors have been visualized anatomically in the 2003). Given the ubiquity of these receptors, it isvestibular nuclei (Raymond et al., 1984; Smith not surprising that coexpression of NMDA andet al., 1991; Petralia and Wenthold, 1992; de Waele AMPA receptor subunits has been reported in aet al., 1994; Petralia et al., 1994b; Reichenberger large proportion of VNC neurons (Chen et al.,and Dieringer, 1994; Vidal et al., 1996; Popper 2000). The roles of these various receptors haveet al., 1997; Chen et al., 2000) (Fig. 7). Using in been studied pharmacologically in several species,situ hybridization, high densities of the AMPA and the findings suggest that the excitatory effectsreceptor subunits GluR2/3 and GluR4, the R1 and of glutamate-like amino acids on vestibular neu-R2C subunits of the NMDA receptor, and the rons are mediated primarily by postsynapticmGluR1, 2, 5, and 7 metabotropic subunits, as well AMPA/kainite receptors (Cochran et al., 1987;as a lower density of the GluR1 AMPA subunit Lewis et al., 1989; Doi et al., 1990; Straka andmRNAs have been reported. Immunocytochemical Dieringer, 1993; Kinney et al., 1994; Peusner and
  • 128. 167Fig. 7. Ionotropic (A–F) and metabotropic (G, H) glutamate receptor immunolabeling in vestibular nuclei and neurons of the squirrelmonkey. (A) GluR1 in the SVN (representative immunoreactive cells are indicated by arrows); (B) GluR2/3 in the y-group; (C, D)GluR4 in the VNC; (E) NR1 in the VNC; (F) NR1 in the SVN; (G) mGluR1a in the VNC; (H) mGluR1a in the SVN. Scale bars: (A,B) 100 mm; (C–E, G) 500 mm; (F, H) 25 mm.Giaume, 1994). In contrast, electrophysiological In concert, it appears that Groups II (mGluR2,and pharmacological evidence indicates that mGluR3) and III (mGluR7) metabotropic gluta-NMDA receptors are essential for shaping the nor- mate receptors inhibit basal glutamate release inmal resting discharge properties of central vestib- the VNC, whereas mGluR1 and mGluR5 (Group Iular neurons (de Waele et al., 1990; Serafin et al., mGluRs) are involved in mediating synaptic1992; Kinney et al., 1994; Straka et al., 1997), as plasticity (Grassi et al., 2002). Lastly, there is somewell as long-term modulation of synaptic transmis- evidence that presynaptic NMDA and metabo-sion (Grassi et al., 1995) and plasticity associated tropic glutamate receptors are co-localized on axonwith vestibular compensation (Smith et al., 1991). terminals in the VNC (Gallagher et al., 1992).
  • 129. 168The roles of excitatory amino acids in primary tions using antibodies against GABA or itsvestibular afferent and vestibular commissural ne- synthesizing enzyme glutamic acid decarboxylaseurotransmission are discussed below. (GAD) revealed labeled neurons in the vestibular nuclei of many species, including mouse (OttersenGABA and GABA receptors and Storm-Mathisen, 1984), guinea pig (KumoiElectrophysiological and biochemical studies pro- et al., 1987), rat (Houser et al., 1984; Mugnainivided early experimental evidence that GABA and Oertel, 1985), rabbit (Blessing et al., 1987), catserves as a neurotransmitter in some vestibular (Walberg et al., 1990; Spencer and Baker, 1992),cells. Subsequent immunocytochemical investiga- and monkey (Holstein et al., 1996) (Fig. 8A–D).Fig. 8. GABA and GABA receptor immunoreactivity in vestibular nuclei and neurons of the Squirrel monkey. GABA immuno-staining of neurons, fibers, and puncta is illustrated in (A) the DVN, (B) the MVN, (C) the dLVN, and (D) the y-group. GABAAreceptor immunolabeling is illustrated in (E) the vLVN, (F) y-group, and (G) the SVN. L-Baclofen-immunoreactivity, indicative ofGABAB receptor localization, is illustrated in a neuronal dendrite in the MVN. Scale bars: (A–G) 50 mm; (H) 100 nm.
  • 130. 169Estimates of the number or density of stained Although initial autoradiographic studies failedcells vary, undoubtedly depending upon species, to reveal GABAA receptor binding sites in theantibody, and/or methodological issues. Conserv- vestibular nuclei, mRNA encoding the a1 subunitatively, such neurons comprise less than 10% of the GABAA receptor was detected by in situof the total cell population in the VNC. However, hybridization histochemistry in the rat (Hironakamost immunocytochemical and in situ hybrid- et al., 1990). Heavy labeling was reported on giantization studies (de Waele et al., 1994) report more Deiters’ neurons, moderate grain densities over theintense labeling of the MVN, SVN, and nPH, MVN and DVN, but no specific labeling waswhere GABAergic cells may constitute 33–43% found in the SVN (but see Fig. 8E–G). GABABof the total cell population. In fact, high densi- receptor localization studies of the vestibular nu-ties of GABA-immunoreactive neurons are present clei have primarily been derived from observationsin SVN, MVN, vLVN, and nPH of rhesus and of L-baclofen-sensitive binding sites utilizing ancynomolgous monkeys (Holstein et al., 1999a). In agonist-specific antibody (Martinelli et al., 1992).general, these cells are small and medium size Immunoreactive myelinated axons, mostly ofmultipolar or fusiform neurons. Fewer cells are small caliber, as well as axonal profiles with smallimmunolabeled in the DVN and dLVN, and none mitochondria and spherical or pleomorphic synap-of them are giant Deiters’ neurons. Functionally, tic vesicles were observed in the MVN. These ax-four types of GABAergic neurons can be distin- onal profiles represent a substrate for presynapticguished in the VNC (for review, see Holstein, inhibition in the MVN. Immunostained perikarya2000): cells with projections to oculomotor neuron and dendrites were also observed, providing anpools, neurons mediating disynaptic commissural anatomical basis for GABAB-mediated postsynap-inhibition, vestibulospinal projection neurons, and tic inhibition in the monkey MVN (Fig. 8H).local circuit neurons. Indeed, functional pre- and postsynaptic GABAB In all parts of the VNC, GABA or GAD receptors have now been demonstrated in severalimmunolabeled fibers of variable diameter course experimental systems, including rat MVN slicesmultidirectionally (Houser et al., 1984; Mugnaini (Dutia et al., 1992) and chick tangential nucleusand Oertel, 1985; Walberg et al., 1990). In the (a homolog of the vestibular nuclei) (Shao et al.,MVN, most of the largest caliber stained fibers 2003).project medially toward nPH, whereas bundles ofimmunostained fibers course longitudinally throughthe DVN. Large diameter GAD-immunoreactive Glycine and glycine receptorsfibers are apparent in the LVN, with a higher den- Behavioral, physiological, and biochemical datasity observed in dLVN (Walberg et al., 1990). These indicate that glycinergic neurons are also presentfibers are often found in close proximity to the so- in the vestibular nuclei (Precht et al., 1973; Walbergmata of Deiters’ neurons. GABA-immunostained et al., 1990; Furuya et al., 1992; Spencer andterminals are observed throughout the VNC ne- Baker, 1992). Anatomically, small- and medium-uropil, often in close proximity to the perikarya and sized glycinergic cells have been reported in theprimary dendrites of vestibular cells. These endings LVN, MVN, and DVN of cat (Walberg et al.,are derived from Purkinje cell afferents (De Zeeuw 1990; Spencer and Baker, 1992), with a distribu-and Berrebi, 1995), as well as from commissural and tion and density similar to that of GABAergicintra-VNC connections. Following extensive lesion- neurons. In fact, extensive co-localization ofing of cerebellar Purkinje cell afferents, only 30% of GABA and glycine has been reported in vestibu-the GAD activity remains in the LVN (Houser lar neurons of rabbit (Wentzel et al., 1993) and catet al., 1984). It is therefore not surprising that the (Walberg et al., 1990). Co-existence of GABA anddLVN, which receives direct Purkinje cell afferents glycine is observed less frequently in DVN, whereand has a higher GABA content (Fonnum et al., glycine-only neuronal elements are prevalent. This1970), also contains more GABA-immunoreactive has fostered the suggestion that glycine serves asfibers than the vLVN (Walberg et al., 1990). the predominant inhibitory agent of the horizontal
  • 131. 170VOR, while GABA serves this role for the vertical addition, small- and medium-sized triangular orsystem (Spencer and Baker, 1992). Glycine- pear-shaped substance P immunoreactive neuronsimmunostained fibers and puncta are also ob- have been reported in the MVN and DVN, alongserved throughout the VNC (Walberg et al., 1990; with a dense plexus of stained fibers (NomuraSpencer and Baker, 1992). Glycinergic fibers et al., 1984). Leu-enkephalin immunostainedinclude axons in the MLF that project to the ab- cells in MVN are small and round, while those inducens nuclei and toward the spinal cord, as well DVN are medium size and multipolar, and a highas axons in the penetrating bundles of the DVN density of labeled fibers is reported in MVN.and some in the hook bundle traversing the LVN However, the rostral portion of MVN has sub-(Walberg et al., 1990; Spencer and Baker, 1992). stantially fewer substance P and leu-enkephalin In the context of inhibitory neurotransmission, immunostained cells. In addition, a small numberglycine acts through a strychnine-sensitive receptor of choline acetyltransferase immunoreactive cellsthat belongs to the family of ligand-gated chloride of varying size have been described in the centralion channel membrane proteins. Glycine also and lateral areas of caudal MVN, as well as thefunctions as a co-agonist with glutamate to acti- adjacent region of DVN in monkeys (Armstrongvate postsynaptic NMDA receptors. In the human et al., 1983; Carpenter, 1987).VNC, high densities of strychnine-sensitive glycine Autoradiographic studies have demonstratedreceptors are present in the MVN and nPH, but a 5-HT-containing nerve terminals in MVN (Fischettelow density is reported in the DVN (Langosch et al., 1987), as well as 5HT-1A, 5HT-1B and 5HT-2et al., 1990). In the rat, however, moderate silver receptor subtypes (Pazos and Palacios, 1985;grain counts are reported in autoradiograms of the Wright et al., 1995). The 5-HT terminals in theMVN (Probst et al., 1986). Nevertheless, neurons VNC are derived from the dorsal raphe nucleuscontaining glycine receptor a1 subunit mRNA (Steinbusch et al., 1985). Endogenous 5-HT (Cransacare plentiful throughout the VNC. In addition, et al., 1996) as well as depolarization-dependentphysiologic recordings from MVN neurons in 5-HT release (Inoue et al., 2002) has been demon-vitro indicate that almost all of these cells are in- strated in vestibular neurons. Microinotophoretichibited in a dose-dependent manner by exogenous application (Licata et al., 1993) and bath perfusionglycine, and this inhibition is blocked by strych- (Johnston et al., 1993) of 5-HT alters neuronalnine pretreatment (de Waele et al., 1995). Thus, it firing in both the MVN and LVN, primarily (butappears that most neurons in MVN have a com- not exclusively) in an excitatory fashion. Theseplement of postsynaptic strychinine-sensitive gly- data suggest that at least a portion of the VNCcinergic receptors. receives a biologically significant serotonergic in- nervation. Similarly, histaminergic neurons in the posterior hypothalamus project to the entire VNCOther putative neurotransmitters/modulators (Takeda et al., 1987), especially MVN and SVNA formidable variety of additional neuroactive (Tighilet and Lacour, 1996), and a moderatesubstances and/or receptors have been localized or density of histamine-immunolabeled fibers areidentified in the VNC. These include acetylcholine, reported in the caudal MVN (Steinbusch, 1991)serotonin, histamine, the monoamines, opioids, — a region with projections to the nucleus of theneuropeptides, tachykinins and various growth solitary tract (NTS) (Fig. 18). Ligand-bindingfactors (for reviews, see Guth et al., 1998; Vidal studies have demonstrated histamine H1 receptorset al., 1999; Anderson and Beitz, 2000). At least in MVN (Bouthenet et al., 1988). In general,one of the group e transmitters is acetylcholine histamine-related excitatory effects have been(Carpenter et al., 1987), which may co-localize recorded from MVN neurons in brainstem slicescalcitonin gene related peptide (Tanaka et al., in vitro (Phelan et al., 1990), and have been1988; Wackym et al., 1991, 1993), the enkephalins attributed to postsynaptic H1 and/or H2 receptors(Carpenter et al., 1987; Perachio and Kevetter, (Serafin et al., 1993; Wang and Dutia, 1995). An1989) and/or substance P (Usami et al., 1991). In increase in histamine release has also been reported
  • 132. 171following unilateral vestibular stimulation (Horiiet al., 1993).Nitric oxideNitric oxide (NO) is a gaseous free radical in-volved in the regulation of cardiovascular, im-mune, and nervous system functions. Because itdiffuses freely across membranes, the modulatoryactions of NO can influence neurons located at asubstantial distance from the production site; nei-ther synaptic contact nor cell contiguity are re-quired. Since NO cannot be visualized directly intissue, the capacity of a neuron to produce NO hasbeen inferred from the localization of the syntheticenzyme neuronal nitric oxide synthase (nNOS).Although the presence of nNOS signifies a cell’spotential to produce NO, it does not indicatenNOS oxidative activity or actual NO production.To address this, an antibody against L-citrullinehas been utilized (Martinelli et al., 2002), since thisamino acid is produced in equimolar amounts withNO and accumulates in the NO-producing cells. Inthe vestibular system, nNOS has been reported infibers of the vestibular ganglion and nerve (Harperet al., 1994), and in some cells and processes of thevestibular nuclei (Grassi and Pettorossi, 2000;Saxon and Beitz, 2000), including a subpopula-tion of efferent (e-group) neurons (Lysakowskiand Singer, 2000). L-Citrulline immunostaining is Fig. 9. Examples of NO-producing vestibular neurons visual- ized with an antibody against L-citrulline (Martinelli et al.,present in medium- and large-diameter multipolar 2002) in (A) DVN, (B) LVN, and (C) MVN. Scale bars in alland fusiform neurons in small clusters of neurons figures: 50 each of the four main vestibular nuclei, as wellas the e-group and nPH (Martinelli et al., 2002)(Fig. 9). Interestingly, some nNOS-positive cell following stimulation of these receptors would bebodies do not show L-citrulline labeling, suggesting sufficient to induce enzyme activation and NOthat one group of nNOS-containing vestibular production. Functionally, several studies suggestneurons tonically produce NO, whereas other cells that NO participates in vestibular neuronal plas-have the potential to produce NO under other ticity (Nagao and Ito, 1991; Li et al., 1995; And-stimulus conditions. Double-immunofluorescence erson et al., 1998; Grassi and Pettorossi, 2000), asand ultrastructural observations of large cells in well as in more reflexive motor control mecha-vLVN have shown enhanced subcellular nNOS ´ nisms (Moreno-Lopez et al., 1996).and L-citrulline immunoreactivity localized at cer-tain postsynaptic densities and portions of theendoplasmic reticulum. It is likely that postsynaptic Calcium-binding proteinsdensities associated with ionotropic glutamate re- Changes in intracellular Ca2+ concentration haveceptors are focal points of L-citrulline and NO pro- been correlated with neuronal functions such asduction, particularly since the local Ca2+ gradient signal transduction, shaping of action potentials,
  • 133. 172neurotransmitter release, and synaptic alterations. Vestibular afferentsCalcium-binding proteins can modulate these ac-tivities by two alternative approaches. Buffer pro- Vestibular nerve inputs to the vestibular nucleiteins such as calretinin and calbindin D-28k candirectly regulate the [Ca2+] inside specific cells, The vestibular nuclei comprise a sensorimotorwhereas trigger proteins such as parvalbumin and complex that senses the movements and positioncalmodulin undergo conformational changes after of the head in space. Signals are generated in thebinding to free Ca2+. This change exposes regions labyrinth of the inner ear, where the three semi-of the protein’s surface that can interact with circular canals respond to angular accelerations ofnearby target molecules and thereby modify activ- the head, and the two otolith organs, the sacculusity. In this light it is perhaps not surprising that and the utricle, respond to linear accelerations,these two types of proteins are localized in a com- including gravity. The information is conveyed toplementary fashion in the four main vestibular the vestibular complex via the eighth cranial nerve,nuclei (Horn et al., 1995; Kevetter, 1996). The and used to make compensatory eye and headpresence of calretinin in the rodent VNC has been movements as well as postural adjustments.evaluated by immunohistochemistry (Kevetter,1996) and in situ hybridization techniques (Sans Gross anatomy of the eighth nerveet al., 1995). These studies demonstrate the pres- Branching patterns of vestibular afferents. Theence of two types of calretinin-immunoreactive vestibulocochlear or eighth nerve is composed of aneurons (Sans et al., 1995; Kevetter, 1996; Kevetter pars inferior — the cochlear nerve, and a pars su-and Leonard, 1997): a group of densely packed perior — the vestibular nerve. The vestibular nervesmall- to medium-sized neurons in the parvocellu- contains the central processes of the bipolar cells inlar MVN adjacent to the fourth ventricle, and a Scarpa’s ganglion. The nerve enters the brainstem atsecond group of medium-sized neurons scattered the ventrolateral corner of the cerebello-pontine an-throughout the VNC. The major source of calbin- gle, just below the cochlear nuclei, and passes overdin D-28k-containing fibers and terminals in the the spinal trigeminal tract to enter the VNC. TheVNC is derived from cerebellar Purkinje cell axons nerve bifurcates centrally into an ascending branch,(Baurle and Grusser-Cornehls, 1994; Kevetter, ¨ composed of fine axons, that passes through the1996; Kevetter and Leonard, 1997; Baurle et al., ¨ center of the SVN (Fig. 10), and a descending1998), although some primary vestibular afferents branch composed of thicker axons, directed towardalso contain the protein. In normal Gunn rats, the MVN and DVN. The ascending branch contin-dense calbindin D-28k immunoreactivity is ob- ues toward the cerebellum, with axons coursing bothserved in the LVN, but only sparse staining in ventral and dorsal to the brachium conjunctivum.SVN, MVN, and DVN (Shaia et al., 2002). Thelabeling in LVN is associated primarily with Overall projection patterns of different end organboutons surrounding the giant Dieters’ neurons. nerves. Primary vestibular afferent terminationAdditional fiber and bouton staining in the ne- sites have been studied utilizing anterograde trans-uropil is also presumably attributable to Purkinje port of radioactive tracers (Carleton and Carpenter,cell afferents. In contrast, little parvalbumin cell 1984; Newlands and Perachio, 2003; Newlandsbody immunostaining is reported in rodent and cat et al., 2003) and nerve degeneration techniquesVNC, although moderate fiber staining is reported (Gacek, 1969; Stein and Carpenter, 1976; Korte,in the MVN, LVN, and DVN, and a few fibers are 1979). Vestibular afferents appear to terminatereportedly immunolabeled in nPH (Kevetter, in all regions of the VNC except dorsal Deiters’1996). This fiber staining is likely to reflect prima- nucleus and small areas within the MVN. In a he-ry afferent innervation. In Gunn rats, more dense roic series of experiments, Gacek (1969) made mi-fiber staining is present in the MVN and SVN, and crolesions in portions of Scarpa’s ganglion andmany immunolabeled cell bodies are reported in traced the peripheral and central courses of thethe SVN, MVN, and DVN (Shaia et al., 2002). degenerating vestibular fibers. He was thus able to
  • 134. 173Fig. 10. Line drawings of the central projections of the semicircular and otolithic nerves; adapted from Gacek (1969). Upper drawing:the large- and small-diameter fibers of the anterior and horizontal canals are represented by thick and thin lines, respectively, while theposterior canal afferents are represented by a line of intermediate width. Lower drawing illustrates the otolith projections to thevestibular nuclei. Abbreviations as in Fig. 9, with the dorsal acoustic stria (DAS), interstitial nucleus of the eighth nerve (in VIII),olivocochlear bundle (OCB), and the posterior canal nerve (PCN) added.specify the vestibular end organ of origin of a summarizes these findings. Another definitivegiven subset of degenerating afferents and the cen- demonstration of the course and central termina-tral termination sites of the afferents. Gacek dem- tion sites of vestibular primary afferents was basedonstrated that canal afferents terminate within the on labeling of individual afferent fibers from eachSVN, MVN, vLVN, and DVN, and that saccular semicircular canal and tracing their projections toafferents terminate in the ventral y-group and the vestibular nuclei (Mannen et al., 1982). Fig. 11LVN. Gacek also determined that posterior canal illustrates the central projections of a primary af-afferents terminate medially in the SVN, while an- ferent from the horizontal semicircular canal. Theterior canal afferents terminate more laterally with- widespread distribution of the terminal field of thisin this nucleus. In general, otolith afferents afferent is typical of the canal afferents studied.terminate more caudally in the VNC than affer- Although the sample size was small, Mannenents derived from the semicircular canals. Fig. 10 confirmed many of Gacek’s observations. The
  • 135. 174 The primary vestibular afferents have been physiologically characterized in several species (Fernandez and Goldberg, 1971; Goldberg and Fernandez, 1971a, b; Lifschitz, 1973; Blanks et al., 1975; Estes et al., 1975; O’Leary and Dunn, 1976; O’Leary and Honrubia, 1976; O’Leary and Wall, 1976; Markham et al., 1977; Yagi et al., 1977; Rossi et al., 1980; Tomko et al., 1981a, b; Boyle et al., 1991). Clearly, the mixture of response properties of the primary afferents is retained as the fibers project centrally to innervate target neu- rons in the brainstem and cerebellum. The central terminations of these afferents appears to be an ordered process apparently designed, at least in part, to match the response dynamics of a partic- ular sensory afferent to the requirements of the potential motor response generated by its activa- tion (Fernandez and Goldberg, 1976; Bilotto et al., 1982; Highstein et al., 1987). Finally, two labora-Fig. 11. A reconstruction of the ramifications of a primary tories have provided data on the number of pri-vestibular afferent from the horizontal canal of the cat, shown mary afferents innervating a given secondaryin horizontal view. The small hatched ellipse in LVN is the neuron. These experiments indicate that 4–15 ves-HRP injection site, while the arrowhead indicates a collateral tibular afferents converge upon each secondarytraveling toward the cerebellum. Abbreviations as above. vestibular neuron (Ito et al., 1969a; Kawai et al.,Adapted from Mannen et al. (1982). 1969; Mitsacos et al., 1983a).subject of central projections of individual afferents Ultrastructure of vestibular afferent synapses.originating from different vestibular endorgans has Several studies have examined the ultrastructuralrecently been reviewed (Newlands and Perachio, anatomy of primary vestibular afferent terminals.2003). Results of single cell fills largely confirm the Two types of such boutons have been distinguishedgeneral vertebrate plan, although some exceptions physiologically and morphologically in the VNCinclude evidence of saccular and light canal projec- of the cat (Sato et al., 1988). Fibers with ‘‘regular’’tions into Deiters’ nucleus (for review, see Buttner- ¨ responses show arborizations with many smallEnnever, 1992). Otolith input to the vestibular (1–4 mm diameter) en passage and terminal bou-complex (VNC) is described later in this chapter. tons, forming axodendritic contacts in which the In all species studied to date, primary afferents postsynaptic element receives many convergent in-differ in their fiber diameters and in their terminal puts. In contrast, fibers with ‘‘irregular’’ physio-arborizations within the peripheral end organs. In logic responses display terminal arborizations withmammals, the thickest afferents tend to have nerve a few large boutons forming synapses in which acalyx terminal expansions and to be innervated by a wide area of the somata or proximal dendrite isfew type I hair cells located toward the center of the covered by one contact with one bouton. Bothcrista ampullaris or the striola of the maculae, while types of afferents form asymmetric synapses withthe thinnest fibers are innervated by numerous type prominent postsynaptic densities. Both types alsoII hair cells situated toward the periphery of the display clear round vesicles, which are denselycrista in the planum semilunatum or the periphery packed in ‘‘regular’’ boutons and loosely scatteredof the macula. There are also many afferents that are in ‘‘irregular’’ types. In the rat MVN (Schwarzdimorphic in character, being innervated by both et al., 1977) and cat SVN (Korte, 1979), primarytype I and type II hair cells (Schessel et al., 1991). afferent terminals are described as small boutons
  • 136. 175Fig. 12. Primary vestibular afferents labeled with WGA-10 nm colloidal gold, visible as small black deposits in the axoplasm. Scalebars in A (for A and C) and B (for B and D) represent 0.25 mm.with spherical vesicles which lack neurofilaments Initially, studies indicated that non-NMDAand typically contact cell bodies and proximal (presumably AMPA/KA) receptors mediate thedendrites at asymmetric synapses. Similar small monosynaptic excitatory transmission from theboutons originating from thinly myelinated fibers eighth nerve to the vestibular nuclear neuronshave been observed in the monkey MVN following (Cochran et al., 1987; Lewis et al., 1989; Doi et al.,implantation of colloidal gold-tagged lectin tracers 1990). For example, excitatory responses in MVNin the vestibular periphery (Fig. 12). neurons to stimulation of eighth nerve and com- missural inputs in vitro were differentially affectedNeurotransmitters and co-transmitters of the primary by application of specific glutamate receptor an-vestibular afferents tagonists (Doi et al., 1990). Such results, togetherAs noted above, the two major glutamatergic in- with those of other investigations (Lewis et al.,puts to the vestibular nuclei are the eighth nerve 1989; Carpenter and Hori, 1992) indicated thatafferents and commissural fibers. The glutamatergic primary afferent innervation of vestibular neuronsnature of the primary afferents was first demon- is mediated almost exclusively by non-NMDA re-strated in lower vertebrates in vitro (Cochran et al., ceptors, whereas NMDA receptors are responsible1987), and subsequently documented anatomically for mediating at least a part of the excitatory(Dememes et al., 1984, 1990; Raymond et al., 1984; commissural activity (Knopfel, 1987; de WaeleReichenberger and Dieringer, 1994; Straka et al., et al., 1990; Smith et al., 1991; Serafin et al., 1992).1995) and physiologically (Yamamoto et al., 1978; However, subsequent investigations have shownLewis et al., 1989; Takahashi et al., 1994) in a va- that NMDA receptors are present on MVN cellsriety of species. In general, the anatomical studies that are critical for the horizontal oculomotorof Scarpa’s ganglion cells indicate that the majority neural integrator (Mettens et al., 1994a, b). A larg-of glutamate-immunostained cells are of small di- er role for the NMDA receptor in vestibular cir-ameter. What remains unclear is the precise role of cuits was proposed on the basis of whole cellthe glutamate receptor subtypes in various aspects voltage clamp recordings from the MVN in ratof this transmission. brainstem slices (Kinney et al., 1994; Takahashi
  • 137. 176et al., 1994). Following eighth nerve stimulation, bouton-only afferents (Lysakowski et al., 1999;the composite excitatory postsynaptic potential Leonard and Kevetter, 2002).included an NMDA receptor-insensitive, AMPAreceptor-sensitive fast component, and an NMDAreceptor-sensitive slower component; both with Characteristics of vestibular nerve inputs to vestibularlatencies consistent with monosynaptic input. This neuronsand similar results (Straka et al., 1995) suggest that Semicircular canal inputs to vestibular neurons.primary afferent input to MVN neurons activates The SVN, vLVN, MVN, and DVN receiveAMPA and NMDA receptors. In the frog, it ap- afferent inputs from the vestibular semicircularpears that activation of thicker primary afferents canals. The MVN and DVN also receiveco-activates NMDA and non-NMDA receptors, a substantive otolithic input. In a recent study,whereas the thinner fibers primarily activate non- Dickman and Angelaki (2002) evaluated the con-NMDA receptor subtypes (Straka et al., 2000). vergence of canal and otolith inputs onto individ- In addition to the excitatory amino acid in- ual vestibular nucleus neurons in alert primatesvolvement in primary afferent neurotransmission, (Fig. 13). It was concluded that roughly 25% ofglycine has been detected in uptake and transport secondary neurons receive vestibular input exclu-studies, and has been visualized by immunocyto- sively from the semicircular canals, with a rela-chemistry in primary afferent neurons (Godfrey tively even distribution from each canal. Althoughet al., 1977). In frog and rat, approximately innervated monosynaptically by primary afferents10–20% of Scarpa’s ganglion cells are glycine- of canal origin, these central neurons differed fromimmunolabeled (Reichenberger and Dieringer, their afferents in sensitivity and response dynam-1994). In complementary fashion to the glutamate ics. Generally the second-order neurons had higherfindings, these glycine-immunoreactive ganglion sensitivity to rotational stimuli than did their in-cells have the larger diameters. In fact, the largest nervating afferent nerves, and during high-fre-diameter ganglion cells and afferent fibers co- quency stimulation their phase and gainlocalize glutamate and glycine. enhancements were greater than those of the Several likely neuromodulators have also been nerves. Another 25% of cells responded to trans-observed in vestibular ganglion cells. For example, lation only, and their response properties also de-it has been estimated that approximately 85% of parted markedly from otolith afferent nerves.the ganglion cells in the guinea pig are substance First, these central neurons were not cosine-tunedP-immunoreactive (Usami et al., 1991), although like otolith nerves, and thus demonstrated differ-such staining only occurs in a minority of ganglion ent dynamics during translation along differentcells (Carpenter et al., 1990) and afferent fibers axes. Even when tested along the translation axis(Matsubara et al., 1995; Scarfone et al., 1996) of of maximum sensitivity, there was great variabilityother species. Cytochrome oxidase has been re- among neurons in response dynamics and re-ported in some vestibular afferent fibers (Kevetter sponse phase at a single frequency. Finally, manyand Perachio, 1994), and parvalbumin is present central neurons responded in phase with stimulusin all vestibular ganglion cells, including their cen- velocity, as opposed to linear acceleration. Thesetral and peripheral processes (Dememes et al., properties were attributed to either spatiotemporal1993; Raymond et al., 1993) (see section entitled convergence or parallel pathway inputs with op-‘‘Calcium-binding proteins’’). A small subset of these posite directional coding. Thus, while the otolithiclatter cells co-localize calretinin, and another small nerve inputs encode translational head motion, thegroup related to calyx-bearing afferents co-localize central neurons encode aspects of the resultantcalbindin-D28k as well as calretinin (Dememes et al., gravitoinertial acceleration.; Raymond et al., 1993; Kevetter and Leonard, 1997;Leonard and Kevetter, 2002). Lastly, peripherin ap-pears to label some efferent cell bodies, as well as a Convergent input from different endorgans. Thesubset of Scarpa’s ganglion cells thought to be the remaining 50% of vestibular nucleus neurons tested
  • 138. 177 monkey (Dickman and Angelaki, 2002) are similar to those in frog and confirm that the majority of vestibular canal recipient neurons receive monosy- naptic input from a single canal only. Straka et al. (2002) have followed up their previous studies with definitive work on the projection patterns of sec- ondary neurons in relation to their patterns of input. Many canal only neurons project rostrally, presumably into the extra ocular motor nuclei, while utricular and horizontal canal convergent cells project both rostrally and caudally. More generally, these studies and others (Sans et al., 1972; Wilson and Felpel, 1972a, b; Kasahara and Uchino, 1974; Fukushima et al., 2000; Isu et al., 2000; Kushiro et al., 2000; Ogawa et al., 2000; Ono et al., 2000; Uchino et al., 2000, 2001) indicate that there was an early evolution of a vertebrate vesti- bular plan that has changed little over time. Reafference through inhibitory interneurons As described above, the majority of vestibular canal recipient neurons receive monosynaptic canal input from a single canal only (Straka et al., 1997). InFig. 13. Canal–otolith interactions demonstrated by mapping frog, these neurons also receive disynaptic excitationrecording site locations and orthodromic activation of vestib- and disynaptic inhibition from the same canalular nuclear neurons onto a top view of the VNC in primates.The outlines of the main nuclear subdivisions are superimposed nerve. Therefore, these secondary neurons maintainon this map, using AP0 (the intersection of midline and inter- their canal spatial specificity. Such disynaptic exci-aural axes) as the reference position. Abbreviations as above. tatory and inhibitory synaptic inputs were alsoAdapted from Dickman and Angelaki (2002). prominent in intracellular studies of primate vesti- bular neurons (Goldberg et al., 1987), and may serve to facilitate or disfacilitate specific responsewere sensitive to both rotations and translations, parameters of the secondary target neurons. Forsuggesting convergent inputs from both the canals example, when activated, these neurons are candi-and otolith organs. These neurons often exhibited dates to help cancel head velocity signals on sec-spatiotemporal tuning properties (noncosine tun- ondary neurons during active head movements (Roying) and a wide variety of response patterns to and Cullen, 2004). These feed forward pathwaystranslation. Their maximum on direction responses may also be involved in the plasticity of the VOR.suggested convergence from multiple canals. Theresponses of these interesting neurons resembledthose of the otolith-only cells described above, Spinal and brainstem nonvestibular afferents to theduring translation. However, during rotation their vestibular nucleiresponses departed from those of canal onlycells, displaying a wide distribution of rotational Spinal cord afferents to the vestibular nucleisensitivity vectors that were not in canal planes. Fibers from the spinal cord to the vestibular nuclei It is interesting to note that Straka, Dieringer are remarkably scanty and are chiefly distributedand colleagues (Straka et al., 1997) previously to regions of the nuclei that receive few primaryinvestigated the convergence of vestibular inputs afferent vestibular fibers (Pompeiano and Brodal,onto secondary neurons in the frog. The results in 1957a, b). Spinovestibular input is limited to the
  • 139. 178caudal parts of the DVN, MVN, Deiters’ nucleus, cells. Purkinje cell axons stream out of the floccularand groups x and z. Spinal afferents to Deiters’ peduncle, travel over the inferior cerebellarnucleus seem to arise exclusively from cord levels peduncle, and then split into several smaller bun-below L3. They are limited to the dorsal regions of dles. Some axons flow caudally and medially intothe nucleus and terminate dorsally in regions that the y-group, while others turn rostrally and medi-have reciprocal connections with the caudal spinal ally into the SVN. Another group of axons formcord. Spinal afferents to the vestibular nuclei take the angular bundle of Lowy and terminate within ¨the route of the dorsal spinocerebellar tract and the MVN and vLVN. The projection to theare likely to be collaterals of this tract. It is likely y-group is clearly the densest of all the floccularthat spinal fibers from all levels contribute to the efferent bundles. Purkinje axon terminals in theascending projections to the vestibular nuclei. SVN are distributed in its caudal and central re-Group x receives a somatotopically organized pat- gions. However, only a portion of the MVN is tar-tern of spinal afferents as demonstrated by lesions geted, namely the rostral pole. Floccular terminalsplaced at different levels of the cord (Pompeiano become progressively less frequent in more caudaland Brodal, 1957b). regions of the MVN. Floccular efferents to the vLVN appear to be a continuation of those in ros- tral MVN. The rostral pole of DVN also receivesOculomotor inputs to the vestibular nuclei some of these terminals. The neurons that receiveMaciewicz et al. (1975) demonstrated that the the heaviest projections from the vestibulocerebel-oculomotor nucleus contains interneurons that lum are located in the rostral portions of the MVN,project to the abducens nucleus motor and inter- while the caudal MVN projects most heavily to thenuclear neurons (see Chapter 4). The function for cerebellum (Langer et al., 1985a). As noted above,these interesting cells remains conjectural. the caudal MVN also receives the heaviest spinal inputs (Pompeiano and Brodal, 1957a).Reticular and nPH projectionsThere are bilateral projections from the reticular Nodulus/uvulaformations and nPH into the vestibular nuclei. The cerebellar cortices of the nodulus and ventralThe nucleus reticularis gigantocellularis, nucleus uvula are the recipients of direct primary otolithicreticularis pontis caudalis and nucleus reticularis input from the eighth nerve (Korte and Mugnaini,parvicellularis all project heavily into the SVN and 1979; Mitsacos et al., 1983a; Kevetter and Perachio,LVN. MVN is the recipient of input from the 1984, 1985; Barmack et al., 1993; Akaogi, 1994;contralateral paramedian medullary tegmentum Dickman and Fang, 1996; Buttner-Ennever, 1999; ¨caudal to the abducens nucleus, from the parame- Purcell and Perachio, 2001; Maklad and Fritzsch,dian reticular formations rostral to the abducens 2003; Newlands et al., 2003). These cortices alsonucleus, from a cap of small neurons overlying the receive heavy secondary vestibular input from thedorsal border of the abducens nucleus (McCrea vestibular nuclei (Barmack et al., 1992; Barmack andet al., 1987b), and from the nucleus reticularis lat- Shojaku, 1995; Buttner-Ennever, 1999; Barmack, ¨eralis. The nPH receives both reticular and vestib- 2003). The nodulus and uvula are reported to beular inputs, and in turn gives rise to bilateral involved in spatial orientation, the torsional VOR,projections to the MVN, vLVN, and DVN velocity storage, and the formation of the gravito-(Corvaja et al., 1979). inertial vector (Wearne et al., 1998; Cohen et al., 1999, 2002; Sheliga et al., 1999).Cerebellar afferents to the vestibular nuclei Cerebral cortical afferents to the vestibular nucleiCerebellar flocculus/paraflocculusAs described above, a major source of vestibular There are substantial direct projections from sixnucleus afferents arises from cerebellar Purkinje regions of cerebral cortex to the vestibular nuclei
  • 140. 179(Akbarian et al., 1993, 1994; Guldin et al., 1993). using axonal degeneration (Ladpli and Brodal,These include parts of the premotor and cingulate 1968), and subsequently shown using HRP injec-cortices, area 3a (referred to as vestibular cortex), tions to involve MVN neurons as well (Gacek,the ventral bank of the intraparietal sulcus or area 1978; Carleton and Carpenter, 1983; Carpenter2v, the PIVC, and superior temporal cortex. Pro- and Cowie, 1985b). It has since been acknowl-jections to the vestibular nuclei are bilateral, are edged that the MVN constitutes the single mostdirected to all parts of the VNC, and are recipro- important source of crossing axons, at least in thecated by vestibulocortical connections. Many of rabbit (Epema et al., 1988). This pathway allowsthe cortical areas receiving semicircular canal- push–pull reactions in the VOR from reciprocalrelated inputs also receive somatosensory inputs semicircular canal pairs, thereby increasing thefrom the limbs (for a thorough review, see sensitivity of second-order vestibular neurons dur-Fukushima, 1997). ing head movements (Kasahara and Uchino, 1971). In addition to this important integrativeLocal circuits within and between the vestibular function for the neural integrator, the commissuralnuclei system is also important for velocity storage, a mechanism which is responsible for prolonging theVestibular commissural pathways dominant time constant of the VOR beyond that of the cupula, thereby enhancing the low frequencyAnatomical organization characteristics of the VOR. Midline section of ves-All parts of the MVN, and areas of SVN, DVN, tibular commissural fibers just caudal to the pon-and nPH, are interconnected bilaterally by com- tomedullary junction abolishes velocity storage,missural fibers (Pompeiano et al., 1978) (Fig. 14). but leaves the direct VOR pathway intact, sug-This fiber system was first demonstrated between gesting that crossing fibers are functionally segre-homonymous areas of peripheral SVN and DVN gated in the commissure (Holstein et al., 1999c).Fig. 14. Schematic diagrams summarizing the vestibular commissural connections. (A) Commissural projections originating from theperipheral shell of SVN. (B–D) Commissural interconnections from DVN (B), MVN (C), the perihypoglossal nuclei (nPH and nucleusintercalatus, nIC), and the y-group (D). Adapted from Pompeiano et al. (1978).
  • 141. 180Vestibular commissural neurons studies (Pompeiano et al., 1978) and physiologicalPhysiologic recordings from second-order MVN recordings (Shimazu and Precht, 1966) in the ves-neurons during contralateral vestibular nerve tibular nuclei led to the conclusion that interca-stimulation have demonstrated disynaptic as well lated neurons are present and participate inas polysynaptic inhibition of commissural target commissural pathway interactions. Moreover, aneurons (Kasahara et al., 1968; Mano et al., 1968). small population of intrinsic GAD-containingThe disynaptic inhibition of contralateral neurons neurons was identified immunocytochemically inis suppressed by application of either picrotoxin the dLVN (Houser et al., 1984), and a similarand bicuculline, or strychnine, but not by both group of GABAergic inhibitory interneurons hastypes of antagonists (Precht et al., 1973). Since pi- been described in the rostral MVN (Holstein et al.,crotoxin and bicuculline block postsynaptic 1999a). Axo-somatic synapses onto these latterGABA receptors, and strychnine is a specific cells are concentrated on polar regions of the so-glycine receptor antagonist, these data suggest mata, and the proximal dendrites of these GABA-that there are separate populations of GABA- ergic cells are surrounded by boutons, althoughreceptive and glycine-receptive postsynaptic MVN their distal dendrites receive only occasionalneurons and imply that the inhibitory portion of synaptic contacts. The terminals of these GABA-the vestibular commissure contains distinct GABA- ergic interneurons are small, and contain a mod-ergic and glycinergic components. Support for erate density of round/pleomorphic vesicles, nu-these physiological observations is derived from merous small round or tubular mitochondria, andimmunocytochemical studies, in which a portion many cisterns and vacuoles. They serve both pre-of the indirect angular VOR(aVOR) commissural and postsynaptic roles in symmetric contacts withpathway mediating velocity storage has been non-GABAergic axon terminals. Pharmacologicdemonstrated to be GABAergic (Holstein et al., studies support these findings, and indicate that1999b). As described above, the GABAergic GABAergic interneurons in MVN are critical forcells of this pathway are small- and medium- the production of long-term depression followingsized neurons located laterally in rostral and high-frequency stimulation of primary vestibularrostro-intermediate MVN. Extracellular spike re- afferents (Grassi et al., 1995).cordings support this notion of two separate in-hibitory transmitter systems in the commissure,and have further indicated that vestibular com- Axo-axonic synapses related to intrinsic vestibularmissural inhibition is mediated by GABAA, but connectionsnot GABAB receptors (Furuya et al., 1992). How-ever, immunocytochemical studies in monkeys Occasional axo-axonic synapses have been re-with midline section of these commissural axons ported in the vestibular nuclei, involving boutonshave provided clear evidence for a significant mul- with spherical vesicles presynaptic to those withtisynaptic role for GABAB receptors in mediating ellipsoid vesicles (Schwarz et al., 1977). Suchcommissural inhibition (Holstein et al., 1992, contacts have been reported by other investigators1999b). in cat (Eager, 1967) and rat (Sotelo and Palay, 1970) LVN and cat SVN (Korte and Friedrich, 1979). Finally, as noted above, the terminals ofInterneurons within vestibular nuclei GABAergic commissural axons involved in medi- ating velocity storage often form axo-axonicThere have been few reports regarding the exist- synapses with non-GABAergic terminals (Holsteinence or characteristics of classic interneurons in et al., 1999b) (Fig. 15). These data are interpretedthe VNC. Golgi-impregnation studies (Ramon y ´ as a structural basis for presynaptic inhibition of ´Cajal, 1909; Lorente de No, 1933; Hauglie- MVN circuits by velocity storage-related commis-Hanssen, 1968) failed to reveal a significant pop- sural neurons. However, since there is evidence forulation of true Golgi type II cells. However, lesion both pre- and postsynaptic inhibitory contacts in
  • 142. 181 Vestibular efferents Vestibulo-spinal pathways Vestibulo-collic pathways Most neck motor neurons receive vestibulo-spinal input that maintains a canal plane organization. However, approximately 30% of vestibulo-spinal neurons receive convergent input from a semicir- cular canal and an otolith organ. Spinal projecting vestibular neurons can be typed by the locations of their axons within the cervical white matter as ei- ther medial or lateral vestibulospinal tract (MVST and LVST, respectively) cells. LVST cells termi- nate ipsilaterally with respect to their origin in Deiters’ nucleus, while MVST cells innervate the cord bilaterally. Another class of spinal projecting vestibular neurons is the vestibulo-oculo-collic or VOC neurons that project both rostrally and cau- dally from their somata in the MVN, vLVN, and rostral DVN. Some MVST neurons innervate the cervical cord along its entire length, suggesting a generalized postural control including a widely dispersed excitatory drive to motor circuits. Other MVST cells appear to target selected spinal segments. Almost half of the retrogradely labeled vest- ibulospinal neurons present in MVN and DVN are GAD-immunostained (Blessing et al., 1987). How- ever, since labyrinthine-evoked inhibition in neck motor neurons is strychnine-sensitive, and bicu- culline and picrotoxin-insensitive, glycine may also play a role in vestibular innervation of the neck. Further support for this speculation derives from the observation that presumed glycinergic inhibi- tory vestibular neurons that project to the ipsilat- eral abducens nucleus issue collaterals thatFig. 15. Axo-axonic synapses involving GABA (A, B) and L- descend in the ipsilateral MLF toward the spinalbaclofen (C, D) immunostained terminals in the monkey MVN. cord (McCrea et al., 1980).Arrows point to the regions of synaptic contact between the twopartners. Scale bars in all panels correspond to 0.5 mm. Adapted Medial vestibulo-spinal tract. Many of the neu-in part from Holstein et al. (1999a). rons that project in the MVST via the descending MLF are located in the rostral MVN and the vLVN. MVST and VOC neurons lie intermingledthe MVN, the synaptology of GABAergic neurons with cervically-projecting LVST and VOR neuronscan readily provide the morphologic basis for dis- in the central regions of the nuclei. MVST neuronsinhibitory activation of local vestibular neuronal innervate the cervical spinal cord and separatecircuits as well. populations project to either side of the cord.
  • 143. 182Lateral vestibulo-spinal tract. Experimental stud- ipsilaterally and presumably mediate the inhibito-ies have shown that the LVST is formed by small, ry limb of the VOR (Highstein and Ito, 1971). Inmedium, and large neurons in Deiters’ nucleus fact, most VOR neurons in the MVN that are ret-(Pompeiano and Brodal, 1957a; Peterson and rogradely labeled by tracers placed in the trochlearCoulter, 1977). This tract exits the nucleus cau- nucleus are glutamate-immunostained, whereasdally and inferiorly and assumes a ventro-medial only a few of those in the SVN are glutamatetrajectory toward the inferior olive, turning cau- immunopositive (Kevetter and Hoffman, 1991).dally near the dorsum of this nucleus (Fig. 5). The However, GABAergic second-order vestibularLVST continues caudally in the ventral funiculus neurons form inhibitory synaptic connections withof the ipsilateral anterior horn of the spinal cord ipsilateral oculomotor and trochlear motoneuronsto terminate in the cervical and lumbosacral spinal (de la Cruz et al., 1992; Spencer and Baker, 1992;cord. There is no evidence that dLVN neurons Spencer et al., 1992; Wentzel et al., 1996). Theseare involved in VOR pathways. There is some cells receive anterior and posterior semicircularevidence that vestibulospinal neurons are glut- canal related input and are critical for mediatingamatergic, since retrogradely labeled LVST neu- the vertical aVOR (McCrea et al., 1987a). Most ofrons in the LVN and the magnocellular portion of the second-order cells of this type are located inthe MVN are immunoreactive for glutamate. the SVN, with a smaller contingent in the MVN.However, less than half the LVST neurons in the Their axons course in the ipsilateral MLF, andparvocellular MVN are double-labeled by the ret- terminate on the somata and proximal dendrites ofrograde tracer and glutamate antibody (Kevetter recipient motor neurons. SVN lesions, or unilat-and Coffey, 1991; Kevetter and Hoffman, 1991). eral section of the MLF, reduce the concentration of GABA in the ipsilateral trochlear nucleus (Spencer and Baker, 1992). Complementary exci-Vestibulo-ocular pathways tatory contralateral projections to the appropriate oculomotor neurons balance these ipsilateral in-Semicircular canal evoked VOR hibitory vertical aVOR projections.It has been known for almost a century that the Dorsally located SVN neurons enter the bra-SVN projects heavily into VOR pathways. Lesion chium conjunctivum (BC) and travel within thisand degeneration studies of the SVN have docu- pathway, at least initially. These neurons terminatemented its projections to the extraocular motor within the oculomotor nucleus and are thought tonuclei (Brodal and Pompeiano, 1957; McMasters relay excitation from the anterior semicircular canalet al., 1966; Tarlov, 1970a, b; Gacek, 1971) and to the superior rectus and inferior oblique extraoc-Gacek (1971) has reviewed the classic literature. ular motoneurons. The definitive demonstration ofMore recently the retrograde transport of HRP SVN projections has been obtained by injectinghas been utilized to document the rostral projec- these neurons intracellularly with HRP (Mitsacostions of the SVN and the projections of the entire et al., 1983a, b; McCrea et al., 1987a, b).vestibular complex (Graybiel and Hartwieg, 1974; The ascending projections of the MVN areGacek, 1977; Maciewicz et al., 1977; Yamamoto almost entirely crossed. This nucleus is thought toet al., 1978; Carpenter and Cowie, 1985a, b; Cowie convey the excitatory limb of the three-neuron arcand Carpenter, 1985; McCrea et al., 1987a, b). for the VOR rostrally (Highstein and Ito, 1971).Graybiel and Hartwieg (1974) and Yamamoto Further, the MVN contains the inhibitory andet al. (1978) have shown that the central portions excitatory VOR neurons that project to the ipsi-of the SVN project rostrally to join the MLF at lateral and contralateral abducens nuclei, respec-a level just caudal to the trochlear nucleus. Many tively. The inhibitory inputs to the abducensSVN neurons are retrogradely labeled following nucleus utilize glycine (Spencer and Baker, 1992;an injection of HRP into the oculomotor complex Spencer et al., 1992). MVN neurons project heav-(not illustrated). Many of these SVN neurons ily to the contralateral abducens nucleus and, inproject to oculomotor and trochlear neurons both monkey and cat project to the vestibular and
  • 144. 183oculomotor cerebellum including the flocculus and and ventrally located fusiform neurons are retro-vermis (Baker and Berthoz, 1975; Baker and High- gradely labeled from the IIIrd nucleus althoughstein, 1975; Brodal and Brodal, 1985; McCrea and the former are much more numerous than the lat-Baker, 1985; Langer et al., 1986; Belknap and ter. The y-group is much larger in the primate thanMcCrea, 1988; Delgado-Garcia et al., 1989). in the cat or rabbit. This nucleus plays a prominent One important exception to the general VOR role in the control of vertical gaze (Chubb andplan is an ipsilateral pathway, the ascending tract Fuchs, 1982; Partsalis et al., 1995a, b).of Deiters’ (ATD) (Muskens, 1913; Gacek, 1971). The majority of vestibular nucleus neurons thatThe ATD pathway has been shown to terminate project to the extraocular motor nuclei lie in themonosynaptically upon medial rectus extraocular rostral portions of the vestibular complex. Fol-motoneurons (Baker and Highstein, 1978) and to lowing injections of HRP into the extraocular nu-extend rostrally to the thalamus (Maciewicz et al., clei, vestibular nucleus neurons in all four major1982). In all probability, the thalamic projecting nuclei and the y-group are retrogradely labeled.vLVN neurons are not a subset of VOR cells but The majority of labeled neurons are located inare a separate population of neurons that may not three main regions: (1) the central and dorsal re-carry an eye-position signal (Highstein, unpub- gions of the SVN throughout the extent of thelished). The vLVN neurons projecting to vertical nucleus, except at the anterior nuclear pole; (2) theextraocular motoneurons are probably physiolog- MVN and vLVN continuing laterally to the en-ically indistinguishable from MVN neurons pro- trance of the vestibular nerve root; and (3) thejecting to the identical sites (McCrea et al., dorsal division of the y-group. These areas contain1987a, b). Ventral LVN neurons also contribute a variety of different cell types that project bothto the ipsi- and contralateral descending MLF ipsi- and contralaterally.pathways to the spinal cord (Akaike, 1973; Akaike Gacek (1979a) demonstrated that the ipsilateraland Westerman, 1973; Akaike et al., 1973a, b). SVN and the head of the contralateral MVN and Gacek (1978) has pointed out that only the ven- vLVN contained labeled neurons following an HRPtral y-group receives direct saccular input and injection into the trochlear nucleus. Vestibularforms a part of the vestibular commissural system nucleus neurons labeled following third and fourthprojecting to the contralateral VNC (Pompeiano nucleus HRP injections appear to be similar in theet al., 1978) and to the cerebellar flocculus squirrel monkey, cat, (Graybiel and Hartwieg,(Kotchabhakdi and Walberg, 1978; Good, 1980; 1974; Gacek, 1979a) and rabbit (Yamamoto et al.,Rubertone and Haines, 1981, 1982; Blanks et al., 1978), although the labeling of the y-group is more1983; Sato et al., 1983a, b; Brodal and Brodal, prominent in the primate.1985). On the other hand, the dorsal division of An injection of HRP into the abducens nucleusthis nucleus projects to the oculomotor complex labels four main regions of cells (Langer et al.,(Graybiel and Hartwieg, 1974; Gacek, 1978). 1986; McCrea et al., 1987a, b). The majority ofHwang and Poon (1975) confirmed that the labeled neurons are clustered in the rostral MVNy-group neurons that project to the oculomotor and vLVN bilaterally. There tends to be somecomplex are polysynaptically, but not monosy- overlap in the regions labeled both ipsi- and cont-naptically activated by eighth nerve stimulation ra-laterally, as neurons projecting to one abducens(Blazquez et al., 2000). Sato and Kawasaki (1987) nucleus or the other are clustered in separate re-have confirmed the organization of the dorsal and gions of the vestibular nuclei. Abducens afferentventral y-group subdivision and have pointed out groups 1 and 4 appear to be intermingled with thethat inhibition from the flocculus is exerted exclu- oculomotor and trochlear afferents located in thesively upon the dorsal subgroup. Following injec- MVN.tions of HRP into the oculomotor complex, The labeled cells in the above experiments in-neurons are labeled in the y-group. In similarity clude neurons that receive direct input from theto the cat (Gacek, 1979b; Highstein and Reisine, vestibular nerve and others that do not. For ex-1979), both dorsally located multipolar neurons ample, the dorsal division of the y-group projects
  • 145. 184directly to the superior rectus and inferior oblique bilaterally when the eyes are converging. Rather,motoneuron pools but these y-group neurons are the labyrinthine control of this muscle is effecteddisynaptically, and not monosynaptically, excited indirectly, in part, by the abducens internuclearby eighth nerve stimulation (Blazquez et al., 2000). neurons (Graybiel and Hartwieg, 1974; HighsteinIt will be shown below that some pathways from and Baker, 1978; Steiger and Buttner-Ennever, ¨the vestibular nuclei to the extraocular motor nu- 1979; Buttner-Ennever and Akert, 1981; Buttner- ¨ ¨clei are excitatory while others are inhibitory. Ennever et al., 1981a, b). Trisynaptic inhibition is thus possible via the internuclear pathway and also via local circuit interneurons (Uchino et al., 1979).Organization of VOR pathways It should not be forgotten that the three neuronAlthough the patterned activation of the extraoc- arc alone is not sufficient for generating a com-ular muscles by semicircular canal stimulation pensatory VOR, and that other, more indirecthad been known for many years (Hogyes, 1880), pathways also participate in generating compen-Szentagothai (1942, 1964) was the first to realize satory eye movements following head movements.that a three-neuron arc was the shortest connec- The details of the synaptic organization of thetion from the vestibular labyrinth to the extraoc- VOR depend upon the spatial relationships of theular motor nuclei and that these three neurons semicircular canals and the extraocular muscles inwere probably the circuitry responsible for much the species being considered (Simpson and Graf,of the behavior of the VOR. He further elaborated 1981, 1985; Ezure and Graf, 1984a, b; Graf andthe connectivity of the labyrinthine semicircular Baker, 1985a, b). For example, rolling the head incanals with the extraocular motor nuclei by point- a primate results in conjugate torsional movementsing out that each canal was linked to two extra- of both eyes, while a rabbit or guinea pig will re-ocular muscles and that this linkage defined the spond to the same head movement with an upwardplane of action of the VOR activated from each movement of one eye and a downward movementcanal (Szentagothai, 1964). Cohen, Suzuki, and of the other. A more extreme example is the VORcoworkers (Cohen and Suzuki, 1963, Cohen et al., of the flatfish where the connections of the vestib-1963, Suzuki et al., 1964) in an elegant series of ular nuclear to oculomotor pathways are reversedexperiments anticipated much of what is known during development (Graf and Baker, 1985a, b).today concerning VOR pathways. They demon- The vertical VOR is likewise different in lateral-strated that each semicircular canal is connected to and frontal-eyed animals. It has been demonstrat-two or more extraocular muscle subgroups, and ed that the horizontal, vertical, and torsionalfurther, utilizing intact, unanesthetized animals VORs can operate independently. For example,demonstrated a ‘‘highly ordered pattern of excita- Berthoz et al. (1981) were able to modify the gaintion and inhibition.’’ Therefore, the accurate of the vertical VOR while the gain of the torsionaldescription of VOR pathways includes both VOR remained unchanged (cf. Bello et al., 1991).inhibitory and excitatory connections of a single When studying VOR pathways it is important tosemicircular canal with four or more subgroups of keep in mind that the oculomotor system is uniqueextraocular motoneurons. Thus, each of the sub- in that the motor neurons that innervate two of thegroups of extraocular motoneurons receives disy- extraocular muscles, (i.e. the superior rectus andnaptic inhibition from the labyrinth on one side of superior oblique) project contralaterally, unlikethe head and disynaptic excitation from the other other motoneurons. Thus the motoneurons thatside (Baker et al., 1969a, b; Precht and Baker, innervate the lateral rectus are located in the ipsi-1972; Highstein, 1973a, b; Baker and Highstein, lateral abducens nucleus while those that innervate1978). The medial rectus subdivision of the third the superior rectus and superior oblique are locat-nucleus is the exception to this rule. Labyrinthine ed contralaterally to the muscles in question. Be-evoked disynaptic inhibition of medial rectus low we will review the VOR pathways in themotoneurons, if present, might interfere with the mammal, in particular in the primate because itsrequirement for co-contraction of the medial recti vestibular reflexes have been most extensively
  • 146. 185studied. Most information has been gathered in ipsilateral abducens nucleus, the ipsilateral MVN,rabbits, cats, and monkeys. Monkeys are frontal and the nPH.eyed, rabbits are lateral eyed, and cats are in bet-ween (Simpson and Graf, 1985). This differential Contralaterally projecting vestibular neurons:eye position is not an issue in the study of the Contralaterally projecting vestibular neurons inhorizontal VOR as the eyes deviate laterally for a the MVN and vLVN (HVc) mediate the disynapticyaw head movement in all three species. Thus, the excitation recorded in abducens neurons followingorganization of the horizontal VOR is much sim- eighth nerve stimulation in alert cats and squirrelpler than its torsional or vertical counterparts and monkeys (Baker et al., 1969a, b; Highstein, 1973b;will be considered first. McCrea et al., 1980, 1987a, b). The axons of HVc cells cross the midline in a plane about the level of the abducens nucleus and terminate in the contra-The horizontal VOR. In most animals, the hor- lateral sixth nucleus. They make excitatory con-izontal VOR (HVOR) involves predominantly the nections with abducens motor neurons andhorizontal semicircular canals and the medial and abducens internuclear neurons, which, in turn, ex-lateral rectus extraocular motoneurons. The mor- cite contralateral medial rectus motoneurons. Thephological substrate for the horizontal VOR be- axon collateral that enters the abducens nucleusgins with the primary vestibular afferents arising gives rise to a terminal arbor that typically spreadsfrom the labyrinthine horizontal semicircular ca- throughout most of the nucleus (Fig. 16). HVcnal. In the squirrel monkey (McCrea et al., axons also give rise to collaterals that project ros-1987a, b), cat (Baker et al., 1969a; Baker and tral and caudal in the MLF. The rostral collateralHighstein, 1978; Reisine and Highstein, 1979; gives rise to terminal arborizations in the dorsalReisine et al., 1981), and rabbit (Highstein, paramedian pontine reticular formations (PPRF)1973a, b) these afferents monosynaptically excite and in the intermediate interstitial nucleus of theneurons in the MVN and vLVN. Electric stimu- MLF or the caudal portions of the dorsal raphe in ´lation of the eighth nerve or selective stimulation the midline (Blanks et al., 1983; Buttner-Ennever ¨of the horizontal canal nerve evokes disynaptic et al., 1989; Buttner-Ennever and Horn, 1996). The ¨inhibition in ipsilateral, and disynaptic excitation rostral collaterals travel as far rostrally as the thirdin contralateral abducens motor and internuclear nucleus where they enter its caudal portions. Theneurons (Baker et al., 1969a; Highstein, 1973a, b; caudal collaterals course in the MLF and differentBaker and Highstein, 1975). Ipsilateral medial neurons tend to terminate in different sites. Mostrectus motoneurons receive disynaptic excitation frequently, HVc neurons terminate in the nPH, thevia the ascending tract of Deiters’ and reciprocal, caudal interstitial nucleus of the MLF and thetrisynaptic inhibition through the abducens inter- ´ nucleus raphe obscurus at the level of Roller’s nu-nuclear pathway (Baker and Highstein, 1978; cleus. The caudal collaterals of some HVc neuronsUchino et al., 1979). project as far caudally as the cervical spinal cord Ipsilateral vestibular pathways: Stimulation of (Isu and Yokota, 1983; McCrea et al., 1987a, b).the ipsilateral eighth nerve or MVN evokes IPSPs In both cat and monkey (and probably alsoin abducens motoneurons (Baker et al., 1969a, b; rabbit), there is an additional disynaptic pathwayMcCrea et al., 1987a, b) and in abducens internu- to the ipsilateral medial rectus extraocular moto-clear neurons that project to the contralateral me- neurons, namely the ascending tract of Deiters’dial rectus motoneurons (Highstein and Baker, (ATD). In the squirrel monkey and cat, the somata1978; McCrea et al., 1987a, b). In the cat, the neu- of ATD neurons lie in the rostral MVN androns that mediate this ipsilateral disynaptic inhi- vLVN. In the monkey, about half of the ATDbition (HVi) have been intracellularly injected with neurons proceed directly rostral in the ATD andHRP. Their axons arborize on the ipsilateral side terminate within the medial rectus subdivision ofof the brain and they do not project rostral to the the third nucleus without giving rise to any axonabducens nucleus. They terminate profusely in the collaterals. About 25% of ATD neurons in the
  • 147. 186 semicircular canals is at least partially accom- plished by the branching of secondary VOR neu- rons to innervate more than one subgroup of extraocular motoneurons. A single vertical VOR neuron characteristically projects to two or more synergistic subgroups of extraocular motoneurons. Most vertical VOR somata are located in the lat- eral part of the rostral MVN, in the adjacent part of the vLVN and in the SVN. Vertical neurons in the MVN or vLVN have axons that cross the midline to travel rostrally in the contralateral MLF while SVN axons travel ipsilaterally in a rostro-medial direction from the nucleus to even- tually join the lateral wing of the MLF. Vertical VOR axons branch soon after crossing the midline to give rise to a caudally directed collateral while the main axon continues rostrally. SVN axons branch within the third nucleus to innervate mul-Fig. 16. A partial reconstruction of the terminal axonal arbor- tiple subgroups of motoneurons.ization of an MVN neuron projecting to the contralateral ab-ducens nucleus. The cross-sectional diameter of the abducens There are four major morphological classes ofnucleus, as indicated in this drawing, is approximately 1 mm. vertical VOR neurons: 1. SVN neurons mediating the inhibitory limbsquirrel monkey have an additional collateral, of the VOR from the posterior semicircularwhich was described as targeting the dorsal nucle- canal to the superior rectus extraocular moto-us of the PPRF and the other 25% project to the neurons; ´ipsilateral nucleus raphe obscurus. It is now clear 2. SVN neurons mediating the inhibitory limb ´that the projection was not to the raphe nuclei but of the VOR from the anterior semicircularto one of the cell groups of the paramedian tracts canal to the superior oblique and inferior re-(PMT), a set of floccular-projecting nuclei de- ctus extraocular motoneurons;scribed below, and in Chapter 5 in more detail. 3. MVN neurons mediating the excitatory limbATD neurons do not appear to terminate in areas of the VOR from the anterior canal to therostral to the third nucleus. superior rectus and inferior oblique moto- It is interesting to speculate upon the function of neurons; andthe ATD. The medial rectus motoneurons are the 4. MVN and vLVN neurons mediating the ex-only subgroup of extraocular motoneurons that citatory limb of the VOR from the posteriorreceive a preformed oculomotor command signal canal to the superior oblique and inferior re-via the abducens internuclear neurons (eye posi- ctus motoneurons.tion and eye velocity commands) and an addition-al vestibular and eye position signal via the ATD. Figure 17 illustrates the areas of the oculomo-The additional ATD input might augment the tor, trochlear, and abducens nuclei occupied by theperformance of the VOR during high-frequency terminals of secondary vestibular axons. Theserotation or might be necessary as an additional projections include both excitatory and inhibitoryinput to the VOR during convergence. termination. All four classes of vertical VOR neuron contin- ue rostral to the third nucleus to terminate in theThe vertical VOR. The sensory to motor trans- interstitial nucleus of Cajal and the rostral inter-formation that is necessary to generate a compen- stitial nucleus of the median longitudinal fasiculussatory eye movement in the plane of the vertical (Buttner-Ennever et al., 1982; Buttner-Ennever ¨ ¨
  • 148. 187Fig. 17. Schematic diagrams summarizing the locations of vestibular axons projecting to the oculomotor nuclei of the squirrel monkey.The left side of each section is ipsilateral to the vestibular cell body of origin, except for the section through the abducens nucleus(upper left), in which the down PVP terminations are contralateral. Adapted from McCrea et al. (1987b).and Buttner, 1988). The excitatory neurons, ¨ that terminate in the extraocular motor nuclei andgroups 3 and 4, have axons that cross the midline the spinal cord appear to be quantitatively less inin the same anterior–posterior plane as their par- the monkey than in the cat. While virtually everyent somata and bifurcate to ascend and descend. feline VOR cell travels to the spinal cord and ex-The caudal collaterals of these cells have variable traocular motor nuclei this is not the case for theterminations but the most common sites are the monkey. The relative lack of cells that carry themidline cell groups of the paramedian tracts (PMT identical signals to the extraocular and neck moto- ´cell groups) — often mistaken for raphe nuclei — neurons probably reflects the fact that the monkeyRoller’s nucleus, and the dorsal paramedian re- VOR is dominant over the vestibulo-collic reflex.ticular formation below the nPH. There are also afew terminals in the ventral portions of the nPH.Terminals in the PMT cell groups of the posterior Otolith-ocular reflexes — tilt and translationmedulla that project heavily to the flocculus of the In addition to an aVOR there is a translationalcerebellum (Blanks et al., 1983; Langer et al., VOR or TVOR that produces compensatory eye1985a; Buttner-Ennever and Holstege, 1986; Butt- ¨ ¨ movements for head translation rather than rota-ner-Ennever and Buttner, 1988; Buttner-Ennever ¨ ¨ tion (Raphan et al., 1992, 1996, 2001; Wearneet al., 1988, 1989) may be one major route by et al., 1999; Moore et al., 2001; Raphan andwhich the flocculus receives oculomotor-related Cohen, 2002; Angelaki, 2004). The sensory signalssignals. Thus far no function for Roller’s nucleus that drive the TVOR arise from both the otolithin oculomotor control has been suggested. organs and the semicircular canals. The demands There are some differences between feline and of the TVOR are different from those of the VOR.primate VOR neurons. The number of neurons While the VOR stabilizes images upon the visual
  • 149. 188fovea this is impossible for the TVOR because of review of this subject, see Balaban and Yatesthe flow of optical images during translation. (2003).Thus, the TVOR depends upon viewing distanceand vergence angle (Moore et al., 1999). Latencyof the TVOR is longer than its aVOR counterpart, Vestibulo-cerebellar pathwaysbeing about 12 ms at its shortest. There are reportsof abducens neurons receiving monosynaptic in- Sources of mossy fiber afferents carrying vestibularput, presumably of otolithic origin (Uchino et al., signals1994, 1996, 1997b); however, most inputs are po- Vestibular nerve. Direct primary afferent input tolysynaptic (Uchino et al., 1994, 1996, 1997a, b, c, the cerebellar cortex is limited to the nodulus (ca-2000; Imagawa et al., 1998; Isu et al., 2000; nals) and uvula (otoliths) (Gerrits et al., 1989;Kushiro et al., 2000; Sato et al., 2000; Zakir Maklad and Fritzsch, 2003; cf. above and Chapter 8).et al., 2000; Zhang et al., 2001, 2002; Bai et al.,2002; Meng et al., 2002). Most of the otolith- Vestibular nuclei. The vestibular nuclei are a ma-activated vestibular nucleus neurons also appear jor source of afferents to the cerebellar floccularto project to the spinal cord, and about 50% of complex. Neurons from the y-group SVN, MVN,utricular activated neurons receive commissural vLVN, and DVD end in the granular layer asinhibition. Thus, the majority of signals that move mossy fibers (Gerrits et al., 1984; Thunnissen et al.,the eyes during translation utilize polysynaptic 1989; Epema et al., 1990). The distribution of ves-pathways. Interested readers are referred to tibular nucleus neurons projecting to flocculus andAngelaki (2004) for a recent review of the subject. nodulus-uvula are overlapping. The majority of neurons are found in the MVN, SVN, and DVN. Deiters’ nucleus is notable by its absence of pro- jections to the nodulus–uvula. Many more neu-Vestibulo-autonomic pathways rons project to the nodulus and uvula than to the flocculus, and still fewer neurons project to bothVertigo, emesis, vestibular baroreceptor, and sites.hemodynamic interactionsFigure 18 illustrates the major vestibulo-autonomicpathways. From this overview one can glean the Nuclei of the paramedian tractsconcept that brainstem regions that regulate motor The nuclei of the PMTs were first noted as pre-and autonomic functions integrate vestibular, floccular structures by Blanks et al. (1983) andproprioceptive, somatosensory, visual, and viscer- have been studied extensively by Buttner-Ennever ¨al inputs, all under the putative influence of the (see Chapter 5; Buttner-Ennever et al., 1989; ¨cerebellar cortex. This anatomical information is Buttner-Ennever and Horn, 1996, 1997). There ¨consistent with the view that multiple sensory mo- are at least six relatively separate ‘‘PMT groups’’dalities are employed to construct the vector rep- scattered in the medial longitudinal fasciculus,resenting the organism’s orientation to gravity. rostral to, and even within, the abducens nucleus.Although the effects of gravitoinertial accelera- They continue back to the level of the hypoglossaltions can be detected by multiple systems, these nucleus. In the cat, rat and monkey they have beendifferent sensory stimuli are reported differentially given different names by different investigators: weby each sensory modality. Thus the integration of use the individual terms introduced by Langer andmultiple sensory systems in regulating autonomic colleagues. The PMT cell groups are the recipientfunction is another example of multi sensory in- of ascending collaterals of many other oculomotortegration that occurs in several regions of the premotor nuclei, specifically the rostrally project-nervous system. As indicated by the diagram, vis- ing vestibular nucleus neurons (McCrea et al.,ceral sensory information reaches the brainstem 1987a, b), and they project to the flocculus. Thus,via multiple anatomical routes. For a complete these cells have been thought to be a source of the
  • 150. 189Fig. 18. Schematic of central nervous system vestibulo-autonomic pathways. The vestibular nuclei project via a direct descendingpathway to the dorsal motor vagal nucleus, ventrolateral medulla, lateral medullary tegmentum, and the nucleus ambiguus/par-ambiguus region. The vestibular nuclei also contribute an ascending projection to the caudal aspect of the lateral parabrachial nucleus(PBN), medial PBN, and the Kolliker–Fuse nucleus. These parabrachial nuclear regions also send projections to brain stem autonomic ¨regions such as the nucleus tractus solitarius, dorsal motor vagal nucleus, ventrolateral medulla, lateral medullary tegmentum, and thenucleus ambiguous–parambiguus region, which contribute to autonomic effector responses.efferent copy of intended eye movement to the Vestibulo-thalamo-cortical pathwaysflocculus (Hirata and Highstein, 2000, 2001) andhave been shown to be a part of the oculomotor There are apparent differences in the literature be-integrator circuit (Nakamagoe et al., 2000). tween the vestibulo-thalamic projections in the primate and rat. In the primate, ascending vest- ibulo-thalamic projections arise from limited ter-Vestibular inputs to the inferior olive ritories of the SVN and vLVN, travel by the MLF, ATD, and in loose ascending bundles between andCells of the b-nucleus and of the dorsal interme- around these fiber tracts to reach the thalamus.diate cell column (dmcc) of the inferior olive re- Axons arising from both the SVN and vLVNspond to dynamic and static roll and tilt of the travel both ispi- and contralaterally to terminate inhead (see Chapter 9). These olivary neurons re- the thalamic ventral posterior lateral nucleus (parsceive their vestibular input via axons of the ipsi- oralis) bilaterally, and to a lesser extent into thelateral parasolitary nucleus, a small GABAergic ventroposterior inferior nucleus and the nucleusnucleus that receives primary vestibular afferent ventralis lateralis (pars caudalis). From theseinput and secondary input from axons of the cont- thalamic nuclei, axons are relayed to the cerebralralateral y-group (Barmack, 2003). Thus, the de- cortex, primarily to area 3a (Lang et al., 1979).scending parasolitary pathway inhibits ipsilateral The vestibulo-thalamic connections in the ratolivary activity. However, the y-group descends to are reported to be much more extensive (e.g.,the contralateral olivary X nucleus and dmcc to Shiroyama et al., 1995, 1999). Fibers are thoughtexcite cells. Thus the olive receives a bilateral vesti- to arise from large portions of the vestibularbular representation (Barmack, 2003). nuclear complex and to terminate in the medial
  • 151. 190geniculate body and suprageniculate thalamic nu- as noted above. There have been extensive record-cleus to be subsequently relayed to the auditory ings taken from the vestibular nuclei of alert an-and insular cortices. There are also projections to imals; presumably neurons with eye movementthe ventral basal complex that project, in turn to related activity were related to the VOR (Henn etthe insular cortex, and to the centrolateral al., 1974; Miles, 1974; Miles and Fuller, 1974;thalamic nucleus that projects to the striatum. Shinoda and Yoshida, 1974a, b; Fuchs and Kimm,The rostral vestibular nuclear complex also 1975; Keller and Daniels, 1975; Waespe and Henn,projects to the thalamic centrolateral nucleus to 1977a, b; Lisberger and Miles, 1980; Reisine et al.,be subsequently relayed to the frontal eye fields, 1981; Chubb and Fuchs, 1982; Chubb et al., 1984;and to the lateral dorsal nucleus to be relayed Tomlinson and Robinson, 1984). These studiesagain to area 7. As in the primate, there are ves- have detailed the responses of vestibular nucleustibular projections to the ventrolateral–ventropos- neurons and have provided a catalog of responseterior lateral areas, which, in turn, connect to types. Responses can be divided into six classes:cortical area 3a. Finally, there is a projection to the (1) vestibular-only responses consisting of signalsthalamic ventrolateral nucleus that is relayed to similar to those recorded from primary afferents,motor cortex. Interested readers are referred to the (2) vestibular– pause cells, similar to those in (1)papers of Shiroyama et al. (1995, 1999) for a tab- except that they pause for all saccades, (3) gaze-ulation of the differential vestibulo-thalamo-cortical velocity cells that modulate their rates in propor-projections in several species (see also Chapter 15). tion to eye-velocity in space, (4) position cells that With the advent of modern imaging techniques change their rates with changes in eye-position buthere has been a recent revival of studies concerning do not burst or pause during saccades, (5) position–the vestibular cortex in human (Tusa and Unger- vestibular– pause cells that carry signals propor-leider, 1988; Tusa et al., 1989; Bucher et al., 1998; tional to eye-position in the head, head velocity,Dieterich et al., 1998, 2003a, b; Brandt and Diete- and pause for all saccades, and (6) position-burstrich, 1999; Bense et al., 2001; Dieterich and cells that carry an eye-position signal but burst forBrandt, 2001; Brandt et al., 2002; Deutschlander saccades in one direction and pause for saccades inet al., 2002; Brodsky and Tusa, 2004). A study by the opposite direction. The challenge is to relate thede Waele et al. (2001) used the evoked potential individual morphological types of neuron to themethod in subjects who were about to undergo a physiological signals carried and then to connectsurgical neurectomy. In these anesthetized pa- these neurons into a meaningful model of the ves-tients, electrical stimulation of the eighth nerve tibular and oculomotor machinery. How manyproduced short latency activation of five distinct neuronal types have been identified to date? Thecortical zones, including the prefrontal and/or best studied neurons in all species are the vestibularfrontal lobe, the ipsilateral temporo-parietal area, PVP neurons. These clearly form an important partanterior supplemental motor cortex, and the cont- of the middle leg of the three neuron arc. Theyralateral parietal cortex. There have also been fur- receive head velocity input from the eighth nervether animal studies in this area (Herdman et al., and eye position and velocity information from one1989; Tusa et al., 1990, 2002). Finally, Meng et al. or perhaps several sources (King et al., 1976; Pola(2001) have documented second-order utricular and Robinson, 1978). These neurons have beenneurons within the four major vestibular nuclei named position–vestibular–pause neurons (PVP).that project to the thalamus. PVP neurons in the horizontal system (both MVN and ATD neurons) terminate in the dorsal nucleus of the PPRF, the region that contains the excita-Physiological signals transmitted by secondary tory medium lead burst neurons (EBNs). Thus thevestibular neurons burst of PVP neurons during large, on-direction saccades may help to recruit the EBNs. The hor-There are several classes of physiologically identi- izontal inhibitory burst neurons (IBNs) terminatefied neurons within the vestibular nuclear complex in the regions of the somata of PVP neurons
  • 152. 191(Strassman et al., 1986a, b), presumably providing neurons, except for electrophysiological studies ofthe pause in the firing of these cells during most their activation by contralateral eighth nerve stim-saccades since IBNs fire during both horizontal and ulation (Shimazu and Precht, 1965, 1966; Shimazu,vertical saccades. 1972) are the vestibular commissural neurons. Species differences in PVP terminations in the SVN commissural neurons, for example, lie in themonkey and the cat might be equated with differ- parvocellular or ventral parts of the nucleus andent behaviors in these two species. The presence of have never been penetrated with microelectrodescollateral projections to the dorsal PPRF in the or injected with HRP. Whether the primate com-monkey, in contrast to the cat, is possibly partly missural system is related to eye movements at allresponsible for the generation of higher saccadic remains an open question which will hopefully beand quick phase velocities in this species. Even answered at the experimental bench.though vestibulo-collic neurons often carry signalsrelated to eye movements the fact that there areseparate VOR and VCR neurons in the monkey Referencesprobably reflects the relative uncoupling of the Akaike, T. (1973) Comparison of neuronal composition of theVOR and VCR in this species and may be the vestibulospinal system between cat and rabbit. Exp. Brainneural substrate that accounts for different gaze Res., 18: 429–432.shifting strategies in the two species. Akaike, T., Fanardjian, V.V., Ito, M. and Ono, T. (1973a) There are several examples of burst-tonic neu- Electrophysiological analysis of the vestibulospinal reflex pathway of rabbit. II. Synaptic actions upon spinal neurones.rons that also form a middle leg of the VOR, pre- Exp. Brain Res., 17: 497–515.sumably the inhibitory leg because their somata Akaike, T., Fanardjian, V.V., Ito, M., Kumada, M. andare located in the SVN (McCrea et al., 1987a, b). Nakajima, H. (1973b) Electrophysiological analysis of theThe sample size is too small to pinpoint projection vestibulospinal reflex pathway of rabbit. I. Classification ofpatterns that might be different from PVP neu- tract cells. Exp. Brain Res., 17: 477–496.rons. One might expect that neurons carrying eye Akaike, T. and Westerman, R.A. (1973) Spinal segmental levels innervated by different types of vestibulo-spinal tract neu-velocity information would tend to project to sac- rones in rabbit. Exp. Brain Res., 17: 443–446.cadic premotor areas more heavily than cells that Akaogi, K. (1994) [Afferent projections to the nodulus in thedo not carry this information. So far this specu- cat. II. Mossy fiber projections]. Nippon Jibiinkoka Gakkailation has not been tested. Kaiho, 97: 12–19. It is unfortunate that structure–function tech- Akbarian, S., Grusser, O.J. and Guldin, W.O. (1993) Cortico- fugal projections to the vestibular nuclei in squirrel monkeys:niques have only been applied to one of the many further evidence of multiple cortical vestibular fields.classes of physiological and/or morphological J. Comp. Neurol., 332: 89–104.types of neuron known to exist to date. There Akbarian, S., Grusser, O.J. and Guldin, W.O. (1994) Co-are no neurons other that PVP cells that have been rticofugal connections between the cerebral cortex and brain- stem vestibular nuclei in the macaque monkey. J. Comp.identified with these techniques. We can presume Neurol., 339: 421–437.that some of the vestibular-only cells project to the Anderson, J.H. and Beitz, A.J. (2000) Neurochemistry of theflocculus because neurons bearing a head velocity Vestibular System. CRC Press, Boca Raton.signal have been recorded there (Lisberger and Anderson, T.V., Moulton, A.R., Sansom, A.J., Kerr, D.R.,Fuchs, 1978a, b; Lisberger and Miles, 1980; Miles Laverty, R., Darlington, C.L. and Smith, P.F. (1998) Evi-and Braitman, 1980; Miles and Eighmy, 1980; dence for reduced nitric oxide synthase (NOS) activity in the ipsilateral medial vestibular nucleus and bilateral prepositusMiles et al., 1980a, b). Because of the paucity or hypoglossi following unilateral vestibular deafferentation inlack of primary afferent input to the flocculus the guinea pig. Brain Res., 787: 311–314.(Langer et al., 1985a) the vestibular nucleus neu- Angelaki, D.E. (2004) Eyes on target: what neurons must do forron is the only remaining candidate to provide this the vestibuloocular reflex during linear motion. J. Neuro- physiol., 92: 20–35.input. Flocculus projecting neurons in the monkey Armstrong, D.M., Saper, C.B., Levey, A.I., Wainer, B.H. andbranch only in the cerebellum (Highstein et al., Terry, R.D. (1983) Distribution of cholinergic neurons in rat1987). That is, there were no brainstem collaterals brain: demonstrated by immunocytochemical localization ofof these neurons. Perhaps the least well studied choline acetyltransferase. J. Comp. Neurol., 216: 53–68.
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  • 165. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 7 Nucleus prepositus Robert A. McCrea1,Ã and Anja K.E. Horn21 Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Abbott 09/MC 0926 947 E. 58th St., Chicago, IL 60637, USA 2 Institute of Anatomy, Ludwig-Maximilian University of Munich, Pettenkoferstrasse 11, 80336 Munich, GermanyAbstract: The cytoarchitecture and the histochemistry of nucleus prepositus hypoglossi and its afferent andefferent connections to oculomotor structures are described. The functional significance of the afferentconnections of the nucleus is discussed in terms of current knowledge of the firing behavior of prepositusneurons in alert animals. The efferent connections of the nucleus and the results of lesion experimentssuggest that it plays a role in a variety of functions related to the control of gaze.Introduction to most of the areas of the brainstem and cerebel- lum that are thought to be involved in controllingThe nucleus prepositus hypoglossi consists of a eye movements. These anatomical observations, incolumn of neurons in the medulla that occupies the conjunction with the findings that many neurons invacancy in the somatic efferent column between the the PH have spiking activity that is related to eyehypoglossal nucleus and the abducens nucleus. Its movements (Baker et al., 1976; Gresty and Baker,proximity to the hypoglossal nucleus gave it its 1976; Lopez-Barneo et al., 1982; Delgado-Garcianame (prepositus hypoglossi, PH), but there is et al., 1989; Escudero et al., 1992; McFarland andabundant anatomical and physiological evidence Fuchs, 1992; Cullen et al., 1993; Sylvestre et al.,that the nucleus is functionally better related to the 2003) and that lesions of the PH produce oculo-abducens motor nucleus that abuts it rostrally, so it motor control deficits (Godaux et al., 1993;is usually referred to simply as the prepositus nu- Mettens et al., 1994; Buttner and Grundei, 1995; ¨cleus. The first compelling reason for including the Kaneko, 1997, 1999), make the PH an importantPH in the oculomotor system was the finding that part of the brainstem circuitry involved in control-many of the cells in the PH project directly to the ling eye movements. In this chapter, the cytologicalextraoculomotor nuclei (Graybiel and Hartwieg, and histochemical characteristics of the PH and our1974; Maciewicz et al., 1977), and synapse with present knowledge of its afferent and efferentmotor neurons that innervate the extraocular mus- connections will be discussed.cles; particularly, the medial and lateral rectus mus-cles (Alley et al., 1975; Delgado-Garcia et al., 1989;Ozaki and Okamura, 1989; Labandeira-Garcia Cytoarchitecture and chemoarchitecture of theet al., 1990; Escudero et al., 1992; Graf et al., primate prepositus nucleus2002). Other anatomical studies, which will be re-viewed below, have shown that the PH is connected The details of the cytoarchitecture of the PH varynot only to the extraocular motor nuclei, but also from species to species, particularly in regard to the relationship of the nucleus to small satelliteÃCorresponding author. Tel.: +1 773 702 6374; cell groups such as Roller’s nucleus, the nucleusE-mail: intercalatus of Staderini, the nucleus supragenualisDOI: 10.1016/S0079-6123(05)51007-0 205
  • 166. 206 the nucleus merges with the MV nucleus. The region in which the two nuclei merge characteris- tically is populated with relatively small cells. Rostrally, the PH is displaced by the genu of the facial nerve (nVIIg) and the nucleus supragenualis nervi facialis (SG) (Fig. 2L and M). There are noticeable regional cytological differ- ences within the PH. The most caudal part of the PH is wedged between the hypoglossal nucleus (XII) and the dorsal motor nucleus of the vagus nerve (X) (Fig. 2A). It can be divided into a dorsolateral region (parvocellular region of prep-Fig. 1. Overview of Macaque prepositus nucleus: saggital sec- ositus nucleus, PHs, Fig. 2A–D) containingtion through the prepositus hypoglossi nucleus (PH) counter- primarily small cells, which merges caudally withstained with cresyl violet. The dotted lines indicate the planes of the nucleus intercalatus, and a ventromedial regionfrontal sections in Fig. 2. Scale bar: 500 mm. XII, Hypoglossalnucleus; RO, Roller’s nucleus; INT, nucleus intercalatus; PH, (magnocellular prepositus nucleus, PHm, Fig.prepositus nucleus; nVII, genu of the facial nerve; SG, nucleus 2A–F), which merges with the RO and containssupragenualis nervi facialis; VI, Abducens nucleus. darkly stained medium-sized and large multipolar cells. In parvalbumin (PV) staining, the cells of thenervi facialis, and cell groups associated with the PHm are moderately labeled, whereas the PHs ismedial longitudinal fasciculus (MLF) (Brodal, rather pale (Fig. 2D). It is probably the same1983). However, the major cytological features of population of PV-positive neurons that is enshea-the PH appear to be present in all mammals. The thed by prominent perineuronal nets, which can bePH is a relatively large nucleus in the posterior visualized with antibodies against chondroitin sul-brainstem, although this is often not appreciated fate proteoglycans, and are presumably associatedbecause of its relatively small size in standard with fast firing neurons (Horn et al., 2003). Infrontal sections. Figure 1 is a photomicrograph of caudal sections, the PH is separated dorsolaterallya sagittal section through the PH of the Rhesus from the MV nucleus by a triangular-shaped fibermacaque monkey. The nucleus spans the rostral tract, the dorsolateral fasciculus, that lies ventralhalf of the medulla between the hypoglossal (XII) to the surface of the fourth ventricle near theand abducens (VI) nuclei. It is bounded caudally faintly visible sulcus limitans (sl) (arrows inby the hypoglossal nucleus (XII), and merges at Fig. 2F). Many of these fibers are strongly labe-that point with the other two perihypoglossal nu- led in PV-stained sections (Fig. 2D and H).clei; the nucleus intercalatus dorsolaterally (INT) Midway between the hypoglossal and abducensand the nucleus of Roller (RO) ventromedially. In nuclei the PHm is no longer recognizable. Thetransverse sections, the PH appears as a relatively nucleus at those levels (Fig. 2E–H) consists of asmall nucleus on the ventral surface of the fourth central core region encapsulated dorsally and lat-ventricle that is wedged between the MLF medi- erally by a belt region containing lightly myelin-ally and the medial vestibular (MV) nucleus later- ated fibers and small cells (Fig. 2E and F). Theally. Figure 2 shows a series of transverse sections central region of the PH is relatively poorly stainedcut through the PH at six different levels indicated in sections reacted for the presence of PV ( the dashed lines in Fig. 1. Dorsolaterally, the 2H), but the neuropil is relatively strongly stainedPH is delimited by the shallow, rostral continua- in sections reacted for the presence of calretinintion of the sulcus limitans (arrows in Fig. 2A–F (CR), which delineates the nucleus clearly fromand G–M). Ventrally, the nucleus is poorly sepa- surrounding structures (Fig. 2K).rated from the reticular formation by transversely In primates, a subnucleus of the MV nucleus, thecoursing fiber bundles. The fibers of the MLF marginal zone (MZ) (Langer et al., 1986; Spencerdefine the medial border of the nucleus. Laterally, et al., 1989), abuts the rostral half of the PH
  • 167. 207Fig. 2. Frontal sections through the perihypoglossal nuclei of the Macaque. Sections on the left are stained with cresyl violet (A, C, E,G, I, L). Sections on the right are corresponding sections showing the distribution of glutamate decarboxylase (GAD) (B), Parv-albumin (PV) (D, H), calretinin (CR) (K, M), or myelin (F) at comparable levels. The arrow indicates the sulcus limitans (sl). Scale bar:500 mm. IFM, medullary intrafascicular nucleus; PHm, magnocellular prepositus; PHs, small cell region of prepositus; MLF, mediallongitudinal fasciculus; MV, medial vestibular nucleus; MZ, marginal zone of the medial vestibular nucleus; SG, nucleus supragenualisnervi facialis.laterally (Fig. 2G–K). The MZ contains tightly the MZ express glutamate decarboxylasepacked, medium-sized neurons, most of which (GAD) immunoreactivity (Fig. 3B; see sectionproject either to the ipsilateral or to the contralat- ‘‘Neurotransmitters of the PH’’3), implying gamma-eral abducens nucleus (Fig. 3A). In contrast to the aminobutyric acid (GABA) as their transmitter.PH, the neurons and neuropil of the MZ are strong- The rostral end of the PH contains primarilyly PV immunoreactive (Fig. 2H). In CR staining, the medium-sized and small cells that are less intenselyMZ is highlighted by its complete lack of immuno- stained with cresyl violet and more loosely arrangedreactivity compared to the labeled adjacent MV and (Fig. 2I and L). Ventrally, the nucleus is dented byPH (Fig. 2K). In addition, many neurons within the accumulating fibers of nVIIg. Laterally, the
  • 168. 208Fig. 2. Continued.nucleus is bounded by the rostral continuation of and axonal morphology of neurons in differentthe MZ and the caudal aspect of the abducens nu- regions of the cat PH has been studied with thecleus (VI). At the level of the abducens, the PH intracellular injection of single neurons in vivomerges imperceptibly with the supragenual nucleus (McCrea and Baker, 1985b). In that study, threeof the facial nerve (SG), which expresses strong CR different types of soma-dendritic architecture wereimmunoreactivity (Fig. 2L and M). In man and observed: (1) ‘‘multidendritic’’ cells in the PHm; (2)chimpanzee, the SG was considered as a loose small cells in the PHs; and (3) medium-sized ‘‘prin-celled continuation of the PH by Brodal (1983). cipal’’ cells in the rostral, central region of the PH. Multidendritic neurons (Fig. 4) typically haveMorphological characteristics of PH neurons complex dendritic trees that radiate within the PHm. The dendritic arbor arises from many thickThe anatomical characteristics of individual neu- proximal dendrites and ramifies extensively withinrons in the PH vary considerably. The dendritic the PH, although it is typically confined to the
  • 169. 209Fig. 3. Frontal section through the marginal zone (MZ) of the medial vestibular nucleus (MV): (A) marginal zone neurons retro-gradely labeled with cholera toxin subunit B (CTB) following an injection in the contralateral abducens nucleus; (B) comparablesection stained for glutamate decarboxylase (GAD) immunoreactivity. Scale bar: 500 mm. PH, prepositus nucleus; MV,medial vestibular nucleus; MLF, medial longitudinal fasciculus; MZ, marginal zone. Fig. 4. Multidendritic prepositus neuron. (Adapted from McCrea and Baker, 1985a.)ventromedial aspect of the nucleus. The axons of ed following stimulation of that structure (McCreamultidendritic cells exit the nucleus, course vent- and Baker, 1985a) and they are retrogradely labe-rally near the midline, and turn laterally after led when horseradish peroxidase (HRP) is injectedreaching the inferior olive (IO); in some cases into the flocculus and nodulus (Brodal and Brodal,passing beneath that nucleus. In autoradiographic 1983; Roste, 1989). Multidendritic PH neuronsstudies, axons in these bundles continue laterally have not been observed to give rise to collateraland project into either the ipsilateral or contralat- projections to other areas of the brainstem.eral inferior cerebellar peduncle. Many multi- The small cells in the PHs typically have smalldendritic neurons project to the cerebellar dendritic trees that are largely confined to that re-flocculus, since they can be antidromically activat- gion of the nucleus (Fig. 5). These cells appear to
  • 170. 210 Fig. 5. Small cells in the dorsolateral prepositus an important role in the intrinsic connectivity whose axons arborize ipsilaterally are illustrated inof the PH, since they give rise to local collaterals, Fig. 7. The cell in Fig. 7A was located in the rostraland many cells in this region are labeled when part of the PH. It gives rise to axon collateralHRP is injected into the contralateral PH. The terminal arborizations within the PH, in adjacentresults of retrograde tracer studies have shown regions of the nuclei of the paramedian tractsthat small neurons in the dorsolateral PH also (PMTs), in regions of the nucleus paragiganto-project to other areas of the brainstem, particu- cellularis dorsalis (PGD) that contains inhibitorylarly the IO (see below) and to the cerebellum. burst neurons (IBNs) and in the ventral lateral ves- Principle cells are the most common cell type in tibular nucleus. The cell in Fig. 7B was located morethe cat PH, and examples are shown in Fig. 6. caudally. It also projected to the ipsilateral PH, ad-These medium-sized principal cells were found in all jacent nuclei of the PMTs, the medullary reticularparts of the nucleus, and constitute the only cell formation, and to the vestibular nuclei with moretype in the rostral part of the prepositus. Their profuse terminations in the MV nucleus.dendritic trees arise from only a few proximal In summary, the neurons in the PH are mor-dendrites and arborize in an isodendritic fashion, phologically heterogeneous in regard to both theirusually extending beyond the boundaries of the soma-dendritic morphology and their axonal pro-nucleus. Many of these principal cells have axons jections. These different types of cells tend to bethat give rise to local collaterals that terminate segregated into different regions that have differ-within the nucleus. Principal cells give rise to col- ent histochemical characteristics.lateral projections to a number of areas of thebrainstem, which are typically confined to one side Neurotransmitters of the PHof the brain; i.e., some neurons project exclusively toipsilateral targets, while others project exclusively A variety of transmitters are found in neuronalcontralaterally. Examples of two principal cells somata and terminals in the PH: Amino acid
  • 171. 211 Fig. 6. Prepositus principal cells.transmitters, such as GABA, glycine (GLY), and caudal PH (Fig. 2B). These GABAergic neuronsglutamate (GLU), monoamines, such as serotonin might represent part of the interneuron population(5-hydroxy tryptophan, 5-HT), peptides, which of the PH (see above; McCrea and Baker, 1985b)include vasopressin and corticotrophin-releasing with strong local connections within the perihypo-factor (CRF), and nitric oxide (NO). In some cases, glossal nuclei contributing to the strong labeling ofspecific neurotransmitters are associated with spe- terminals and fibers (see below). Combined tracingcific efferent pathways from the prepositus. For ex- and electron microscopic studies in the rabbitample, the pathway from the PH to the contralateral demonstrated that the commissural connectionsabducens nucleus arises primarily from glycinergic between the PH are predominantly GABAergic,PH neurons (Spencer et al., 1989), and the pathway and in turn contact in part GABAergic neuronsfrom the PH to the IO arises from both GABAergic (Arts et al., 2000). Some GABAergic neurons sendand cholinergic small cells in the PH (see Chapter 9; projections to the superior colliculus (guinea pig:Barmack et al., 1993; De Zeeuw et al., 1993). Hardy and Corvisier, 1991; cat: Appell and Behan, 1990), or the dorsal cap of the IO (De Zeeuw et al.,Gamma-aminobutyric acid 1993). A major GABAergic projection from the PH to the locus coeruleus (LC) is only shown in ratMost information about the presence of GABAergic so far (Aston-Jones et al., 1991). None of theneurons comes from studies applying antibodies GABAergic cells in the PH of monkey were shownagainst GABA itself or the GABA-synthesizing to project to the oculomotor nucleus (Carpenterenzyme GAD. Immunocytochemical staining et al., 1992).revealed that in cat only a very low number of GABA-positive fibers and punctate profiles,small neurons are GABAergic that are scattered presumably representing GABAergic terminals,throughout the PH (Yingcharoen et al., 1989). In are very prominent in the PH of cat and monkeymonkey, a similar collection of small GAD- (Fig. 2B). Aside from local neurons, afferentpositive neurons is located in the medial aspect of GABAergic terminal labeling might derive fromthe nucleus and along the lateral margin of the fibers originating in the flocculus of the cerebellum
  • 172. 212 are small neurons, and o5% are medium-sized or large (Yingcharoen et al., 1989). The highest con- centration of predominantly small GLY-positive neurons is found rostrolaterally in the PH. Based on cell size and location, most of these GLY- positive neurons belong to the population of small local circuit neurons and commissural neurons (see section ‘‘Morphological characteristics of PH neu- rons’’; Yingcharoen et al., 1989). The latter as- sumption is supported by the observation that the density of GLY-positive terminals and fibers is particularly high in the dorsolateral part of the PH—a location where a majority of commissural fibers of the PH appear to end (McCrea and Baker, 1985b). Moderately stained medium-sized GLY-positive neurons are located in the central portion and ventral margin of the cat PH (Spencer et al., 1989; Yingcharoen et al., 1989). These cells include projection neurons that send their axons to the contralateral abducens nucleus (Spencer et al., 1989). A slightly different distribution of GLY-positive neurons was noted in the PH of the rat, where a higher concentration of small- sized round neurons in the caudal part and a small number of large-sized neurons in the rostral part of the PH was found (Rampon et al., 1996). GLY-positive terminals are present throughout the neuropil of the PH, but exhibit their highest density in the dorsal and lateral parts of the PH.Fig. 7. Local projections of two prepositus principal cells.(Adapted from McCrea and Baker, 1985b.) DV, descending Except for a few small glycinergic neurons thevestibular nucleus; LV, lateral vestibular nucleus; MV, medial dendrites and somata of all cells in the PH arevestibular nucleus; RB, restiform body. contacted by GLY-positive terminals, some of which are linked together by thin GLY-immunoreactive(see Chapter 10; Yingcharoen and Rinvik, 1983) or fibers suggestive of boutons en passantthe vestibular nuclei (Walberg et al., 1990). In cat (Yingcharoen et al., 1989). One major portion ofand monkey, the presence of GABA-A-receptors the GLY-positive terminals in the PH might orig-within the PH is indicated by pharmacological inate from intrinsic and commissural neurons, butstudies with muscimol or bicuculline injections in- other important sources for glycinergic afferentsto the PH region, which result in a gaze-holding are the saccadic IBNs in the PGD, and neurons infailure (Mettens et al., 1994; Arnold et al., 1999). the ipsilateral MV nucleus, which also project toThe distribution of GABA receptors in the the abducens nucleus (Spencer et al., 1989).adjacent vestibular nuclei is described in Chapter 6. Glutamate and aspartateGlycine Approximately 90% of the neurons in the PHIn cats, E30% of the neurons within the PH are express GLU immunoreactivity. In a comparisonGLY immunoreactive. More than 75% of these of adjacent immunostained semithin sections,
  • 173. 213Yingcharoen et al. (1989) found that all GLU- of the IO indicative for the PH as source of thepositive neurons in the PH nuclei also express as- cholinergic terminals (see also Chapter 9; Departate (ASP) immunoreactivity, including those Zeeuw et al., 1993). Surprisingly, the PH-IOthat are GLY immunoreactive. Many of the GLU- projection in the rabbit is not cholinergic—as al-and ASP-positive neurons are multipolar, which ready obvious from the weak and diffuse CHATmight correspond to the multidendritic neurons staining in the IO of this species, but may use an-within the PH (see section ‘‘Morphological char- other transmitter, such as GABA (De Zeeuw et al.,acteristics of PH neurons’’). GLU- and/or ASP- 1993; see above). Combined tract-tracing andpositive neurons in the PH could be one source of immunocytochemistry revealed a cholinergic pro-excitatory afferents to the trochlear nucleus and jection from the caudal PH to the cerebellummedial rectus motoneurons in the oculomotor nu- (Barmack et al., 1992; Ikeda et al., 1992; Jaarsmacleus (see section ‘‘Projections to the extraocular et al., 1997), particularly to the contralateral cer-motor nuclei’’; Belknap and McCrea, 1988). How- ebellar flocculus and to a less extent to the ventralever, the significance of the somatal GLU and paraflocculus (Barmack et al., 1992).ASP immunolabeling (see below) for transmitter The PH is strongly positive for acetyl cholinefunction is not proven, since the metabolic pools esterase activity, which is probably due primarilymay be equal or exceed those of the transmitter to strong cholinergic inputs that the nucleus re-pools. Quantitative electron microscopic studies ceives. With different markers a considerable den-indicate a better correlation with terminal staining, sity of cholinergic terminals was observed in thesince GLU is much more strongly concentrated in PH of rat and monkey (Henderson and Sherriff,the terminals, when functioning as a transmitter, 1991; Kus et al., 2003).compared to metabolic pools (see Yingcharoen etal., 1989). GLU- and ASP-positive terminals are Serotonin—5-HTprimarily associated with dendrites of PH neuronsand could derive from several sources, such as the In monkeys, the lateral and ventral aspects of thevestibular nuclei or the paramedian pontine reticular PH receive a relatively dense supply of 5-HT-formation (PPRF) (see section ‘‘Projections to the immunoreactive varicosities (Horn, personalextraocular motor nuclei’’). observations). The PH of the rat is one of the nu- clei in the brainstem that exhibits a rather strong immunolabeling with antibodies against theAcetylcholine 5-HT2A-receptor (Fay and Kubin, 2000). Electro- physiological studies show that 5-HT has bothThe application of antibodies against the synthe- excitatory and inhibitory effects on PH neuronssizing enzyme choline acetyl transferase (CHAT) (Bobker, 1994), indicating that the PH may alsorevealed cholinergic neurons in the PH in several contain 5-HT1A receptors, which mediate anmammalian species (Henderson and Sherriff, 1991; inhibitory action of serotonin. The effects ofBarmack et al., 1992, 1993; Carpenter et al., 1992). 5-HT have been considered to be important forIn monkey, CHAT-positive neurons are present in regulating the activity of noradrenergic LCrostral portions of the PH, and only very few pro- neurons (Gorea et al., 1991).jection neurons to the oculomotor nucleus, whichlie further caudally, were shown to be cholinergic(Carpenter et al., 1992). There is some evidence for Neuropeptidesa cholinergic projection from the PH to the cont-ralateral dorsal cap of the IO, which is exclusively Galanin-immunoreactive neurons are foundlabeled by CHAT-positive fibers and terminals in throughout the rostrocaudal length of the PH inrat and monkey (Barmack et al., 1993). A lesion of the Cebus monkey (Kordower et al., 1992). Thethe PH in rat resulted in a reduced CHAT PH also contains a high density of CRF-immuno-immunoreactivity in the contralateral dorsal cap reactive neurons (Cummings and King, 1990;
  • 174. 214Ikeda et al., 1992). Combined retrograde tracing mals are treated with a NO donor prior to fixation.experiments revealed a strong CRF-positive pro- Intense neuropil labeling with the cGMP antibodyjection from the PH to the posterior vermis in the is seen in the dorsal part of the PH in the catrabbit, which makes up less than 10% of the CRF- (Moreno-Lopez et al., 1998). Interestingly, the MZpositive neuron population in the PH (Errico and between the PH and the MV nucleus contains nu-Barmack, 1993). An enkephalin input from PH to merous strongly labeled cGMP-immunoreactivethe LC has also been reported (Drolet et al., 1992). neurons, indicating NO-sensitive neurons, but is devoid of NO-releasing neurons, whereas the PH expresses strong NOS immunoreactivity, a markerNitric oxide for NO-releasing neurons. Since the MV nucleus contains only few cGMP-immunoreactive neu-NO is a diffusible gas that has been shown to act rons, this histochemical distinction between theas an intercellular messenger participating in many PH, MZ, and MV was used to define the MZ infunctional roles, e.g., in ischemia, neurotoxicity, the cat anatomically for the first time (Moreno-neurodegenerative processes, and modulation of Lopez et al., 2001). Combined tract-tracingsensory function (Cudeiro and Rivadulla, 1999). It revealed that the PH receives projections fromis converted from L-arginine to NO by the cGMP-positive neurons in the MZ and MV,NADPH-dependent NO-synthase (NOS). Either predominantly from the ipsilateral side.nicotinamide adenine dinucleotide phosphate Pharmacological studies in the alert cat demon-(NADPH) diaphorase histochemistry or NOS strated that the balanced production of NO by theimmunocytochemistry has been employed to study PH is necessary for the correct performance of eyethe location of NO-releasing neurons. movements, since unilateral injections of NOS The PH of the cat and monkey exhibits a strong inhibitors into the PH produce a severe long-lastingNOS immunoreactivity of neurons and the nystagmus (Moreno-Lopez et al., 1996). Further-neuropil (Satoh et al., 1995; Moreno-Lopez more, the results of the authors show that aet al., 2001). In the cat, approximately a third of velocity imbalance without apparent changes inthe Nissl-stained cells in the PH express NOS the eye position signals during spontaneous eyeimmunoreactivity. These NO-releasing neurons movements was evident. This indicates that theare present throughout the whole length of the NO produced by NO-releasing neurons in the PHPH, starting caudally as two columns—a medial is exclusively involved in the processing of hori-group of oval medium-sized neurons and a lateral zontal velocity signals, but not in the velocity-group of smaller multipolar neurons—which to-position integration mechanism, probably bymerge in the rostral PH into one central group of acting on the cGMP-immunoreactive neuropil insimilar sized neurons (Moreno-Lopez et al., 2001). the dorsal PH (Moreno-Lopez et al., 1998). On theCombined tract-tracing showed that 20–28% of other hand, the local administration of NO donorsthe PH-projection neurons to the abducens nucle- (S-nitroso-N-acetylpenicillamine) resulted in aus express NADPH activity, representing o2% of velocity imbalance combined with a gaze-holdingthe NO-releasing neurons in the PH (Moreno- deficit for horizontal spontaneous eye movements,Lopez et al., 2001). Double-labeling studies in the possibly due to affecting the cGMP-positive, NO-cat demonstrated that few neurons in the PH sensitive neurons in the MZ (Moreno-Lopez et al.,colocalize NADPH diaphorase activity and 1998), which suggests that the MZ is part of asomatostatin, or NADPH activity and GLU saccade-specific gaze-holding mechanism.immunoreactivity (Maqbool et al., 1995). The cellular mechanism of NO is to activatesoluble guanyl cyclase, resulting in an increase in Afferent projections to the PHintracellular cyclic guanosine monophosphate(cGMP), which can be used as a histochemical The PH receives inputs from a wide variety of areasmarker for NO-sensitive neurons, when the ani- in the brain (Belknap and McCrea, 1988; McCrea
  • 175. 215et al., 1989; Iwasaki et al., 1999). Afferents arise 4. The nucleus of the optic tract.from regions as far caudal as the spinal cord and as Many of the inputs to the PH share certainfar rostral as the prefrontal cortex. The nucleus functional and anatomical characteristics that canreceives inputs from cells in diverse sensory nuclei be encompassed in the following generalizations:such as the nucleus of the optic tract, the vestibularnuclei, the caudal spinal trigeminal nucleus, and the 1. The PH receives inputs from areas of the braincentral cervical nucleus; from cells in the extraocular that project to the extraocular motor nuclei ormotor nuclei and the ventral horn of the cervical the cervical spinal cord. This generalizationspinal cord; from the cerebral cortex, the cerebellar seems to be particularly true for neurons thatcortex, and the superior colliculus; from widespread project to the abducens nucleus. Every regionregions of the reticular formation; and from itself. of the brain that projects to the abducens nucleus also projects to the PH, and most of the reticular and vestibular neurons stainedOrigin of afferent inputs to the PH by intracellular HRP injections that termi- nate in the abducens nucleus also give rise toThe most important inputs arise from seven regions: collateral projections to the PH (Ishizuka 1. The perihypoglossal nuclei; particularly the et al., 1980; McCrea et al., 1980, 1987; prepositus itself, its contralateral counterpart, Yoshida et al., 1982; Strassman et al., and the nucleus intercalatus. 1986a, b; Grantyn et al., 1987; Ohgaki 2. The vestibular nuclei; particularly the medial, et al., 1988; Scudder et al., 1996; Iwasaki inferior, and ventrolateral vestibular nuclei et al., 1999). These inputs arise from premo- bilaterally. tor neurons that are involved in producing 3. The medullary reticular formation; particu- saccades as well as smooth eye movements. larly the regions of the PGD contralateral to Figure 8 shows collateral terminations of an the PH that contain inhibitory saccadic burst excitatory burst neuron (EBN) (A) and a neurons. position-vestibular pause (PVP) (B) premotor 4. The ipsilateral PPRF. neuron in the PH. Each axon was labeled af- 5. Mesencephalic peri-oculomotor nuclei; e.g., ter recording its firing behavior in alert squir- the ipsilateral rostral interstitial nucleus of rel monkey (Strassman et al., 1986a; McCrea the MLF, the interstitial nucleus of Cajal, the et al., 1987). The reconstructed terminal nucleus of the posterior commissure. arborization illustrated in Fig. 8A arose from 6. The extraocular motor nuclei and the cells in an EBN whose cell body was located in the their immediate environs. contralateral medullary reticular formation. 7. The cerebellum. The fastigial nucleus projects Its main axon continued rostrally to termi- to the prepositus nucleus in every species that nate in the abducens nucleus. Fig. 8B shows has been examined. The PH also receives inputs the PH collateral termination of an abducens from Purkinje cells in the cerebellar flocculus. projecting vestibular nucleus PVP. Neurons of this type are important components of Weaker, but notable inputs arise from several vestibulo-ocular reflex (VOR) pathways.other regions: Figure 9 illustrates diagrammatically the col- 1. The superior colliculus. lateral organization of the crossed excitatory 2. Regions of the cerebral cortex related to eye and uncrossed inhibitory secondary VOR path- movement control—the frontal eye fields, ways. Some neurons that project to the cervical supplementary eye fields, and the posterior spinal cord also give rise to axon collateral parietal cortex (area 7). projections to the prepositus (Grantyn et al., 3. Regions that receive inputs from neck 1987; Minor et al., 1990; Isa and Sasaki, 1992). proprioceptors—cervical spinal cord, area X 2. The PH receives inputs from areas that are of the vestibular nucleus. involved in the control of horizontal and
  • 176. 216 Fig. 9. Horizontal canal vestibulo-ocular pathway collateral inputs to the prepositus nucleus (PH). 3. The PH receives afferents from areas that provide inputs to the immediate premotor substrate for the control of gaze. Examples of such areas are the supplemental and fron- tal eye fields (Leichnetz, 1985; Stanton et al., 1988; Shook et al., 1990; Leichnetz and Gonzalo-Ruiz, 1996), the superior colliculus (Grantyn and Grantyn, 1982), the flocculus (De Zeeuw et al., 1993; Balaban et al., 2000), the fastigial nucleus (Ohtsuka, 1988; OmoriFig. 8. Terminations of collaterals of premotor neurons that et al., 1997), and the pretectal nuclei (Korpprojected to the abducens nucleus in the squirrel monkey PH:(A) reconstruction of the part of the terminal arborization of an et al., 1989; Magnin et al., 1989; Mustariexcitatory burst neuron in the PH (Strassman et al., 1986); (B) et al., 1994; Kato et al., 1995; Schmidt et al.,photomicrograph of the terminal arborization of a position- 1995; Buttner-Ennever et al., 1996; Vargas ¨vestibular-pause neuron in the PH (McCrea et al., 1987). et al., 1996; Iwasaki et al., 1999). These areas project to regions of the brainstem that con- tain premotor neurons mediating saccadic, vertical eye movements. Regions that provide pursuit, vestibular, and optokinetic eye inputs to the PH usually contain neurons movements. whose activity is related to eye and/or head 4. The PH receives inputs from some central movements and are areas in which lesions pro- autonomic nuclei. Notable in this regard are duce oculomotor deficits (Belknap and the dorsal raphe nucleus (Belknap and McCrea, 1988). As a rule, regions involved McCrea, 1988; Iwasaki et al., 1999; Vertes in controlling horizontal eye movements (e.g., and Kocsis, 1994) and the LC (Schuerger and the PPRF, horizontal secondary vestibular Balaban, 1999). In the monkey, the highest neurons) provide more numerous afferents density with noradrenergic fibers was found than those primarily involved in controlling in the dorsal and rostral parts of the PH vertical eye movements (e.g., the interstitial (Schuerger and Balaban, 1999). The dorsal nucleus of Cajal and the superior vestibular raphe nucleus is presumably an important (SV) nucleus). source of serotonergic inputs to the PH.
  • 177. 217Responses of PH neurons to sensory stimuli et al., 1993; Sylvestre et al., 2003). The single-unit recordings were obtained usually from the rostralThe results of electrophysiological and single-unit parts of the prepositus nucleus. The majority ofrecording studies confirm that PH neurons receive the neurons in the rostral part of the PH havevestibular, visual, and neck proprioceptive sensory spiking activity that is related to horizontal eyeinputs. Electrical stimulation of the vestibular nerve movements, although some cells have firing ratestypically evokes synaptic potentials in PH neurons that are better correlated with vertical or obliqueat disynaptic latencies (Baker and Berthoz, 1975; eye movements. Different classes of PH neuronBlanks et al., 1977; McCrea and Baker, 1985a). have been described, based on the correlation inMost neurons receive excitatory inputs from the their firing rate with eye movements:contralateral vestibular nerve and inhibitory inputsfrom the ipsilateral vestibular nerve. The firing rate 1. Position– velocity neurons that have ‘‘burst-of most PH neurons is modulated during passive tonic’’ firing behavior related to eye positionangular rotation in the horizontal plane (Baker and and eye velocity. This firing behavior is similarBerthoz, 1975; Lopez-Barneo et al., 1982; McFarland to that observed in abducens motoneurons. Theand Fuchs, 1992). In most cases the modulation firing rate of most of these neurons is best re-phase lags contralateral head velocity. There is some lated to ipsilateral eye movements (Delgado-evidence in the guinea pig that a fraction of the Garcia et al., 1989; McFarland and Fuchs, 1992;neurons in the PH are sensitive to linear translation Escudero et al., 1996; Sylvestre et al., 2003).as well as angular rotation (Kaufman et al., 2000). 2. Velocity– position neurons also have burst-tonic Some PH cells are sensitive to passive neck ro- firing patterns, but their firing rate is muchtation (Gresty and Baker, 1976) and others are more strongly related to eye velocity than tosensitive to retinal image slip that is presumably eye position (Delgado-Garcia et al., 1989).due to cervical neck proprioceptive inputs from the 3. Position neurons are relatively insensitive tospinal cord and external cuneate nucleus (McCrea eye velocity and but have a tonic firing ratedand Baker, 1985a; Stechison and Saint-Cyr, 1986; related to eye position. They have been re-Prihoda et al., 1991; Lan et al., 1994) and inputs ported to be located more ventrally than neu-from the accessory optic nuclei (medial, lateral, rons that are sensitive to eye velocityand dorsal terminal nuclei) and the nucleus tractus (Delgado-Garcia et al., 1989).opticus in the pretectum (PT), respectively (see 4. Burst-driver neurons generate bursts of spikesChapter 12). The neck proprioceptive inputs have during contralateral quick phases of nystag-been suggested to play a role in the construction of mus and have a slow build-up in firing ratean internal estimate of gaze position (McCrea and during the contralaterally directed headGdowski, 2001). The visual inputs probably play movements (which evokes an ipsilaterallyan important prominent role in the transmission of directed slow phase of vestibular nystagmus).visual optokinetic signals to vestibular neurons These neurons tend to be located in the ven-and VOR pathways (Cazin et al., 1982, 1984; tral part of the rostral PH, and are thought toCheron et al., 1986; Kaneko, 1999). play a crucial role in triggering anticompen- satory quick phases of vestibular nystagmusFiring behavior of PH neurons related to eye (Ohki et al., 1988).movements 5. Eye– head– vestibular neurons have been de- scribed in the primate prepositus nucleus. TheDetailed descriptions of the eye-movement-related firing rate of these neurons is strongly relatedresponses of PH neurons have been provided in to smooth pursuit eye movements. Duringrodents (Lannou et al., 1984; Kaufman et al., VOR cancellation, their firing rate of these2000), cats (Lopez-Barneo et al., 1982; Escudero cells is related to angular head velocity in theand Delgado-Garcia, 1988; Kitama et al., 1995), same direction as their eye movement on di-and primates (McFarland and Fuchs, 1992; Cullen rection. They are thought to play an important
  • 178. 218 role in VOR suppression and cancellation. of these projections are summarized in Figs. 10 Similar neurons have been found in the MV and 11. nucleus and in more lateral regions of the ves- tibular nuclei (McFarland and Fuchs, 1992). Projections to the cerebellum 6. Various other saccade-related neurons have been described. Some cells have no apparent The first efferent connection of the PH described sensitivity to eye movement other than to with modern techniques was its projection to the pause or burst during saccades. cerebellum (Brodal, 1952). The extensive projec- 7. Vestibular-related neurons. Many PH neurons tions of the PH to the cerebellum make it an im- have firing behavior that is poorly correlated portant precerebellar nucleus, and the suggestion with eye movements, although they remain that its function is closely tied to that structure sensitive to head movements (Delgado- (Brodal, 1952) remains valid. Figure 10 is a map of Garcia et al., 1989). the location of labeled mossy fiber terminations Most of these single-unit recordings were ob- QJ;in the cerebellar cortex of the squirrel monkeytained primarily from the rostral part of the prep- (Belknap and McCrea, 1988). The regions of theositus nucleus. Consequently, it is not clear what cerebellar cortex that receive the heaviest inputssignals the neurons in the caudal regions of the PH from the PH are regions that are thought to begenerated during eye or head movements. involved in controlling eye movements, i.e., the floccular-nodular lobe, the ventral paraflocculus, and the posterior vermis (see Chapter 10). InEfferent projections of the PH primates, the PH also gives rise to significant projections to the cerebellar hemispheres.The PH has widespread projections to many ar- Much of our knowledge concerning the origin ofeas of the cerebellum and brainstem. The targets PH projections to the cerebellum has come from Fig. 10. Location of prepositus mossy fiber afferents to the cerebellum. (Adapted from Belknap and McCrea, 1988.)
  • 179. 219Fig. 11. Schematic diagram of the brainstem efferent projections of the PH. Thick traces indicate strong pathways. MAO, medialaccessory inferior olive; DC, dorsal cap of Kooy of the inferior olive; INT, nucleus intercalatus; MV, medial vestibular nucleus; DV,inferior vestibular nucleus; X, vestibular subnucleus X; VLV, ventral lateral vestibular nucleus; SV, superior vestibular nucleus; SG,nucleus supragenualis facialis; VI, abducens nucleus; CBL, cerebellum; PPRF, paramedian pontine reticular formation; PPRFc, caudalPPRF; PPRFo, rostral PPRF; RP, pontine raphe nuclei—including raphe interpositus, nucleus of the paramedian tracts, and nucleusreticularis tegmenti pontis; IV, trochlear nucleus; III, oculomotor nucleus, including the medial rectus (MR) subdivision; MRF,mesencephalic reticular formation; PB, peri-parabigeminal nucleus; PT, pretectum—particularly the nucleus of the optic tract; LGNv,ventral lateral geniculate nucleus; CM, CL, central medial and central lateral thalamic nuclei.studies in which the location of labeled cells in the (Alley et al., 1975; Ruggiero et al., 1977; RubertonePH was mapped following injections of retrograde and Haines, 1981; Yingcharoen and Rinvik, 1982;tracers into different regions of the cerebellum Brodal and Brodal, 1983; Sato et al., 1983;
  • 180. 220Yamada and Noda, 1987; Roste, 1989; Gonzalo- (Ruggiero et al., 1977; Gonzalo-Ruiz andRuiz and Leichnetz, 1990a, b; Barmack et al., Leichnetz, 1990a; Talman and Robertson, 1991;1992; Errico and Barmack, 1993; Jaarsma et al., Leichnetz and Gonzalo-Ruiz, 1996).1997; Nagao et al., 1997). The main findings thathave emerged from these studies are summarizedas follows: Projections to the medulla 1. Neurons of all sizes in virtually every region In the medulla, the PH projects bilaterally to four of the PH provide mossy fibers to the cere- main areas: the perihypoglossal nuclei, the IO, the bellar cortex. A smaller percentage of the vestibular nuclei, and the PGD in medullary re- cells in the rostral PH project to the cerebel- ticular formation. The PH projects to all parts of lum compared to the projection from cells in the perihypoglossal nuclei bilaterally, but the the caudal part of the nucleus. Most of the strongest projections are to the contralateral nu- multidendritic cells in the caudal ventral PH cleus intercalatus and PH (McCrea and Baker, project to the flocculus and nodulus (Alley 1985b). et al., 1975; McCrea and Baker, 1985a; The projections to the IO are bilateral (McCrea Roste, 1989). and Baker, 1985a). The contralateral projections to 2. More PH neurons project to the ipsilateral the IO terminate primarily in the dorsal cap of cerebellar cortex than project contralaterally. Kooy and adjacent ventrolateral outgrowth of the The cortical regions that receive the strongest principal olive, and arise from GABAergic and projections are the flocculus, the ventral par- non-GABAergic small cells in the caudal PH aflocculus, and the posterior vermis; i.e., re- (Barmack et al., 1993; De Zeeuw et al., 1993). An gions that are thought to be involved in ipsilateral projection from the PH to the IO arises controlling eye movements. The PH is one of from neurons scattered throughout the PH and the sources of cholinergic mossy fiber affer- terminates primarily in the dorsomedial aspect of ents to the cerebellar cortex (Barmack et al., the rostral half of the medial accessory olive; an 1992; Jaarsma et al., 1997). area corresponding to the subnucleus b of the me- 3. The majority of the antidromically activated dial accessory olive (McCrea and Baker, 1985a; neurons that project to the contralateral Balaban and Beryozkin, 1994). Double labeling flocculus have firing behavior related to studies suggest that olivary projecting PH neurons ipsilateral eye position and eye velocity do not project to the oculomotor nucleus (Wentzel (Escudero et al., 1996). Other precerebellar et al., 1995). Thus, the PH projects to regions PH neurons have spiking behavior that is of the IO that receive inputs from the PT poorly correlated with eye movements or (Mizuno et al., 1973), accessory optic nuclei burst during saccades. Some burst-driver- (Mizuno et al., 1973; Maekawa and Takeda, type neurons also project to the flocculus. 1979; Simpson et al., 1979) and the superior 4. The projection from the PH to the cerebellar colliculus (Frankfurter et al., 1976; Graham, cortex tends to be topographically organized, 1977). These regions of the IO send climbing fib- although the sites of origin of afferents to ers to the flocculus, nodulus, and posterior vermis different cerebellar regions seem to overlap (Alley et al., 1975; Hoddevik et al., 1976; Hoddevik considerably. Some PH neurons projected to and Brodal, 1977; Frankfurter et al., 1977). several areas of the cerebellum by collateral- The projections from the PH to the vestibular izing (Ruigrok, 2003). A few cells in the ros- nuclei are bilateral, although the contralateral ter- tral PH project to both the rostral brainstem minations are slightly stronger (Carleton and and the cerebellum (Yingcharoen and Rinvik, Carpenter, 1983; McCrea and Baker, 1985a). The 1982). medial, inferior, and ventrolateral vestibular nuclei The PH provides sparse projections to the cer- are major recipients of PH efferents, particularlyebellar nuclei; particularly the fastigial nucleus the ventromedial aspects of these nuclei. The SV
  • 181. 221nucleus receives relatively few inputs, and there ipsilateral PH and a relatively strong disinhibitorydoes not appear to be a projection from the PH to input from many neurons in the contralateral PH.the dorsal lateral vestibular nucleus. The projec- The PH neurons that can be antidromically ac-tion from the PH to the vestibular nuclei arises in tivated from the oculomotor region tend to bepart from collaterals of neurons projecting to oth- more sensitive to eye velocity than those thater areas of the brainstem or the cerebellum, and is project to the abducens nucleus, and most wereprobably not topographically organized at the categorized as position–velocity or velocity–gross level, since single PH neurons project to sev- position cells, although pure position neuronseral vestibular nuclei (Fig. 7B). were antidromically identified as well. They typi- The PH projects bilaterally to the PGD just cally resided in the ipsilateral PH, and had firingventral to the rostral half of the PH. In the cat, the behavior related to ipsilateral eye movements andregion of heavy termination is bounded rostrally contralateral head movements (Delgado-Garciaby the abducens nucleus and dorsally by the PH et al., 1989).(Fig. 7A). It extends mediolaterally approximately The PH also projects to regions adjacent to thethe width of the PH, and ventrally 1–2 mm from extraocular motor nuclei; i.e. the nucleus sup-the ventral border of the PH. The medal aspect of ragenualis nervi facialis, the periaqueductal graythis region of the reticular formation is the area of dorsal to the oculomotor nucleus, and thedensest termination, and corresponds to the region Edinger–Westphal nucleus (McCrea and Baker,in which inhibitory saccadic burst neurons are lo- 1985a; Belknap and McCrea, 1988). Each of thesecated (Hikosaka et al., 1980; Yoshida et al., 1982; regions projects back to the PH.Strassman et al., 1986b). The role of the PH in the oculomotor integratorProjections to the extraocular motor nuclei Most central eye movement motor commands are primarily related to eye velocity. For example, theThe PH projects bilaterally to all parts of all of the firing rate of premotor saccadic burst neurons andextraocular motor nuclei, although the strongest secondary VOR neurons is related primarily to eyeprojections are to the contralateral abducens nu- velocity. The elastic properties of the orbital plantcleus and the ipsilateral medial rectus subdivision of require that the eye velocity commands be cen-the oculomotor nucleus (Baker and Berthoz, 1975; trally integrated into a tonic signal that drivesMcCrea and Baker, 1985a; Belknap and McCrea, motor units to hold the eye in a new position1988; Ozaki and Okamura, 1989; Delgado-Garcia (Robinson, 1970). There is now considerable evi-et al., 1989; Robinson et al., 1994). The PH neurons dence that the PH is a necessary part of the neuralthat project to the contralateral abducens nucleus substrate that is used for gaze holding in the hor-have been shown to evoke spike triggered averaged izontal plane. As noted above, prepositus neuronsfield potentials that correspond to inhibitory that project to the abducens nucleus and to thepostsynaptic currents, while the spike triggered av- oculomotor nucleus carry signals related to eyeeraged field potentials evoked by PH neurons that position. These signals, together with weaker eyeprojected to the ipsilateral abducens nucleus cor- position signals carried by VOR pathways, areresponded to excitatory postsynaptic currents apparently the sufficient premotor neural inputs to(Escudero et al., 1992). The firing rates of both horizontal motoneurons to maintain eye position.ipsi- and contralaterally projecting PH neurons Lesions that compromise the PH and adjacent re-were correlated primarily with ipsilateral eye posi- gions of the MV nucleus, as well as injections oftion. Thus, the net input from the PH to the ab- chemicals that inhibit neurons in these regions,ducens nucleus after an ipsiversive saccade is a produce a profound gaze nystagmus characterizedcombination of a relatively weak increase in exci- by an inability to maintain eccentric gaze in thetatory input from eye position neurons in the ipsilateral direction (Godaux et al., 1993; Godaux
  • 182. 222and Cheron, 1996; Kaneko, 1997; Arnold et al., to the LC is considered to be one of that nucleus’s1999). It is generally thought that the temporal major inputs (Ennis and Aston-Jones, 1989;integration of eye velocity commands into signals Pieribone and Aston-Jones, 1991; Van Bockstaelerelated to eye position is accomplished by recip- and Aston-Jones, 1992; Luppi et al., 1995), althoughrocal connectivity within the PH and the MV nu- this projection has not been observed in other spe-cleus (Fukushima and Kaneko, 1995; Draye et al., cies and was not reported in recent careful studies1997; Moschovakis, 1997). However, it is possible carried out in the rat (Iwasaki et al., 1999).that a cellular mechanism may mediate this func- In the caudal mesencephalic reticular formationtion (Rekling and Laursen, 1989). (MRF) the PH terminates bilaterally in the lateral One feature of the velocity–position integrator mesencephalic tegmental region (McCrea andthat must be kept in mind is that recent evidence Baker, 1985a; Gerlach and Thier, 1995), which in-suggests that the neural commands to each eye, if cludes in particular a region of the reticular for-not each extra-ocular muscle, must be separately mation that surrounds the parabigeminal nucleusintegrated and stored during linear translation on all sides, except the side on the surface of the(King et al., 1994; McConville et al., 1994). This brainstem. A few PH axons also project diffuselyconsideration may explain why the PH has sepa- to the central MRF dorsal and lateral to the cau-rate projections to both the medial and lateral re- dal part of the contralateral red nucleus. The PHctus motoneurons, and why the nucleus has such a has weak efferent connections with the interstitiallarge population of neurons compared to other nucleus of Cajal (Ostrowska et al., 1990) and thepremotor nuclei related to oculomotor control. rostral interstitial nucleus of the MLF (Belknap and McCrea, 1988).Projections to the pontine and mesencephalicreticular formation Projections to the superior colliculus and pretectumIn the caudal part of the pons (at the level of the The PH projects to the superior colliculus bilater-trigeminal motor nucleus), PH axons terminate ally, although the contralateral projection appearsprimarily contralaterally in the dorsomedial part to be much more important (McCrea and Baker,of the PPRF ventral and lateral to the MLF 1985a; Hartwich-Young et al., 1990). Axons aris-(Leichnetz et al., 1987; Belknap and McCrea, ing from neurons in the middle and caudal regions1988; Iwasaki et al., 1999). In addition, at this level of the PH terminate in the intermediate layers ofaxons terminate in the periventricular gray dorso- the superior colliculus (Stechison et al., 1985; Higolateral to the MLF (Cornwall et al., 1990) the et al., 1992; Corvisier and Hardy, 1993). The pro-dorsal tegmental nucleus (Liu et al., 1984) and bi- jection tends to be denser in the caudal half of thelaterally in the nucleus raphe pontis (Langer and colliculus, where it also extends to deeper layersKaneko, 1984). The part of the nucleus pontis just (Corvisier and Hardy, 1993). Similar to other in-beneath the MLF must be considered as one of the puts to the superior colliculus, the PH termina-floccular-projecting cell groups of the PMTs (Langer tions occasionally appear to be concentrated inet al., 1985, Buttner-Ennever and Horn, 1996; ¨ patches spanning the intermediate layers, separat-Chapter 5). The termination in these midline nuclei ed by regions that are poorly labeled. In the guineacontinues rostrally, and is densest over the cell pig, this projection originates in part from small-groups that lie just dorsal to the nucleus reticularis and medium-sized GABAergic neurons and in parttegmenti pontis. A few axons terminate in the from glutaminergic neurons located mainly in thedorsal part of the tegmental reticular nucleus itself. caudal ventral half of the PH (Corvisier and PH axons have been reported to terminate in lat- Hardy, 1991; Hardy and Corvisier, 1991). The fir-eral regions of the pontine tegmentum (Cornwall ing behavior of PH neurons that project to theet al., 1990), including the pedunculopontine region superior colliculus is related to both eye position(Higo et al., 1990) and the LC. In rats, the projection and eye velocity, although these signals lead the
  • 183. 223comparable signals generated by extraocular mo- terminate in the nucleus centralis medialis. Thesetor neurons (Delgado-Garcia et al., 1989; Hardy thalamic projections tend to be stronger contra-and Corvisier, 1996). One possible function of the laterally. The fibers reaching the LGNv coursepathway could be to provide the eye-movement laterally and dorsally through the zona incerta,feedback signals that update the gaze error map where some may terminate.that is constructed in the intermediate layers of thesuperior colliculus based on internal estimates of The role of the PH in the control of gazefuture eye position (Corvisier and Hardy, 1997). The PH also projects bilaterally to the lateral The afferent and efferent projections of the prep-part of the PT, including the nucleus of the optic ositus nucleus clearly make it an important part oftract (McCrea and Baker, 1985a; Ohtsuki et al., the brainstem network that is involved in control-1992). Their termination in this area is stronger ling gaze. Figure 12 summarizes the major afferentcontralaterally, but it sparse compared to the ter-minations in the nearby superior colliculus. and efferent connections of the PH with other re- gions of the brain that are involved in gaze control. The nucleus receives strong inputs from regions ofProjections to the thalamus the brainstem reticular formation that are provide premotor commands to oculomotor and cervicalFibers originating primarily from the rostral PH motoneurons that change the direction of gaze. Itproject bilaterally to the ventral lateral geniculate also receives strong inputs from regions such as thenucleus (LGNv) and to the nucleus centralis lat- vestibular nuclei that give rise to pathways thateralis in the thalamus (Fig. 11) (Kotchabhakdi function to stabilize gaze in space. The PH receiveset al., 1980; McCrea and Baker, 1985a; Nakano weaker inputs from higher gaze control centers inet al., 1985; Niimi et al., 1990). A few fibers also the cerebral cortex, the tectum, and the cerebellum Fig. 12. Relationship of the prepositus nucleus to gaze control centers in the brain.
  • 184. 224that are more indirectly involved in producing eye internal estimate or efference copy of eye positionand head movements. Although the nucleus re- and velocity and possibly gaze position and veloc-ceives inputs from regions that are involved in ity. Neurons in the two nuclei have the appropriateproducing eye and head movements in more than physiological signals and have the anatomical con-one direction, the firing behavior of PH neurons is nections to distribute it to regions of the brain thatpredominantly related to horizontal eye and head are involved in controlling the generation andmovements. metrics of gaze shifts. The anatomical projections The most noticeable effect of lesions or inactiva- of the PH to the thalamus raise the possibility thattion of the PH is to produce a profound inability to it could be a primary source of extraretinal signalsstabilize gaze in the horizontal plane (Godaux et al., to cortical circuits that are involved in the cogni-1993; Mettens et al., 1994; Buttner and Grundei, ¨ tive distinction between sensory experiences that1995; Kaneko, 1997; Arnold et al., 1999). Conse- are produced by movements of objects in extra-quently, it is generally thought that the PH is the personal space from self-generated gaze shifts.most important source of eye, and possibly gaze, Helmholz (1896) suggested that the brain mustposition signals to brainstem circuits that are generate an internal estimate of the effort of willinvolved in stabilizing horizontal gaze (Fukushima used to move the eyes. Since that time the evidenceand Kaneko, 1995; Draye et al., 1997; for the existence of this centrally generated signalMoschovakis, 1997; Hazel et al., 2002). The direct has accumulated. The nucleus PH is an ideal placepathways from the PH to the abducens nucleus and to construct an internal representation of the effortthe medial rectus subdivision of the oculomotor it takes to move the eyes and hold them in a newnucleus seem likely to be an important component position, and it is well positioned to distribute thisof the brainstem circuitry for stabilizing gaze in the information to the diverse regions of the brain thathorizontal plane. But it is also likely that the PH can make use of it in a variety of functions.plays important and varied roles in maintaininggaze stability via its connections with central path- Abbreviationsways that produce the VOR and vestibulo-collicreflexes. The projection of the PH to the dorsal cap 5-HT 5 -hydroxy tryptophanof Kooy in the IO and the flocculus suggest that the III oculomotor nucleusnucleus plays an essential role in shaping the output IV trochlear nucleusof the regions of the cerebellar cortex that combine VI abducens nucleusvisual, oculomotor, and vestibular signals so that X motor nucleus of the vagal nervethe VOR is adaptively modified to provide image XII hypoglossal nucleusstability on the retina. ASP aspartate The PH also provides signals to brainstem cir- CGMP cyclic guanosine monophosphatecuits that change the direction of gaze. Burst-driver CHAT choline acetyl transferaseneurons in the PH that project to the pontine CR calretininreticular formation appear to play a critical role in CRF corticotrophin-releasing factorproducing quick phases of nystagmus (Kitama GABA gamma-aminobutyric acidet al., 1995). The PH is the most likely source of GAD glutamate decarboxylaselocal feedback eye movement efference copy sig- GLU glutamatenals to saccade-related burst neurons in the med- GLY glycineullary and pontine reticular formation. It provides HRP horseradish peroxidasesignificant inputs to the superior colliculus, to sac- INT nucleus intercalatuscade-related regions of the posterior vermis, and to LC locus coeruleusregions of the thalamus that project to the frontal LGNv ventral lateral geniculate nucleuseye fields. MLF medial longitudinal fasciculus A general function of the PH, together with the MRF mesencephalic reticularinterstitial nucleus of Cajal, may be to construct an formation
  • 185. 225MV medial vestibular Baker, R., Gresty, M. and Berthoz, A. (1976) Neuronal activityMZ marginal zone in the prepositus hypoglossi nucleus correlated with vertical and horizontal eye movement in the cat. Brain Res., 101:NADPH nicotinamide adenine 366–371. dinucleotide phosphate Balaban, C.D. and Beryozkin, G. (1994) Organization of ves-NO nitric oxide tibular nucleus projections to the caudal dorsal cap of kooyNOS nitric oxide synthase in rabbits. Neuroscience, 62: 1217–1236.nVII facial nerve Balaban, C.D., Schuerger, R.J. and Porter, J.D. (2000) ZonalnVIIg genu of the facial nerve organization of flocculo-vestibular connections in rats. Neuroscience, 99: 669–682.PGD paragigantocellularis dorsalis Barmack, N.H., Baughman, R.W. and Eckenstein, F.P. (1992)PH prepositus hypoglossi Cholinergic innervation of the cerebellum of rat, rabbit, cat,PHm magnocellular prepositus nucleus and monkey as revealed by choline acetyltransferase activityPHs parvocellular region of and immunohistochemistry. J. Comp. Neurol., 317: 233–249. Barmack, N.H., Fagerson, M. and Errico, P. (1993) Cholinergic prepositus nucleus projection to the dorsal cap of the inferior olive of the rat,PMT paramedian tract rabbit, and monkey. J. Comp. Neurol., 328: 263–281.PPRF paramedian pontine reticular Belknap, D.B. and McCrea, R.A. (1988) Anatomical connec- formation tions of the prepositus and abducens nuclei in the squirrelPT pretectum monkey. J. Comp. Neurol., 268: 13–28.PV parvalbumin Blanks, R.H., Volkind, R., Precht, W. and Baker, R. (1977) Responses of cat prepositus hypoglossi neurons to horizontalRO nucleus of Roller angular acceleration. Neuroscience, 2: 391–403.SG nucleus supragenualis nervi Bobker, D.H. (1994) A slow excitatory postsynaptic potential facalis mediated by 5-HT2 receptors in nucleus prepositus hypo-Sl sulcus limitans glossi. J. Neurosci., 14: 2428–2434.SV superior vestibular Brodal, A. (1952) Experimental demonstration of cerebellar connexions from the perihypoglossal nuclei (nucleus inter-VOR vestibulo-ocular reflex calatus, nucleus praepositus hypoglossal and nucleus of roller) in the cat. J. Anat., 86: 110–129. Brodal, A. (1983) The perihypglossal nuclei in the macaque monkey and the chimpanzee. J. Comp. Neurol., 218: 257–269.References Brodal, A. and Brodal, P. (1983) Observations on the projec- tion from the perihypoglossal nuclei onto the cerebellum inAlley, K., Baker, R. and Simpson, J.I. (1975) Afferents to the the macaque monkey. Arch. Ital. Biol., 121: 151–166. vestibulo-cerebellum and the origin of the visual climbing Buttner, U. and Grundei, T. (1995) Gaze-evoked nystagmus ¨ fibers in the rabbit. Brain Res., 98: 582–589. and smooth pursuit deficits: their relationship studied in 52Appell, P.P. and Behan, M. (1990) Sources of subcortical patients. J. Neurol., 242: 384–389. GABAergic projections to the superior colliculus in the cat. Buttner-Ennever, J.A. and Horn, A.K.E. (1996) Pathways from ¨ J. Comp. Neurol., 302: 143–158. cell groups of the paramedian tracts to the floccular region.Arnold, D.B., Robinson, D.A. and Leigh, R.J. (1999) N. Y. Acad. Sci., 781: 532–540. Nystagmus induced by pharmacological inactivation of the Buttner-Ennever, J.A., Cohen, B., Horn, A.K. and Reisine, H. ¨ brainstem ocular motor integrator in monkey. Vision Res., (1996) Efferent pathways of the nucleus of the optic tract in 39: 4286–4295. monkey and their role in eye movements. J. Comp. Neurol.,Arts, M.P., De Zeeuw, C.I., Lips, J., Rosbak, E. and Simpson, 373: 90–107. J.I. (2000) Effects of nucleus prepositus hypoglossi lesions on Carleton, S.C. and Carpenter, M.B. (1983) Afferent and effer- visual climbing fiber activity in the rabbit flocculus. ent connections of the medial, inferior and lateral vestibular J. Neurophysiol., 84: 2552–2563. nuclei in the cat and monkey. Brain Res., 278: 29–51.Aston-Jones, G., Shipley, M.T., Chouvet, G., Ennis, M., van Carpenter, M.B., Periera, A.B. and Guha, N. (1992) Bockstaele, E.J., Pieribone, V.A., Shikhattar, R., Akoaka, Immunocytochemistry of oculomotor afferents in the squirrel H., Drolet, G., Astier, B., Charlety, P., Valentino, R.J. and monkey (Saimiri sciureus). J. Hirnforsch., 33: 151–167. Williams, J.T. (1991) Afferent regulation of the locus co- Cazin, L., Lannou, J. and Precht, W. (1984) An electrophys- eruleus neurons: anatomy, physiology and pharmacology. iological study of pathways mediating optokinetic responses Prog. Brain Res., 88: 47–75. to the vestibular nucleus in the rat. Exp. Brain Res., 54:Baker, R. and Berthoz, A. (1975) Is the prepositus hypoglossi 337–348. nucleus the source of another vestibulo-ocular pathway? Cazin, L., Magnin, M. and Lannou, J. (1982) Non-cerebellar Brain Res., 86: 121–127. visual afferents to the vestibular nuclei involving the prepositus
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  • 191. Progress in Brain Research, Vol. 151ISSN 0079-6123Copyright r 2006 Elsevier B.V. All rights reserved CHAPTER 8 Oculomotor cerebellum Jan Voogd1,Ã and Neal H. Barmack2 1 Department of Neuroscience, Erasmus Medical Center Rotterdam, Box 1738, 3000 DR Rotterdam, The Netherlands2 Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USAAbstract: The anatomical, physiological, and behavioral evidence for the involvement of three regions ofthe cerebellum in oculomotor behavior is reviewed here: (1) the oculomotor vermis and paravermis oflobules V, IV, and VII; (2) the uvula and