Anatomy of a Nerve A nerve is an organ composed of multiple nerve fibers bound together by sheaths of connective tissue In large nerves, fibers are bundled into fascicles, and wrapped in a fibrous perineurium The entire nerve is covered with a fibrous epineurium. Fibers are classified in several ways - the direction in which signals are transmitted (afferent and efferent) - the types of organs they innervate (somatic and visceral) - how widespread or local the distribution of innervated organs (general or special) are. Mixed nerves contain both motor and sensory fibers. Sensory nerves (optic and olfactory) contain mostly sensory fibers. Motor nerves contain motor fibers
Final common pathway Lower motor neurons from the ventral horn of the spinal cord innervate skeletal muscles, releasing acetylcholine which acts on nicotinic receptors to cause muscle contraction. It is through this final common pathway that all motor behavior of organisms is mediated. Action potentials in motor neurons release sufficient acetylcholine to initiate an action potential in the skeletal muscle, which leads to the contraction of the muscle fiber. Motor neurons A motor unit is the motor neuron and the muscle fibers that it innervates, while a motor neuron pool includes all the motor neurons that innervate one muscle. Some muscles such as those found in the axial musculature are innervated by a few neurons that activate a large array of fibers. Others, including those that control the fingers, are innervated by many neurons that each synapse upon a single muscle fiber. Motor neurons innervating fast motor units (fast twitch muscle) are generally large-diameter, fast-conducting axons, while slower, smaller neurons innervate the slow motor units. Motor neurons derive from the ventral horn of the spinal cord at all levels, although there are more motor neurons in the cervical and lumbar enlargements that provide innervation to the limbs. The neurons innervating the arms and legs derive from C3-T1 and L1-S3, respectively. Motor neurons in the ventral horn maintain a topographical relationship similar to that found for the somatosensory afferents. Motor neurons within the medial ventral horn innervate axial muscles (i.e., midline musculature) while more lateral neurons innervate the more distal muscles such as in the fingers or toes. In the same fashion, interneurons in the intermediate zone of the spinal cord maintain a topographical projection from lateral interneurons innervating ipsilaterally the motor neurons for the distal musculature and medial interneurons innervating the motor neurons involved in controlling axial muscles on both sides of the body. Propriospinal neurons within the intermediate zone project up and down the spinal cord to terminate within homologous regions several segments away. Medial neurons travel several segments within the cord while lateral propriospinal neurons extend only a segment or two in either direction. Regulation of motor neuron activity Within the spinal cord, a variety of influences can regulate the firing activity of the motor neurons in the ventral horn. Spinal reflexes derive directly from proprioceptive information mediated through primary sensory afferents (muscle spindles). Large sensory axons (Ia) are activated by the stretching of muscle spindles. These in turn synapse within the spinal cord upon interneurons and on the alpha motor neurons that innervate the muscle, causing it to contract. This forms the basis for the myotatic reflex. Gamma motor neurons innervate the muscle spindle, to maintain control of movement through feedback on muscle stretching. Activation of gamma motor neurons causes the ends to contract, which stretches the muscle spindle and activates Ia neurons. Golgi tendon organs relay information about tension to the spinal cord. Ib fibers synapse upon inhibitory interneurons, which regulate alpha motor neurons innervating the muscle. Interneurons within the spinal cord are important in regulating muscle activity. As one set of muscles are activated, the opposing set of muscles must be relaxed to allow movement. Inhibitory interneurons can prevent the firing of motor neurons innervating the set of antagonistic muscles. Descending fibers from the brainstem nuclei or cortex also can modulate motor neuron activity. Corticospinal neurons generally activate alpha motor neurons. In contrast, neurons in the pons fire during rapid eye movement (REM) sleep to inhibit the motor neurons in the spinal cord, thereby preventing movement during dreaming. In addition, interneurons within the spinal cord can modulate activity, thereby helping initiate motor patterns that are essentially driven at the spinal cord level. Supraspinal control: Brainstem The ventromedial pathway descends in the ipsilateral ventral funiculus and terminates on the medial motor neurons in the ventral horn, on interneurons and on propriospinal neurons in the ventromedial part of the intermediate zone. The ventromedial pathway contains three major components. 1. The lateral and medial vestibulospinal tracts project from the vestibular nuclei and carry information regarding equilibrium. 2. The tectospinal tract originates within the superior colliculus (optic tectum) a structure involved in tracking eye movements. 3. The reticulospinal tract originates within the reticular formation of the pons and the medulla. All of these pathways terminate within the spinal regions controlling axial musculature. Dorsolateral pathways The dorsolateral pathways have much more precisely defined projections than the ventromedial pathways. The dorsolateral pathways terminate within the lateral components of the spinal cord to innervate motor neurons which activate distal musculature. The lateral pathways are involved in voluntary movement of the distal musculature. The topographical relationship is maintained within the projections from cortical and brainstem areas. From the cortex, these fibers descend through the posterior limb of the internal capsule through the pons to the medulla where the fibers join to form the medullary pyramids. At the base of the medulla, the majority of fibers cross the midline to project laterally to various levels of the spinal cord. Lateral corticospinal tract Projections through the lateral corticospinal tract arise from the motor cortex (area 4) as well as from area 6, located within the frontal cortex. A large component from sensory areas in the parietal cortex also descends through the lateral corticospinal tracts. The terminations of the corticospinal tract are varied and depend on the source of the fibers. Generally, innervation from motor cortex terminates in the ventral horn of the spinal column while information from somatosensory cortex ends within the dorsal column nuclei. A significant projection from motor cortex does not cross in the medulla but innervates the medial portions of the ventral horn. These unilateral projections largely innervate motor neurons (or corresponding interneurons) which in turn activate axial or proximal muscles. With many lower mammals, there is no direct projection from motor cortex to the motor neurons within the spinal cord. Many of the projections derive from both sensory and motor cortex and synapse upon dorsal horn neurons which in turn project to the motor neurons within the ventral horn. In primates, the area devoted to motor cortex is more highly specialized (and segregated from the sensory cortex) and direct synapses from corticospinal neurons can be found on primary motor neurons within the ventral horn. The development of the corticospinal tract is the greatest in humans, where cortical neurons exert a profound direct innervation of the motor neurons. The most dramatic example of how this organization is reflected functionally is in the consequences of disruption of the corticospinal tracts. In humans this leads to a total loss of voluntary movement, while lower primates retain the ability to maintain posture and even climb although they lose the ability to grasp and manipulate objects. In contrast, lesions of the precentral gyrus lead to a temporary paralysis. Recovery is dependent on the development of corticospinal synaptic synapses. Motor cortex The primary motor cortex is located in the precentral gyrus (Brodmann's area 4). As in the somatosensory system, area 4 exhibits a topographical organization with neurons involved in activating the lower limbs found medially, and neurons innervating the motor neurons activating the upper limbs more laterally. Area 6 also regulates motor activity, particularly in the initiation of movement. Area 6 projects to area 4 to initiate movement. Posterior parietal cortex (areas 5 and 7) integrates sensory information and projects extensively to the prefontal cortex and to area 6. These areas are important in the planning of movement. Extrapyramidal motor systems Extrapyramidal motor systems include all of the brain areas involved in regulating motor function that are outside of the pyramidal tract (primary motor neurons). The extrapyramidal motor systems include the striatum (consisting of the caudate and putamen) and the globus pallidus, the subthalamic nucleus, the substantia nigra and the cerebellum. In humans, the caudate and the putamen are separated by the internal capsule (motor neurons traversing the striatum on their way to the spinal cord). In rodents the division is not as clear. The ventral pallidum extends to the basal forebrain and includes the nucleus accumbens and part of the olfactory tubercle. The striatum contains groups of cells compartmentalized by the myelinated fibers of the internal capsule. The division appears to be more than mechanical however since the groups of neurons differ with respect to histochemical characteristics. Patches of low acetylcholinesterase (AChE) staining are prominent features of the striatum and have been named striosomes. Low levels of AChE staining are associated with high levels of enkephalin, substance P and glutamic acid decarboxylase immunoreactivity (indicative of GABA neurons). The clusters of neurons interdigitate with a rich AChE matrix. Afferent pathways The striatum receives several major inputs. 1. Cortical innervation is topographically organized and derives from all neocortical and allocortical levels. There is strong evidence for glutamate serving as the neurotransmitter in this pathway. 2. Intralaminar thalamic nuclei. These in turn receive input from the cerebellum and the pallidum, in addition to sensory input from the spinal cord (pain and temperature). 3. The substantia nigra (pars compacta) sends a dopamine projection to the striatum. 4. Basolateral amygdala. 5. Hippocampus. Efferent pathways The striatum projects to two major areas. Medium size, densely-spined striatal neurons are the major projection neuron of the striatum. These GABAergic neurons were originally thought to be interneurons. 1. The globus pallidus and entopeduncular nucleus are the major projection. 2. A GABAergic projection to the substantia nigra plays an important role in the regulation of movement. Loss of the striatonigral pathway occurs in Huntington's disease and is associated with wild, choreic gestures and cognitive decline. Huntington's disease is one of a growing number of hereditary illnesses associated with a high number of triplet repeats within the culprit gene. Interneurons Perhaps the most notable interneurons are the large, aspiny cholinergic and medium-sized, nonspiny GABAergic interneurons. Thalamus Both ventral lateral and ventral anterior thalamic nuclei receive input from the striatum through the internal pallidum. In turn, these thalamic nuclei, which also receive input from the cerebellum, project to the cerebral cortex (prefrontal cortex and precentral gyrus). Cerebellum The cerebellum is involved with at least three broad functions. 1. Maintenance of posture and balance. This is mediated in part by information from the spinocerebellar tracts (muscle spindles) and from the vestibular nuclei. 2. Maintenance of muscle tone. 3. Coordination of voluntary movements. Initiation takes place in the motor cortex but is modified at the level of the cerebellum. Afferent pathways The cerebellum receives information from the spinal cord and vestibular nuclei. Input derives from mossy fibers and climbing fibers. Mossy fibers include the projections from the spinocerebellar tracts (muscle spindles) and from the vestibular nuclei to the granule cell layer. Climbing fibers originate in the inferior olivary complex and project to the dendritic arbors of the Purkinje cells. Efferent pathways The Purkinje cell is the major projection neuron of the cerebellum. It projects to deep cerebellar nuclei, the red nucleus and the reticular system. Intrinsic neurons Intrinsic neurons include the granule cells, the stellate cells, basket cells and Golgi cells. Granule cells send parallel fibers to the molecular layer where they run perpendicular to the Purkinje cell dendrites. Basket cells are located in the molecular layer and engulf the Purkinje cell bodies. Most of the neurotransmitters in the cerebellum are inhibitory (GABA). References 1. Neuroscience: Exploring the Brain. by M.F. Bear, B.W. Conners and M.A. Paradiso. Williams & Wilkins. First Edition, 1996. 2. Principles of Neural Science. by E.R. Kandel and J.H. Schwarz. Elsevier. Second Edition, 1985. This page was produced by Dr. William S. Messer, Jr., Professor of Medicinal and Biological Chemistry at The University of Toledo.
Somatosensory system In addition to taste, smell, vision and hearing, the nervous system is able to detect a variety of physical stimuli through the somatosensory system. A variety of sensory receptors mediate transduction of peripheral stimuli, including touch, pain, temperature and body position. Somatic sensation depends upon mechanoreceptors, nociceptors, chemoreceptors thermoreceptors and proprioceptors. The information from each modality is carried to the brain through well-defined pathways in the spinal cord. Sensory receptors Mechanoreceptors mediate the sensation of touch by responding to the physical distortion of the body. Mechanoreceptors are specialized nerve endings that detect and transduce physical stimuli into changes in ionic conductance. Several types of mechanoreceptors are known, including free nerve endings, Merkel's disks, Meissner's corpuscles, Pacinian corpuscles, Ruffini endings and the hair follicle receptors. Each of these mechanoreceptors responds to different types of stimuli with varying receptive field size. Pacinian corpuscles consist of a nerve terminal with surrounding layers of connective tissue, mediate sensation of vibrations and high frequency (200 Hz) stimuli and rapidly adapt to stimuli. As the corpuscle is depressed, the physical pressure exerted upon the nerve terminal causes mechanosensitive ion channels to open, thereby depolarizing the membrane. If enough pressure is applied, an action potential is generated. As pressure is continually applied, the connective tissue accommodates and the terminal is no longer deformed and no longer fires action potentials. Nociceptors mediate the sensation associated with painful stimuli. Nociceptors are generally free, unmyelinated fibers and can detect mechanical, thermal, chemical or multiple stimuli. Although nociceptors can respond to similar stimuli as other sensory receptors (e.g., mechanical stimuli), their response is relayed through separate pathways. Thermal receptors detect changes in the temperature of the environment. Separate receptors mediate the sensations of heat and cold. Warm receptors begin firing when the skin temperature rises above 30 C, and increase their firing rate as the temperature reaches 45 C. Cold receptors fire when the skin temperature drops below about 35 C. Thermal receptors are particularly sensitive to changes in skin temperature. Proprioceptors provide information about the location of the body in space. Muscle spindles and Golgi tendon organs relay information about the length and tension of the muscles and tension of the tendons, respectively. Joints also contain mechanoreceptors that provide information about the angle, direction and velocity of limb movement. Primary afferents Information from sensory receptors is relayed to the brain through the primary afferents. The primary afferents have cell bodies in the dorsal root ganglia and enter into the dorsal spinal cord. Information is segregated into two general pathways that carry touch and proprioception and pain and temperature sensation. These pathways project to different parts of the brain. Information from the mechanoreceptors mediating touch and body position are generally large, myelinated fibers, while axons that relay some pain and temperature information are usually unmyelinated fibers. These axons generally conduct stimuli at a slower rate than myelinated axons. Some painful stimuli are projected at faster rates to the CNS through myelinated axons from mechanical or chemical receptors. Primary afferent axons vary greatly in size and degree of myelination, which has formed the basis for categorization. Large axons from sensory receptors are myelinated and designated A axons, while unmyelinated fibers mediating pain information are called C fibers. B fibers are myelinated and derive from the autonomic ganglia. Fibers from muscles and tendons are given Roman numeral designations (I through IV). C fibers conduct much slower than the larger A fibers, which is why we can detect or localize sensory stimulation before we take note of the pain associated with the sensation. The A group of axons can be subdivided further into four subgroups (alpha, beta, gamma and delta) based on their relative size and conduction velocity. A alpha mediate proprioception from muscle, A beta mediate mechanosensitive receptors in the skin, while A delta mediate some pain and temperature information. Thalamic nuclei Neurons from the dorsal column nuclei project to the contralateral thalamus via the medial lemniscus. Information from modalities of touch and proprioception is received by the neurons in the ventral posterior (VP) thalamus. The sensory modalities of pain and temperature sensation are relayed directly from neurons in the spinal cord, through the spinothalamic tract to the thalamus. There, spinothalamic axons synapse upon neurons in the ventral posterior and intralaminar nuclei. Trigeminal pathways The trigeminal nerves (Vth cranial nerves) relay sensory information from the face to the trigeminal nuclei in the brainstem. Large-diameter axons in the trigeminal nerve carry tactile and body position information and synapse in the principal sensory trigeminal nucleus. Smaller-diameter axons carry the sensations of pain and temperature from the face to the spinal trigeminal nucleus. These neurons project to the medial aspect of the ventral posterior nucleus. Somatosensory cortex Neurons arising in the ventral posterior nucleus synapse within the primary somatosensory cortex (S1), which is located within the postcentral gyrus. The thalamus generally projects first to the most rostral aspect of S1 (Brodmann's areas 3a and 3b), which then relays information to and receives a reciprocal projection from Brodmann's areas 1 and 2. Area 3b is primarily concerned with texture, size and shape of objects; area 1 receives primarily information about texture; and area 2 receive information about size and shape. The projection from the thalamus to the somatosensory cortex maintains a topographical organization. Information from the lower limbs and genitals project along the midline, while the trunk, head, arms and hands project more laterally. A large region near the base of the postcentral gyrus is devoted to the lips, mouth and tongue. The fingers, lips and tongue are very well represented, due to the relatively high density of sensory receptors in these regions. The somatotopic map of the body is repeated throughout the somatosensory cortical areas. For example, separate maps in Brodmann's areas 3b and 1 exist dealing with the textural aspects of object recognition. Within each cortical map, information from different modalities are segregated into cortical columns, much in the same way that orientation selectivity is mapped in cortical columns the visual system. For example, rapidly adapting sensory responses are segregated from slowly adapting responses in a columnar arrangement. Information about objects can be interpreted by the combination of inputs received from sensory modalities. We can recognize objects, even in the dark, from the combination of physical stimuli at different body positions. The somatosensory cortex projects to the posterior parietal cortex, which integrates sensory information from different modalities to help identify objects. Pain Nociceptors mediate the sensation of painful stimuli, but the perception of pain at the level of the cerebral cortex depends upon more than just the activation of nociceptors. The detection of painful stimuli can be modulated by stimulation of large fibers in other sensory modalities such as the A alpha and A beta fibers. It is hypothesized that both large and smaller fibers synapse upon neurons in the dorsal horn that send fibers up through the spinothalamic tract. The activity of these neurons may be inhibited by interneurons which are excited by large sensory neurons, yet inhibited by the smaller fibers relaying painful stimuli. Activation of both systems results in less pain information reaching the brain. This is referred to the gate theory of pain. Pain is mediated by the release of glutamate and the peptide substance P from small primary afferents within the dorsal horn. Capsaicin (found in chili peppers) can enhance the release and action of substance P from primary afferents, thereby increasing the sensation of pain. Painful information can be decreased by activation of neurons within the periaqueductual gray matter, located in the midbrain at the level of the superior colliculus and ventral tegmentum. Neurons from the PAG innervate serotonergic neurons in the raphe nuclei, which in turn descend to the spinal cord and depress activity in the nociceptive pathways. The PAG neurons are sensitive to morphine and other opioid ligands due to the presence of opioid receptors. Naturally-occuring peptides such as beta-endorphin and leu-enkephalin modulate the activity of the periaqueductal gray neurons. References 1. Neuroscience: Exploring the Brain. by M.F. Bear, B.W. Conners and M.A. Paradiso. Williams & Wilkins. First Edition, 1996. 2. Principles of Neural Science. by E.R. Kandel and J.H. Schwarz. Elsevier. Second Edition, 1985. This page was produced by Dr. William S. Messer, Jr., Professor of Medicinal and Biological Chemistry at The University of Toledo.
Neurons and glia The human nervous system consists of three main cell types: neurons, glia and Schwann cells. Neurons, numbering about 1011 in the human brain, come in all shapes and sizes, but have much in common. All neurons have similar metabolism, structure and function, differing mainly in the relative size and length of axons and dendrites. Neurons receive input from a variety of sources, including visual, olfactory, auditory, somatosensory and chemical cues. Neurons communicate with each other via release of neurotransmitters, which interact with receptors in the synaptic junction. It should be noted that the nervous system accomplishes a variety of functions through utilizing a limited array of neurotransmitters and receptors. Similar motifs are utilized by motor neurons releasing acetylcholine onto skeletal muscle, and by opioid interneurons in the spinal cord that regulate sensory neuronal activity. Each neuronal population expresses its own unique set of neurotransmitters and/or neuromodulators, which in turn can exert multiple actions depending on the types and subtypes of receptor on the pre- and postsynaptic neurons. Subcellular anatomy The neuron represents a specialized cell with all of the subcellular elements found in eukaryotic cells. The neuron is generally thought to be bipolar in that information is received on one end and transmitted through the cell to another cell at the other end of the cell, but there are relatively few neurons that follow this simple organizing principle. Neurons can be unipolar with a single axonal process or multipolar with more than two processes. Important features common (in fact unique) to neurons include the axonal and dendritic processes. Axons send electrical signals from the cell body to the axon terminal for transmission to another cell. Dendrites receive information from other cells, and dendritic branching increases the surface area available to a cell for receiving input. Other common cellular features may have modified roles in neurons. Cell body or soma Nucleus - contains chromosomes made up of DNA; does not divide after maturity; determines gene expression, which in turn determines the phenotype of the neuron. Nucleolus - site of transcription. Rough endoplasmic reticulum - enclosed stacks of membrane with globular structures called ribosomes extend throughout the cell for protein synthesis, particularly for membrane proteins. Free ribosomes also occur, and appear to play a role in the synthesis of cytosolic proteins (contrast sites of synthesis for receptors vs. neuropeptides). Smooth endoplasmic reticulum - tubular structure throughout the cell including nerve endings; may play a role in protein folding; site of the calcium pump and source of intracellular calcium. Golgi apparatus - important in protein modification (e.g., glycosylation) and as a source of vesicles. Lysosomes - important for protein degradation. Mitochondria - present in the cell body and synapses, limited in axons; involved in oxidative phosphorylation coupling with electron transport; generates ATP; may regulate calcium concentrations at synapse by high capacity, low affinity transport. Neuronal membranes Neuronal membranes contain a number of unique molecules, including neurotransmitter receptors and a variety of ion channels that regulate ionic gradients. These will be discussed in more detail later. Cytoskeleton Microtubules - (20 - 25 nm) composed of both alpha and beta tubulin, which polymerize to form a stable cell structure; important for cytoskeletal framework; may be modified by microtubule associated proteins (MAPs). Microfilaments (5 nm) composed of actin; important for axoplasmic transport (fast - 400 mm/day). Neurofilaments - (10 nm) composed of tau proteins; important for cytoskeletal integrity; degenerate in Alzheimer's disease through abnormal phosphorylation. Axons The axon begins at the region known as the axon hillock, which tapers into the axon proper. The axon hillock is the site of integration for ionic conductance, which determines whether an action potential is triggered. Axons contain no rough e.r. and few free ribosomes. All protein must come directly from the cell body. Axons are frequently myelinated by Schwan cells in the PNS and by oligodendrocytes in the CNS. More on those later. Axons may travel great distances -- consider the length of motor neurons in the giraffe, or only a few microns. They may branch into collaterals, and even synapse back upon the cell body (recurrent collaterals). Axons form synapses (points of contact) with other cells, releasing neurotransmitter into the synaptic cleft. Axons and dendrites have specific requirements for transporting proteins and membranes to distal sites. Axon transport occurs through two mechanisms: a fast component transporting membranes and mitochondria and a slow component for cytoskeletal elements. Fast transport moves at 50 - 300 mm/day using the proteins kinesin and dynein for antero- and retrograde transport, respectively. For example, kinesin attaches to mitochondria and transports the organelle down the axon to the axon terminal by forming and breaking bonds with actin. Dynein, in contrast, moves cellular debris (e.g., lysosomes) from the terminus to the cell body through a similar interaction with actin. Slow transport, which moves at the rate of 0.1 - 10 mm/day, is responsible for moving the cytoskeletal proteins such as tubulin and actin. Dendrites Dendritic spines - Microtubules may be important for plasticity of synapse formation. Synaptic matrix - Thickened cell membrane in region of synaptic transmission. Synapses can be characterized by the appearance of the synaptic matrix. Cell adhesion molecules (e.g., N-CAM) play a role in joining the pre- and postsynaptic elements together. Glia Astrocytes are abundant in the brain, and help regulate the chemical milieu of the extracellular space. Astrocytes can take up neurotransmitters, and even possess neurotransmitter receptors, so their role in regulating brain activity is not entirely passive. Astrocytes also regulate neuronal migration -- radial glia guide the developing neurons as they migrate from the ependymal layer near the brain ventricles and take up position in the various layers of the cerebral cortex. Astrocytes also proliferate in response to brain injury, and contribute significantly to the scarring process that appears to prevent reinnervation after stroke or spinal injuries. Another type of glial cell in the CNS, the microglia, are the immune cells of the brain. They respond in a similar fashion to macrophages peripherally, and possess complement proteins that may contribute to CNS disorders such as Alzheimer's disease. In the brain, oligodendrocytes myelinate axons. Extensions of oligodendroglial cells wrap around neurons forming a myelin sheath with interspersed nodes of Ranvier. A single oligodendrocyte can myelinate several axons in the CNS. Myelin is composed of myelin basic protein, which is deposited by oligodendrocytes in the CNS and Schwan cells in the PNS. Two neural disorders, multiple sclerosis and Guillain-Barre syndrome, are associated with a loss of myelination. In multiple sclerosis, patients exhibit a variety of neuronal deficits, including blurred vision, which can undergo remission and exacerbation, occasionally never reappearing, but some times leading quickly to death. Guillain-Barre patients exhibit signs of peripheral neuropathy, including muscle weakness. Useful animal models of these diseases have been developed using injections of myelin, which induce an immune response leading to demyelination. Injections of myelin from the CNS leads to experimental allergic myelitis, which closely resembles the condition found in multiple sclerosis. In contrast, injections of peripheral myelin lead to experimental allergic neuritis, which is similar to Guillain-Barre syndrome. References 1. Neuroscience: Exploring the Brain. by M.F. Bear, B.W. Conners and M.A. Paradiso. Williams & Wilkins. First Edition, 1996. 2. Principles of Neural Science. by E.R. Kandel and J.H. Schwarz. Elsevier. Second Edition, 1985. This page was produced by Dr. William S. Messer, Jr., Professor of Medicinal and Biological Chemistry at The University of Toledo.
The Motor Unit Muscle fibers are innervated by neurons whose cell bodies are located in spinal cord. The nerve fibers, or axons, of these motor neurons leave the spinal cord and are distributed to the motor nerves. Each motor axon branches several times and innervates many muscle fibers. The combination of a single motor neuron and all the muscle fibers it innervates is called a motor unit. Although the muscle fibers of a given motor unit tend to be located near one another, motor units have overlapping territories. In response to an action potential from the neuron, a muscle fiber depolarizes as the signal propagates along its surface and the fiber twitches (contracts). This depolarization generates an electric field in the vicinity of the muscle fibers which can be detected by a skin surface electrode located near this field, or by a quadrifillar electrode inserted in the muscle. The resulting signal is called the muscle fiber action potential. The combination of the muscle fiber potentials from all the muscle fibers of a single motor unit is the motor unit action potential (MUAP). All of the muscle fibers in a motor unit are fired each time a motor unit fires. The repetitive firing of a motor unit creates a train of impulses known as the motor unit action potential train (MUAPT). The summation of electrical activity created by each active motor unit is the myoelectrical signal (ME) (4). To sustain muscle contraction, the motor units must be repeatedly activated (2). As the firing rates of motor units active in a contraction increase, the twitches associated with each firing will eventually fuse to yield large forces.
Neurotransmitters In the last lecture we have discussed the role of ionic conductance in generating the resting membrane potential and action potentials. Ionic conductance, particularly K+ conductance, helps hold the resting membrane potential near the potassium equilibrium potential (EK+). Na+ conductance, through voltage-gated ion channels produces the depolarization found in the action potential. Ionic conductance and changes in voltage potential are responsible for ongoing neuronal activity, and relay information from dendrite to axon. Neurotransmitter release transmits information from one neuron to another. These changes in neuronal activity provide information from the environment and determine the response of the organism to its surroundings. Central to the processing of information is the activation of receptors by neurotransmitters. Several criteria need to be fulfilled in order for a substance to be classified as a neurotransmitter. First, neurotransmitters must be synthesized and stored in the presynaptic neuron. The neurotransmitter also must be released by the presynaptic neuron in response to stimulation. Finally, the molecule itself must produce a response in the postsynaptic cell that mimics the response produced by the release of the neurotransmitter from the presynaptic neuron. Other important criteria include a mechanism for eliminating the neurotransmitter from the synapse, and a pharmacologically relevant response at a defined postsynaptic receptor (e.g., blockade by an antagonist). Neurotransmitter synthesis Synthesis of neurotransmitters may occur through a single step, such as in the case of acetylcholine, or through multiple steps, as found for norepinephrine. The enzyme(s) responsible for neurotransmitter synthesis are generally synthesized in the cell body and transported down the axon to the axon terminal. There, they synthesize the neurotransmitter, which is then transported into vesicles for eventual release. In the case of acetylcholine, the enzyme responsible for synthesis is choline acetyltransferase, which esterifies choline with an acetyl group from acetyl coenzyme A. Choline itself must be taken up by cells through a Na+-dependent, high affinity uptake system. Once acetylcholine is synthesized in the cytoplasm, it must be packaged in vesicles for release. Synaptic vesicles contain transporter proteins, which can translocate neurotransmitter molecules across the membrane for storage and eventual release. Acetylcholine is transported into synaptic vesicles by a vesamicol-sensitive transporter. Neurotransmitter receptors: ligand-gated ion channels The release of neurotransmitters can produce a variety of consequences, depending on the nature of the interaction of the ligand with the receptors. Excitatory neurotransmitters, such as acetylcholine and glutamate, activate postsynaptic receptors that belong to the superfamily of ligand-gated ion channels. Upon release, neurotransmitter molecules bind to receptors on the postsynaptic neuron. Binding of the ligand stabilizes the active conformation of the receptor, thereby opening an ion channel, which is created by the arrangement of four to five receptor subunits. The nicotinic receptor mediates many of the excitatory responses upon stimulation and release of acetylcholine from presynaptic neurons. The ligand-gated ion channels differ from voltage-gated ion channels in that they are activated by binding of neurotransmitters. In addition, they also differ in terms of selective ion permeability. Upon activation and channel opening, both Na+ and K+ can flow through the channel. At first this might seem to exert no net effect on a neuron, due to the counterbalancing effects of Na+ influx and K+ efflux. Based on the resting membrane potential (near -70 mV) and the equilibrium potentials for each ion however, we can see that there is a tremendous potential difference for Na+, yet a very small differential for K+. As a result, at rest, acetylcholine triggers a rapid influx of Na+. This influx of Na+ leads to an excitatory postsynaptic potential (epsp). Release of neurotransmitter at low levels of stimulation cause very small changes in the voltage of the postsynaptic cell. In fact, at very low stimulation, the effects of releasing single packets of neurotransmitter can be seen. These are termed quantal events, caused by the fusion of individual vesicles with the neuronal presynaptic membrane. They also have been referred to as miniature end-plate potentials, since they were first observed at the endplate found in the electric organ of Torpedo californica, the electric ray. Individual epsp's produce small changes in membrane voltage, but in combination with many other epsp's can summate to depolarize the cell sufficiently to trigger an action potential. Counterbalancing the effects of excitatory neurotransmitters are the inhibitory neurotransmitters such as gamma-amino butyric acid (GABA). The activity of postsynaptic neurons depends upon the combined action of excitatory and inhibitory neurotransmitters. Neurotransmitter receptors - G protein-coupled receptors In contrast to the direct effects of ligand-gated ion channels on neuronal activity, some neurotransmitter receptors mediate responses through activation of second messenger systems. These proteins constitute a second superfamily of receptors called G protein-coupled receptors. The receptors get their name from the small heterotrimeric proteins that bind GTP and serve as intermediary signaling proteins in activating a host of intracellular responses. Depending upon the type of receptor, ligands can exert a variety of responses by activation of G protein subunits. At least 12 different kinds of G proteins are known. They consist of separate alpha, beta and gamma subunits. The alpha subunits are the most diverse group, and can function independently to activate or inhibit intracellular responses. The beta-gamma subunits generally have higher sequence homology and work in tandem to regulate cellular processes. At rest, G protein-coupled receptors have a high affinity for agonist and low affinity for G proteins. Upon ligand binding, a conformational change in the receptor increases its affinity for the G protein. As this occurs, GDP is released from the G protein and GTP binds to the alpha subunit, whereupon the alpha and beta-gamma subunits dissociate. This in turn leads to a decrease in the affinity of the receptor for the agonist. The alpha subunit with GTP bound can activate a host of intracellular responses, depending upon the nature of the subunit. For example, transducin, Gat, activates a phosphodiesterase that breaks down cyclic GMP in the photoreceptor cells. It is activated upon photoactivation of rhodopsin in rod cells. Other G proteins activate or inhibit adenylate cyclase via Galphas or Galphai subunits. Still others stimulate arachidonic acid and phosphoinositide metabolism through Galphao or Galphaq interactions with phospholipase A2 and phospholipase Cbeta respectively. The targets for the alpha subunits of G proteins are generally enzymes that regulate phosphorylation of cellular proteins, thereby regulating ongoing cellular activity. The beta-gamma complexes can also exert an independent action to open K+ channels. The G proteins exhibit GTPase activity, and interaction with the enzymes leads to GTPase activation and formation of GDP from GTP. Thus the G protein returns to the initial state, which can interact with ligand-bound receptors for reactivation. Muscarinic receptors can exert multiple actions upon a neuron, depending upon the subtypes of receptor, G proteins, and target proteins. For example, in the CNS, activation of M1 receptors, generally postsynaptic, leads to an increase in phospholipase C activity via Gaq. This in turn leads to the formation of 1,2-diacylglycerol and inositol triphosphate. 1,2-Diacylglycerol stimulates protein kinase C activity, which leads to phosphorlyation of intracellular proteins. In addition, IP3 generation leads to mobilization of Ca2+ from intracellular stores. Increases in Ca2+ can enhance the release of neurotransmitters and activate calmodulin. Activation of M2 receptors, which have been found on presynaptic neurons, leads to the opening of potassium channels, which tends to hyperpolarize the cell and prevent neurotransmitter release. Neurotransmitter uptake and metabolism Activation of presynaptic receptors represents one mechanism for regulating neurotransmitter levels. Other mechanisms include neurotransmitter reuptake and metabolism by inactivating enzymes. Neurotransmitter reuptake represents an important mechanism for inactivating neurotransmitters. Specific transporter proteins have been identified for several neurotransmitters, including GABA, glycine, dopamine, and serotonin. A number of neuroactive drugs exert their action through inhibition of neurotransmitter reuptake. For example, cocaine strongly inhibits the dopamine reuptake mechanism, while fluoxetine (Prozac(R)) blocks the uptake of serotonin, thereby exerting an antidepressant effect. A variety of enzymes play a role in the inactivation of neurotransmitters. Acetylcholinesterase inactivates acetylcholine. Two enzymes are responsible for the metabolism of monoamines like epinephrine and noradrenaline: monoamine oxidase and catechol-O-methyl transferase, while histamine is inactivated by histamine-methyl transferase. The enzymes that metabolize neurotransmitters represent important targets for drug intervention. Monoamine oxidase inhibitors have been used clinically to treat depression, while acetylcholinesterase inhibitors such as Donepezil have been used in the treatment of Alzheimer's disease. References 1. Neuroscience: Exploring the Brain. by M.F. Bear, B.W. Conners and M.A. Paradiso. Williams & Wilkins. First Edition, 1996. 2. Principles of Neural Science. by E.R. Kandel and J.H. Schwarz. Elsevier. Second Edition, 1985. This page was produced by Dr. William S. Messer, Jr., Professor of Medicinal and Biological Chemistry at The University of Toledo.
Motor System <ul><li>Movement commands are generated by the brain and transmitted to muscles through the spinal cord and nerves. </li></ul>
Sensory System <ul><li>Many types of sensors receive information and send it to the brain through the nerves </li></ul>
Basic Nerve Elements <ul><li>Neuron </li></ul><ul><li>Synapse </li></ul><ul><li>Motor Unit </li></ul><ul><li>Endplate (Neuromuscular Junction) </li></ul><ul><li>Motor and Sensory Nerves </li></ul>
Neuron <ul><li>The neuron (nerve cell) is the basic unit of the nervous system. A neuron consists of a cell body, axon (nerve fiber), etc. </li></ul><ul><li>Electric impulses are generated by the neuron and travel on the axon. The impulse travels faster where the axon is covered by myelin. </li></ul>
Synapse <ul><li>The synapse is the neuron to neuron junction. Signal processing is done at the synapse. </li></ul>Synapse
Motor Unit <ul><li>The motor unit consists of an anterior horn cell, its axon, and all the muscle fibers innervated by that axon and its branches. </li></ul>Muscle fiber Dendrites Axon Myelin Muscle fiber Nucleus Soma Endplate
Endplate (Neuromuscular Junction) <ul><li>When impulses reach the endplate, the muscle fibers contract. </li></ul>
Motor and Sensory Nerves <ul><li>A motor neuron connects to muscle fibers (other cells). A sensory neuron has a sensor, but it is part of the same cell. </li></ul>
Conduction Velocity <ul><li>There are several types of nerves. </li></ul><ul><li>A nerve consists of many fibers (axons). </li></ul><ul><li>The velocity of myelinated (covered with myelin) nerve fiber is higher than non-myelinated fiber. </li></ul><ul><li>Conduction velocity is higher in thicker nerve fiber than thinner nerve fiber. </li></ul><ul><li>Each fiber has its own velocity, different than other fibers. </li></ul><ul><li>The higher the temperature, the higher the velocity. </li></ul>
Nerve Types, Diameter and Conduction Velocity <ul><li>The thicker the nerve, the higher the conduction velocity. </li></ul>Sensory receptor Proprioceptor of skeletal muscle Pain, temp. Pain, temp, itch Mechanoreceptors of skin
Symptoms of neuropathy <ul><li>Pain - burning, short jabs , tight or band like pressure, painful </li></ul><ul><li>hypersensitivity of non noxious stimuli </li></ul><ul><li>Paresthesia “pain and needle” sensations </li></ul><ul><li>Sensory loss “ ชา ” “ no sensation” “like block of wood” </li></ul><ul><li>Weakness - distal symmetrical weakness </li></ul><ul><li> - proximal symmetrical weakness – GBS </li></ul><ul><li> - unilateral limb weakness </li></ul><ul><li>- brachial plexus </li></ul><ul><li>- lumbosacral plexus </li></ul><ul><li>Unstable balance - sensory loss </li></ul><ul><li> - weakness in the legs </li></ul>
Classification of Diabetic neuropathies Symmetric 1. Distal, primarily sensory polyneuropathy a. Mainly large fibers affected b. Mixed ( a) c. Mainly small fibers affected (a) 2. Autonomic neuropathy 3. Chronically evolving proximal motor neuropathy ( a,b) Asymmetric 1. Acute or subacute proximal motor neuropathy ( a,b) 2. Cranial mononeuropathy ( b) 3. Truncal neuropathy ( a,b) 4. Entrapment neuropathy in the limbs a Often painful. b Recovery, partial or complete, is likely.
Guillain-Barre Syndrome <ul><li>Most common type --- </li></ul><ul><li>Acute inflammatory demyelinating polyneuropathy (AIDP) </li></ul>
Diagnostic Criteria for Guillain-Barre Syndrome REQUIRED 1. Progressive weakness of 2 or more limbs due to neuropathy 2. Areflexia 3. Disease course <4 weeks 4. Exclusion of other causes [e.g., vasculitis (polyarteritis nodosa, systemic lupus erythematosus, Churg-Strauss syndrome), toxins (organophosphates, lead), botulism, diphtheria, porphyria, localized spinal cord or cauda equina syndrome] SUPPORTIVE 1. Relatively symmetric weakness 2. Mild sensory involvement 3. Facial nerve or other cranial nerve involvement 4. Absence of fever 5. Typical CSF profile (acellular, increase in protein level) 6. Electrophysiologic evidence of demyelination a Excluding M. Fisher and other variant syndromes. SOURCE: Modified from AK Asbury, DR Cornblath: Ann Neurol 27:S21, 1990
Scattered distribution of sensory loss in Multiple Mononeuropathy
Multiple mononeuropathy <ul><li>Can found in: </li></ul><ul><li>Classic PAN </li></ul><ul><li>Churg-Strauss disease </li></ul><ul><li>Wegener’s granulomatosis </li></ul><ul><li>Overlap syndrome </li></ul><ul><li>Vasculitis associated with connective tissue disease </li></ul><ul><li>Sjóģren syndrome </li></ul><ul><li>Lyme disease </li></ul><ul><li>Leprosy </li></ul><ul><li>Diabetes mellitus </li></ul>
Leprous neuritis (infectious cause of multiple mononeuropathy) <ul><li>Mycobacterium leprae – coolest tissue in the body </li></ul><ul><li>Tuberculoid (high-resistance) leprosy – single patch of hypoesthesia or anesthetic skin in any location </li></ul><ul><li>Lepromatous (low resistance) leprosy – numerous bacilli, wide spread skin thickening, cutaneous anesthesia, anhydrosis sparing axilla, groin and skin beneath the scalp hair </li></ul>
Dermatome <ul><li>No C1 dermatome </li></ul><ul><li>C4 and T2 dermatome are contiguous on trunk </li></ul><ul><li>Thumb, middle finger, and fifth digits are innervated by C6, C7, and C8, respectively </li></ul><ul><li>Nipple is at T4 level </li></ul><ul><li>Umbilicus is at T10 level </li></ul><ul><li>Lumbar and sacral dermatome are contiguous in the posterior axial line of leg </li></ul>
Long thoracic nerve to serratus anterior Dorsal scapular n. to rhomboids Thoracodorsal nerve to latissimus dorsi Ulnar n. Radial n. Axillary n. Median n. Musculocutaneous n. Suprascapular n.
Brachial plexus <ul><li>Symptoms and signs </li></ul><ul><ul><li>Sensory : </li></ul></ul><ul><ul><ul><li>acute pain in shoulder and arm, deep and nonlocalized </li></ul></ul></ul><ul><ul><ul><li>Paresthesia </li></ul></ul></ul><ul><ul><ul><li>Sensory loss, when existed, will be limited to outer surface of arm and radial aspect of forearm </li></ul></ul></ul><ul><ul><li>Motor </li></ul></ul><ul><ul><ul><li>Weakness of shoulder girdle, deltoid, spinati, biceps and triceps </li></ul></ul></ul><ul><ul><ul><li>Atrophy of affected muscle </li></ul></ul></ul>
Brachial plexus <ul><li>N. ที่แยกก่อนเข้า plexus </li></ul><ul><ul><li>Dorsal scapular nerve : to rhomboid </li></ul></ul><ul><ul><li>Long thoracic nerve : to serratus anterior </li></ul></ul>
Long thoracic nerve to serratus anterior Dorsal scapular n. to rhomboids
Main sites of brachial plexus damage <ul><li>1.upper trunk : ถูกยิงหรือแทงที่คอ </li></ul><ul><ul><li>C5,6 destroyed </li></ul></ul><ul><ul><li>Numbness : lateral arm, forearm, hand </li></ul></ul><ul><ul><li>Weakness : abduct, internal and external rotate of shoulder, elbow flexion, radial wrist extension </li></ul></ul><ul><ul><li>Bicep and supinator jerk absent </li></ul></ul><ul><ul><li>Spare rhomboid and serratus anterior </li></ul></ul>
Main sites of brachial plexus damage <ul><li>2.lower trunk :cervical rib syndrome, CA lung apex (Pancoast’s syndrome), metastatic disease in axillary gland </li></ul><ul><ul><li>Pain : in shoulder at night time </li></ul></ul><ul><ul><li>Tingling and numbness : medial arm, forearm, little and ring finger </li></ul></ul><ul><ul><li>Weakness : finger flexor and extensor, intrinsic m. of hand </li></ul></ul>
Main sites of brachial plexus damage <ul><li>3.radial lesion in axilla : crutch injury, stab wound, neoplastic disease in axillary gland </li></ul><ul><ul><li>Weakness : radial nerve innervated muscle including triceps </li></ul></ul>
Main sites of brachial plexus damage <ul><li>4. posterior cord : small caliber low-velocitiy bullet wound to plexus </li></ul><ul><ul><li>Radial nerve palsy and axillary nerve lesion </li></ul></ul><ul><ul><li>Weakness : elbow, wrist, finger extension, second 90 of shoulder abduction(deltoid paralysed) </li></ul></ul>
Radiation damage to plexus <ul><li>มักโดน C7 มากสุด เพราะเป็น center of radiation field </li></ul><ul><li>C8,T1 โดนน้อยกว่า </li></ul><ul><li>มักเกิด 12-18 เดือนหลัง radiation </li></ul><ul><li>Numbness and weakness of forearm and hand </li></ul><ul><li>NO PAIN </li></ul><ul><li>Symptom progress over a few weeks </li></ul>
Causes of brachial plexopathy <ul><li>Trauma </li></ul><ul><li>Tumor infiltration </li></ul><ul><li>Infection by viral </li></ul><ul><li>Immune-mediated </li></ul><ul><li>Delayed effects of radiotherapy </li></ul>
Traction birth injury (Erb’s palsy) Acute pain in back of shoulder Postmastectomy and radiation Brachial plexopathy
Brachial plexus <ul><li>Upper C5,6 or Erb-Duchenne type </li></ul><ul><li>Lower C8, T1 or Dejerine-Klumpke type </li></ul><ul><li>Total </li></ul>
Klumpke’s palsy (injury of lower brachial plexus C7,C8,T1) and often Horner’s syndrome Erb’s palsy (injury of upper brachial plexus C5,C6 )
Ulnar nerve Lesion at condylar groove Lesion at wrist and hand Guyon’s canal
Ulnar nerve <ul><li>At elbow : Condylar groove or in cubital tunnel </li></ul><ul><ul><li>ชานิ้ว 4+5+ มือด้าน medial </li></ul></ul><ul><ul><li>Wasting hypothenar eminence and web space of นิ้วโป้ง + ชี้ (1 st dorsal interossei) </li></ul></ul><ul><ul><li>Claw hand </li></ul></ul>
Radial nerve <ul><li>Axillary lesion : weak triceps and radial innervated m. </li></ul><ul><li>Mid-upper arm lesion : ‘ Saturday night palsy ’ (spiral groove or intermuscular septum) : wrist drop, normal triceps, variable motor and sensory deficit </li></ul><ul><li>Posterior interosseous : weak extensor of thumb and other fingers, no sensory loss </li></ul><ul><li>Superficial radial n. : terminal cutaneous br. </li></ul>
Femoral nerve (L2,3,4) <ul><li>Mix sensorimotor </li></ul><ul><li>Quadriceps femoris or knee extensor </li></ul><ul><li>Weakness of hip flexor in intraabdominal lesion </li></ul><ul><li>Sensory deficit over anteromedial aspect of thigh and perhaps leg </li></ul><ul><li>Absent or diminished knee jerk </li></ul>
Obturator nerves <ul><li>L2,3,4 </li></ul><ul><li>Hip adductors </li></ul><ul><li>vulnerable during obstetric and gynecological procedures </li></ul>
Sciatic nerve <ul><li>Composed of 2 main nerves of leg : common peroneal and tibial nerve </li></ul><ul><li>Paralysis of all muscles below knee plus hamstrings and for high lesion, external rotators of thigh </li></ul><ul><li>Sensory loss below knee except anteromedial aspect of leg and foot </li></ul>
Common peroneal nerve <ul><li>Foot-drop </li></ul><ul><li>Paralysis of anterior and lateral compartment of leg </li></ul><ul><li>Sensory loss over dorsum of foot and toes and anterolateral aspect of leg </li></ul>
Tibial nerve <ul><li>Medial division of sciatic nerve </li></ul><ul><li>Lesions at ankle </li></ul><ul><ul><li>Tarsal tunnel syndrome </li></ul></ul><ul><ul><ul><li>Pain and paresthesia in sole </li></ul></ul></ul><ul><ul><ul><li>Paralysis of intrinsic muscles of foot </li></ul></ul></ul><ul><ul><ul><li>Tenderness of Tinel’s sign at flexor retinaculum </li></ul></ul></ul><ul><ul><li>Sural nerve compression syndrome </li></ul></ul><ul><ul><ul><li>Pure sensory </li></ul></ul></ul><ul><ul><ul><li>Numbness on lateral aspect of foot </li></ul></ul></ul>
Facial nerve palsy <ul><li>Bell’s palsy : idiopathic, HSV 1 </li></ul><ul><li>Ramsay Hunt syndrome : external ear pain with presence of herpes zoster vesicles in auditory canal and pinna, VZV </li></ul><ul><li>Trauma : blunt impact to temporal bone </li></ul><ul><li>Middle ear infection : otitis media (infrequent in ATB era), mastoid pain persist after acute infection resolved </li></ul><ul><li>Neoplasm : rarely compressed by CPA tumor but due to surgery for tumor removal </li></ul>
Bell’s palsy <ul><li>Management </li></ul><ul><li> Reassurance – not a stroke </li></ul><ul><li>Short course of prednisolone 60 mg/day </li></ul><ul><li> Prognosis : </li></ul><ul><li> complete recovery 75% </li></ul><ul><li> satisfactory 15% </li></ul><ul><li> poor function 10% </li></ul>