The document provides an overview of neurophysiology and the structure and function of the nervous system. It describes the development of the central nervous system from the neural tube, and defines the major subdivisions of the brain and spinal cord. It also discusses the types of neurons and glial cells, their roles, and the protective mechanisms of the central nervous system like the meninges and blood-brain barrier.

1. AHMADU BELLO UNIVERSITY, ZARIA - NIGERIA
FACULTY OF MEDICINE
DEPARTMENT OF HUMAN PHYSIOLOGY
NEUROPHYSIOLOGY (HPHY 305)
Rabiu AbduSSALAM Magaji, Ph.D.
E-mails: ramagaji@abu.edu.ng; rabiumagaji@yahoo.co.uk

2. Learning Objectives
At the end of this lecture, it is expected that the student
would be able to:
 List and describe the parts of the nervous system and their
components
 List the various types of glia and their functions.
 Name the parts of a neuron and their functions.
 Describe the role of myelin in nerve conduction.
 List the types of nerve fibers found in the mammalian
nervous system.

3. Need for Review
 Excitable Tissues
 Nerves (Structures and functions)
 Muscles (Structures and functions)
 Organization of the Nervous System in general
 Organization of the Central Nervous System (CNS)
specifically
 Anatomy of the different parts of the brain

4. Organization of the Nervous System - Origin
In the developing embryo, the Nervous system (NS) develops
from ectoderm, that forms the neural plate.
The neural plate differentiates into neural tube and a neural
crest.
The neural tube then differentiates into the Central Nervous
System (CNS), which consists of the Brain and the Spinal
cord.
The neural crest gives rise to most of the Peripheral Nervous
System (PNS), which consists of 12 pairs of cranial nerves
and 31 pairs of spinal nerves.

5. The Central Nervous System
The brain develops at the cranial end of the embryonic neural tube.
By the end of the first month of development, three (3) Primary
vesicles are formed: Forebrain (Prosencephalon), the Midbrain
(Mesencephalon), and the Hindbrain (Rhombencephalon).
A week later, the forebrain gives rise to the Telencephalon and the
Diencephalon, and the hindbrain gives rise to the Metencephalon
and the Myelencephalon resulting in a total of five (5) secondary
vesicles.

6. In adults:
Telencephalon develops into
Cerebral hemispheres.
Diencephalon gives rise to
the Thalamus and the
Hypothalamus and other
structures.
Mesencephalon becomes
the Midbrain. Mylencephalon becomes
Medulla oblongata. The
Metencephalon gives rise to medulla oblongata, pons and
the Pons and the the midbrain form the adult
Cerebellum. Brain stem.

7. Subdivisions of the Central Nervous System
The central nervous system (defined as the brain and spinal
cord) is usually considered to have seven basic parts:
 spinal cord,
 medulla,
 pons,
 cerebellum,
 midbrain,
 diencephalon, and
 cerebral hemispheres

8. Running through all of these subdivisions are fluid-filled
spaces called ventricles
These ventricles are the remnants of the continuous lumen
initially enclosed by the neural plate as it rounded to become
the neural tube during early development.
Variations in the shape and size of the mature ventricular
space are characteristic of each adult brain region.
The brainstem surrounds the 4th ventricle (medulla
and pons) and cerebral aqueduct (midbrain).

9. The forebrain encloses the 3rd and lateral ventricles.
The diencephalon and cerebral hemispheres
(telencephalon) are collectively called the forebrain, and
they enclose the 3rd and lateral ventricles, respectively.
Within the brainstem are the cranial nerve nuclei that
either receive input from the cranial sensory ganglia via the
cranial sensory nerves, or give rise to axons that constitute
the cranial motor nerves.

10. OVERVIEW OF NEUROPHYSIOLOGY
The nervous system can be divided into two parts:
the central nervous system (CNS), which is composed of
the brain and spinal cord, and
the peripheral nervous system, which is composed of
nerves that connect the CNS to muscles, glands, and sense
organs.
Neurons are the basic building blocks of the nervous
system. The human brain contains about 100 billion neurons.
It also contains 10–50 times this number of glial cells or
glia.

11. Organization of the Nervous System

12. Structure and location of the three functional classes of neurons. *Efferent autonomic nerve pathways consist of a two-
neuron chain between the CNS and the effector organ.

13. The CNS is a complex organ; it has been calculated that
40% of the human genes participate, at least to a degree, in
its formation.
Glia Cells
The word glia is Greek for glue; for many years, glia were
thought to function merely as connective tissue.
However, these cells are now recognized for their role in
communication within the CNS in partnership with neurons.
Unlike neurons, glial cells continue to undergo cell division
in adulthood and their ability to proliferate is particularly
noticeable after brain injury.
There are two major types of glia, microglia and
macroglia.

14. Microglia arise from macrophages outside of the CNS and are
physiologically and embryologically unrelated to other neural cell
types.
Microglia are scavenger cells that resemble tissue macrophages
and remove debris resulting from injury, infection, and disease.
There are three types of macroglia: oligodendrocytes, Schwann
cells, and astrocytes.
Oligodendrocytes and Schwann cells are involved in myelin
formation around axons in the CNS and peripheral nervous system,
respectively.
Astrocytes, which are found throughout the brain, are of two
subtypes:

15.  Fibrous astrocytes, which contain many intermediate
filaments are found primarily in white matter; and the
 Protoplasmic astrocytes are found in gray matter and have
a granular cytoplasm.
• Both types of astrocytes send processes to blood vessels,
where they induce capillaries to form the tight junctions
making up the blood–brain barrier.
• The blood–brain barrier prevents the diffusion of large or
hydrophilic molecules (e.g., proteins) into the cerebrospinal
fluid and brain, while allowing diffusion of small molecules.
The astrocytes also send processes that envelop synapses
and the surface of nerve cells.

16. Principal types of glial cells in the nervous system (Adapted from Medical Physiology: a Systems Approach by
Hershel and Michael. McGraw-Hill Company, 2011).

17. Functions of the Neuroglia
Astrocytes
 Physically support neurons in proper spatial relationships
 Serve as a scaffold during fetal brain development
 Induce formation of blood–brain barrier
 Help transfer nutrients to neurons
 Form neural scar tissue
 Take up and degrade released neurotransmitters
 Take up excess K to help maintain proper brain-ECF ion
concentration and normal neural excitability
 Enhance synapse formation and strengthen synaptic
transmission via chemical signaling with neurons
 Communicate by chemical means with neurons and among
themselves

18. Oligodendrocytes
 Form myelin sheaths in CNS
Microglia
 Play a role in defense of brain as phagocytic scavengers
 Release nerve growth factor
Ependymal Cells
 Line internal cavities of brain and spinal cord
 Contribute to formation of cerebrospinal fl uid
 Serve as neural stem cells with the potential to form new
neurons and glial cells

19. Glial cells of the central nervous system. The glial cells include the astrocytes, oligodendrocytes, microglia, and ependymal
cells

20. The peripheral nervous system transmits information from the
CNS to the effector organs throughout the body.
It contains 12 pairs of cranial nerves and 31 pairs of spinal
nerves.
The cranial nerves have rather well-defined sensory and
motor functions.
Spinal nerves are named on the basis of the vertebral level
from which the nerve exits (cervical, thoracic, lumbar,
sacral, and coccygeal).
These nerves include motor and sensory fibers of muscles,
skin, and glands throughout the body.

21. Food for Thought
“A basic principle to remember when studying
the brain is that one function, even an
apparently simple one such as bending your
finger, will involve multiple brain regions (as
well as the spinal cord). Conversely, one
brain region may be involved in several
functions at the same time. In other words,
understanding the brain is not simple and
straightforward”.

22. THE SPINAL CORD
The spinal cord is the major pathway for information owing
back and forth between the brain and the skin, joints, and
muscles of the body.
In addition, the spinal cord contains neural networks
responsible for locomotion.
If the spinal cord is severed, there is loss of sensation from
the skin and muscles as well as paralysis, loss of the ability to
voluntarily control muscles.
The spinal cord is divided into four regions (cervical,
thoracic, lumbar, and sacral), named to correspond to the
adjacent vertebrae.

23. Each spinal region is subdivided into segments, and each
segment gives rise to a bilateral pair of spinal nerves.
Just before a spinal nerve joins the spinal cord, it divides into
two branches called roots.
The dorsal root of each spinal nerve is specialized to carry
incoming sensory information.
The dorsal root ganglia, swellings found on the dorsal roots
just before they enter the cord, contain cell bodies of sensory
neurons.
The ventral root carries information from the CNS to
muscles and glands.

24. In cross section, the spinal cord has a butter y- or H-shaped
core of gray matter and a surrounding rim of white matter.
Sensory fibers from the dorsal roots synapse with
interneurons in the dorsal horns of the gray matter.
The dorsal horn cell bodies are organized into two distinct
nuclei, one for somatic information and one for visceral
information.
The ventral horns of the gray matter contain cell bodies of
motor neurons that carry efferent signals to muscles and
glands.
The ventral horns are organized into somatic motor and
autonomic nuclei.
Efferent fibers leave the spinal cord via the ventral root.

25. The white matter of the spinal cord is the biological equivalent
of fiber-optic cables that telephone companies use to carry our
communications systems.
White matter can be divided into a number of columns
composed of tracts of axons that transfer information up and
down the cord.
Ascending tracts take sensory information to the brain. They
occupy the dorsal and external lateral portions of the spinal cord.
Descending tracts carry mostly efferent (motor) signals from
the brain to the cord. They occupy the ventral and interior lateral
portions of the white matter.

26. Propriospinal tracts (proprius, one’s own) are those that
remain within the cord.
The spinal cord can function as a self-contained integrating
center for simple spinal re exes, with signals passing from a
sensory neuron through the gray matter to an efferent neuron.
In addition, spinal interneurons may route sensory
information to the brain through ascending tracts or bring
commands from the brain to motor neurons.
In many cases, the interneurons also modify information as it
passes through them.
Reflexes play a critical role in the coordination of movement.

27. Neural Growth and Regeneration
The elaborate networks of nerve-cell processes that
characterize the nervous system are remarkably similar in all
human beings and depend upon the outgrowth of specific
axons to specific targets.
Development of the nervous system in the embryo begins
with a series of divisions of precursor cells that can develop
into neurons or glia.
After the last cell division, each neuronal daughter cell
differentiates, migrates to its final location, and sends out
processes that will become its axon and dendrites.
A specialized enlargement, called the growth cone, forms
the tip of each extending axon and is involved in finding the
correct route and final target for the process.

28. As the axon grows, it is guided along the surfaces of other
cells, most commonly glial cells.
Which particular route is followed depends largely on
attracting, supporting, deflecting, or inhibiting influences
exerted by several types of molecules.
Some of these molecules, such as cell adhesion
molecules, reside on the membranes of the glia and
embryonic neurons.
Others are soluble neurotropic factors (growth factors for
neural tissue) in the extracellular fluid surrounding the growth
cone or its distant target.

29. Once the target of the advancing growth cone is reached,
synapses are formed.
The synapses are active, however, before their final
maturation occurs, and this early activity, in part, determines
their final use.
During these intricate early stages of neural development,
which occur during all trimesters of pregnancy and into infancy,
alcohol and other drugs, radiation, malnutrition, and viruses
can exert effects that cause permanent damage to the
developing fetal nervous system.

30. A normal, although unexpected, aspect of development of the
nervous system occurs after growth and projection of the axons.
Many of the newly formed neurons and synapses degenerate.
In fact, as many as 50 to 70 percent of neurons die by
apoptosis in some regions of the developing nervous system!
Exactly why this seemingly wasteful process occurs is
unknown although neuroscientists speculate that in this way
connectivity in the nervous system is refined, or “fine tuned.”
Although the basic shape and location of existing neurons in
the mature central nervous system do not change, the creation
and removal of synaptic contacts begun during fetal development
continue, albeit at a slower pace, throughout life as part of
normal growth, learning, and aging.

31. Division of neuron precursors is largely complete before
birth, and after early infancy new neurons are formed at a
slower pace to replace those that die.
Severed axons can repair themselves, however, and
significant function regained, provided that the damage occurs
outside the central nervous system and does not affect the
neuron’s cell body.
After repairable injury, the axon segment now separated
from the cell body degenerates.
The proximal part of the axon (the stump still attached to the
cell body) then gives rise to a growth cone, which grows out to
the effector organ so that in some cases function is restored.

32. In contrast, severed axons within the central nervous system
attempt sprouting, but no significant regeneration of the axon
occurs across the damaged site, and there are no well-
documented reports of significant function return.
Either some basic difference of central nervous system
neurons or some property of their environment, such as
inhibitory factors associated with nearby glia, prevents their
functional regeneration.
In humans, however, spinal injuries typically crush rather
than cut the tissue, leaving the axons intact.
In this case, a primary problem is self-destruction (apoptosis)
of the nearby oligodendroglia, because when these cells die
and their associated axons lose their myelin coat, the axons
cannot transmit information effectively.

33. PROTECTION AND NOURISHMENT OF THE BRAIN
Due to the very delicate nature of the CNS tissue and the fact
that its damaged nerve cells cannot be replaced, makes it
imperative that this fragile, irreplaceable tissue be well
protected
Four (4) major features help protect the CNS from injury:
1. It is enclosed by hard, bony structures. The cranium (skull)
encases the brain, and the vertebral column surrounds the
spinal cord.
2. Three protective and nourishing membranes called the
meninges,lie between the bony covering and the nervous
tissue.
3. The brain “floats” in a special cushioning fluid known as the
cerebrospinal fluid (CSF).

34. 4. A highly selective blood–brain barrier limits access of blood
borne materials into the vulnerable brain tissue.
The role of the first of these protective devices, the bony
covering, is self-evident while the latter three protective
mechanisms warrant further discussion.
Meninges
The three meningeal membranes wrap, protect, and nourish
the central nervous system.
From the outermost to the innermost layer they are the dura
mater, the arachnoid mater, and the pia mater (Mater means
“mother,” indicative of these membranes’ protective and
supportive role).

35. The dura mater is a tough, inelastic covering that consists
of two layers (dura means “tough”).
Usually, these layers adhere closely, but in some regions
they are separated to form blood filled cavities, dural sinuses,
or in the case of the larger cavities, venous sinuses.
Venous blood draining from the brain empties into these
sinuses to be returned to the heart.
Cerebrospinal fluid also reenters the blood at one of these
sinus sites.
The arachnoid mater is a delicate, richly vascularized layer
with a “cobwebby” appearance (arachnoid means “spiderlike”).

36. The space between the arachnoid layer and the underlying
pia mater, the subarachnoid space, is filled with CSF.
Protrusions of arachnoid tissue, the arachnoid villi,
penetrate through gaps in the overlying dura and project into
the dural sinuses.
CSF is reabsorbed across the surfaces of these villi into the
blood circulating within the sinuses.
The innermost meningeal layer, the pia mater, is the most
fragile (pia means “gentle”).
It is highly vascular and closely adheres to the surfaces of the
brain and spinal cord, following every ridge and valley.

37. In certain areas it dips deeply into the brain to bring a rich
blood supply into close contact with the ependymal cells lining the
ventricles.
This relationship is important in the formation of CSF, a topic to
which we now turn our attention.

38. Cerebro-Spinal Fluid (CSF)
Cerebrospinal fluid is formed primarily by the choroid
plexuses found in particular regions of the ventricles.
Choroid plexuses consist of richly vascularized, cauliflower-
like masses of pia mater tissue that dip into pockets formed by
ependymal cells.
Cerebrospinal fluid forms as a result of selective transport
mechanisms across the membranes of the choroid plexuses.
The composition of CSF differs from that of blood.
Cerebrospinal fluid (CSF) surrounds and cushions the brain
and spinal cord.

39. Cerebrospinal Fluid (CSF) Composition
Composition CSF Blood Plasma
Na+ (mEq/L) 140 – 145 135 – 147
K+ (mEq/L) 3 3.5 – 5
Cl- (mEq/L) 115 – 120 95 – 105
HCO3- (mEq/L) 20 22 – 28
Glucose (mg/ml) 50 – 75 70 – 110
Protein (g/dL) 0.05 – 0.07 6 – 7.8
pH 7.3 7.35 – 7.45
Frank et al. (2002). Atlas of Neuroanatomy and Neurophysiology. Icons Custom Communications, USA, p 61

40. The CSF has about the same density as the brain itself, so
the brain essentially floats or is suspended in this special fluid
environment.
The major function of CSF is to serve as a shock-absorbing
fluid to prevent the brain from bumping against the interior of
the hard skull when the head is subjected to sudden, jarring
movements.
In addition to protecting the delicate brain from mechanical
trauma, the CSF plays an important role in the exchange of
materials between the neural cells and the interstitial fluid
surrounding the brain.
Only the brain interstitial fluid but not the blood or CSF comes
into direct contact with the neurons and glial cells.

41. Because the brain interstitial fluid directly bathes the neural
cells, its composition is critical.
The composition of the brain interstitial fluid is influenced
more by changes in the composition of the CSF than by
alterations in the blood.
Materials are exchanged fairly freely between the CSF and
brain interstitial fluid, whereas only limited exchange occurs
between the blood and brain interstitial fluid.
Thus, the composition of the CSF must be carefully
regulated.

42. For example, CSF is lower in K and slightly higher in Na,
making the brain interstitial fluid an ideal environment for
movement of these ions down concentration gradients, a process
essential for conduction of nerve impulses.
The biggest difference is the presence of plasma proteins in
the blood but almost no proteins normally present in the CSF.
Plasma proteins cannot exit the brain capillaries to leave the
blood during formation of CSF.
Once CSF is formed, it flows through the four interconnected
ventricles of the brain and through the spinal cord’s narrow
central canal, which is continuous with the last ventricle.

43. • Cerebrospinal fluid also escapes through small openings from
the fourth ventricle at the base of the brain to enter the
subarachnoid space and subsequently flows between the
meningeal layers over the entire surface of the brain and spinal
cord.
• When the CSF reaches the upper regions of the brain, it is
reabsorbed from the subarachnoid space into the venous blood
through the arachnoid villi.
• Flow of CSF through this system is facilitated by ciliary beating
along with circulatory and postural factors that result in a CSF
pressure of about 10 mm Hg.

45. Reduction of this pressure by removal of even a few milliliters
(ml) of CSF during a spinal tap for laboratory analysis may
produce severe headaches.
Through the ongoing processes of formation, circulation, and
reabsorption, the entire CSF volume of about 125 to 150 ml is
replaced more than three times a day.
If any one of these processes is defective so that excess
CSF accumulates causing hydrocephalus (“water on the
brain”) occurs.
The resulting increase in CSF pressure can lead to brain
damage and mental retardation if untreated. Treatment consists
of surgically shunting the excess CSF to veins elsewhere in the
body.

46. Blood Brain Barrier
The brain is carefully shielded from harmful changes in the
blood by a highly selective blood–brain barrier (BBB).
Throughout the body, materials can be exchanged between
the blood and interstitial fluid only across the walls of capillaries,
the smallest blood vessels.
Unlike the rather free exchange across capillaries elsewhere,
only selected, carefully regulated exchanges can be made
across the BBB.
For example, even if the K+ level in the blood is doubled, little
change occurs in the K+ concentration of the fluid bathing the
central neurons.
This is beneficial because alterations in interstitial fluid K+
would be detrimental to neuronal function.

47. The BBB has both anatomic and physiologic features.
Capillary walls throughout the body are formed by a single
layer of cells.
Usually, all blood plasma components (except the large
plasma proteins) can be freely exchanged between the blood
and the interstitial fluid through holes or pores between the cells
of the capillary wall.
In brain capillaries, however, the cells are joined by tight
junctions, which completely seal the capillary wall so that
nothing can be exchanged across the wall by passing between
the cells.
The only possible exchanges are through the capillary cells
themselves.

48. Lipid-soluble substances such as O2, CO2, alcohol, and steroid
hormones penetrate these cells easily by dissolving in their lipid
plasma membrane.
Small water molecules also diff use through readily, by passing
between the phospholipid molecules of the plasma membrane or
through aquaporins (water channels).
All other substances exchanged between the blood and brain
interstitial fluid, including such essential materials as glucose,
amino acids, and ions, are transported by highly selective
membrane-bound carriers.
Thus, transport across brain capillary walls between the wall-
forming cells is prevented anatomically and transport through the
cells is restricted physiologically.
Together, these mechanisms constitute the BBB.

49. By strictly limiting exchange between the blood and brain,
the BBB protects the delicate brain:
 from chemical fluctuations in the blood;
 minimizes the possibility that potentially harmful blood-borne
substances might reach the central neural tissue; and
 it further prevents certain circulating hormones that could
also act as neurotransmitters from reaching the brain, where
they could produce uncontrolled nervous activity.
On the negative side, the BBB limits the use of drugs for the
treatment of brain and spinal cord disorders because many
drugs are unable to penetrate this barrier.

50. Certain areas of the brain, most notably a portion of the
hypothalamus, are not subject to the BBB.
Functioning of the hypothalamus depends on its “sampling”
the blood and adjusting its controlling output accordingly to
maintain homeostasis.
Part of this output is in the form of water-soluble hormones
that must enter hypothalamic capillaries to be transported to
their sites of action.
Appropriately, these hypothalamic capillaries are not sealed
by tight junctions.

51. Brain Oxygen and Glucose Delivery
Even though many substances in the blood never actually come
in contact with the brain tissue, the brain is more dependent than
any other tissue on a constant blood supply.
Unlike most tissues, which can resort to anaerobic metabolism
to produce ATP in the absence of O2 for at least short periods, the
brain cannot produce ATP without O2.
Scientists recently discovered an O2-binding protein,
neuroglobin, in the brain.
This molecule, which is similar to hemoglobin, the O2-carrying
protein in red blood cells, is thought to play a key role in O2
handling in the brain, although its exact function remains to be
determined.

52. Also in contrast to most tissues, which can use other sources
of fuel for energy production in lieu of glucose, the brain normally
uses only glucose but does not store any of this nutrient.
Because of its high rate of demand for ATP, under resting
conditions the brain uses 20% of the O2 and 50% of the glucose
consumed in the body.
Therefore, the brain depends on a continuous, adequate blood
supply of O2 and glucose.
Although it constitutes only 2% of body weight, the brain
receives 15% of the blood pumped out by the heart.
Instead of using glucose during starvation, the brain can resort
to using ketone bodies produced by the liver, but this alternate
nutrient source also must be delivered by the blood to the brain.

53. Brain damage results if this organ is deprived of its critical O2
supply for more than 4 to 5 minutes or if its glucose supply is cut
off for more than 10 to 15 minutes.
The most common cause of inadequate blood supply to the
brain is a stroke.

54. INTRODUCTORY NOTES
The term “autonomic” implies independent, self-controlling
function without conscious effort.
The ANS therefore helps to regulate our internal environment
(visceral functions).
The ANS is activated mainly by centers that are located in the
spinal cord, brain stem and the hypothalamus.
It comprises of the Sympathetic and parasympathetic nervous
system but Enteric Nervous System (ENS) can also be considered
as part of the ANS.
Portions of cerebral cortex, especially the limbic cortex can
transmit impulses to the lower centers thereby influencing
autonomic control.
The ANS also operates via visceral reflexes.

55. INTRODUCTORY NOTES

56. THE AUTONOMIC NERVOUS
SYSTEM
The autonomic nervous
system (ANS) regulates
physiologic processes without
conscious control.
The ANS consists of two
sets of nerve bodies:
preganglionic and
postganglionic fibers.
The two major divisions of
the ANS are the sympathetic
and parasympathetic
systems.

57. Anatomy of the Autonomic Nervous System
Sympathetic:
The preganglionic cell bodies
of the sympathetic system are
located in the intermediolateral
horn of the spinal cord between
T1 and L2 or L3.
The sympathetic ganglia are
adjacent to the spine and
consist of the vertebral
(sympathetic chain) and
prevertebral ganglia
Long fibers run from these
ganglia to effector organs,
including the smooth muscle of
blood vessels, viscera, lungs,
scalp (piloerector muscles), and
pupils; the heart; and glands
(sweat, salivary, and digestive).

58. Parasympathetic
The preganglionic cell bodies of
the parasympathetic system are
located in the nuclei of the brain
stem and sacral portion of the
spinal cord (S2-S4).
These preganglionic fibers exit
the brain stem with the 3rd, 7th,
9th, and 10th cranial nerves.
Parasympathetic ganglia are
located in the blood vessels of the
head, neck, and thoracoabdominal
viscera; lacrimal and salivary
glands; smooth muscle of viscera
and glands.
Postganglionic parasympathetic
fibers are relatively short (only
about 1 or 2 mm long) thereby
producing specific, localized
responses in the effector organs.

59. Inputs to the Autonomic Nervous System
 The ANS receives input from
parts of the CNS that
process and integrate stimuli
from the body and external
environment.
 These parts include the
hypothalamus, nucleus of the
solitary tract, reticular
formation, amygdala,
hippocampus, and olfactory
cortex.

60. Neurotransmitters of the ANS
Two most common neurotransmitters released by neurons of
the ANS are acetylcholine (cholinergic) and
norepinephrine/noradrenaline (adrenergic).
Acetylcholine:
All preganglionic nerve fibers
All postganglionic fibers of the parasympathetic system
Sympathetic postganglionic fibers innervating sweat glands
Adrenaline:
In most sympathetic postganglionic fibers

61. Receptors of the ANS Neurotransmitters
 Cholinergic receptors: nicotinic or muscarinic.
 Adrenergic receptors: alpha (α) and beta (β), with α being
more abundant.
The adrenergic receptors are further divided into (α1, α2,
β1 and β2) according to some factors.

62. Functions of the ANS
 The two divisions of the ANS are dominant under different
conditions.
 The sympathetic system is activated during emergency
“fight-or-flight” reactions and during exercise.
 The parasympathetic system is predominant during quiet
conditions (“rest and digest”). As such, the physiological
effects caused by each system are quite predictable.
 In other words, all of the changes in organ and tissue
function induced by the sympathetic system work together to
support strenuous physical activity and the changes induced
by the parasympathetic system are appropriate for when the
body is resting.

64. AUTONOMIC GANGLIA
 These are small swellings along the course of the autonomic
nerves that contain a collection of nerve cells.
 Efferent autonomic fibers that arise from the lateral horn cells
are called the preganglionic fibers which are thick, white and
myelinated fibers.
 The preganglionic fibers enter the autonomic ganglia where
they take either of two courses:
i) terminate into several nerve terminals in the ganglion that relay
impulses into the ganglionic nerve cells.
 Postganlionic fibers emerge from these ganglionic fibers and
proceed to supply the effector organs. These are thin, gray and
unmyelinated fibers.

65. ii) Pass via the ganglion uninterrupted without relay and
emerge on the other side still as preganglionic fibers to
proceed to the adrenal medulla or to another ganglion where
they terminate and relay
 The postganglionic nerve fibers emerge from the later
ganglion to supply the effector organs.
Types of the Autonomic Ganglia
a) Lateral or Paravertebral Ganglia: Form sympathetic
chain on both sides of the vertebral column with each chain
forming 23 ganglia (3 cervical – superior, middle and inferior
ganglia; 12 thoracic; 4 lumbar and 4 sacral) connected to
each other by nerve fibers.

66. b) Collateral or Prevertebral ganglia: These are celiac, the
superior and inferior mesenteric ganglia. They are found along the
course of sympathetic nerves, midway between the spinal cord and
the viscera. These are sympathetic ganglia i.e. sites of relay for
sympathetic nerves only.
c) Terminal Ganglia: These are present near or inside the effector
organ e.g. the eye, heart and the stomach. They are parasympathetic
ganglia i.e. sites of relay for parasympathetic nerves only.
 The Autonomic ganglia serve as: relay stations, expansion as well
as distribution centers.

67. REGULATORY SYSTEMS OF THE ANS
 Autonomic reflexes represent the
simplest level of ANS control
 The ANS involvement with the
limbic system, hypothalamus,
solitary nucleus of the medulla and
other brain stem nuclei has
explained the ANS regulation.
 In fact, the limbic system has
Stimulation of the limbic
been termed the “cerebral cortex of
system areas can evoke a broad
the ANS”. So the limbic system
range of feelings and behaviors,
represents one of the highest levels including rage, anger, fear, and
of the hierarchy of normal control of aggression.
the ANS.

68.  In addition, stimulation of the limbic system, either directly or by input
from the senses, can evoke ANS-mediated physiological changes such as
increased heart rate, sexual arousal, and nausea.
Autonomic Functions of the Hypothalamus
 Hypothalamus is known as the main ganglion of the ANS and the
activation of its different parts produces a variety of coordinated autonomic
responses:
 Activation of the dorsal hypothalamus, for e.g. increases blood pressure,
intestinal motility, and intestinal blood supply but decreases supply to the
skeletal muscles. These are associated with feeding behavior.
 However, activation of ventral hypothalamus increases blood pressure
and the blood supply to the skeletal muscles but decreases intestinal motility
and blood flow to the intestines. These are associated with flight or flight
responses.

69. CHEMICAL TRANSMISSION
• Chemical transmissions (synapses) enable cell-to-cell
communication via the secretion of neurotransmitters by activating
specific receptor molecules.
•
• A synapse is a junctional area between a neuronal terminal and
another cell that could be another neuron, muscle cell or a gland.
• If the second cell is a neuron, the synapse is called a neuronal
synapse.
• The neuron that conducts the signals is the presynaptic neuron
having a presynaptic membrane at the synapse. However, the
neuron that receives the signals and its membrane are postsynaptic
neuron and postsynaptic membrane respectively.
• The space between the presynaptic and postsynaptic membranes is
called synaptic cleft and measures about 30-50 nm.

70.  A key feature of all chemical synapses is the presence of small,
membrane-bounded organelles called the synaptic vesicles within the
presynaptic terminal
Neurotransmitters
 There are more than 100 types of neurotransmitters and they
virtually undergo a similar cycle of use:
 synthesis and packaging into synaptic vesicles
 Release from the presynaptic cell
 Binding to postsynaptic receptor
 Rapid removal and degradation
 The secretion of the neurotransmitters is triggered by the influx of Ca2+
through the voltage-gated channels that give rise to transient increase in
Ca2+ concentration within the presynaptic terminal.

71. Sequence of Events involved in Transmission at a Typical
Chemical Synapse

72.  The rise in the Ca2+ causes synaptic vesicles to fuse with presynaptic
plasma membrane and release their contents into the space between the
pre- and postsynaptic cells.
 Neurotransmitters released therefore evoke postsynaptic electrical
responses by binding to members of a diverse group of
neurotransmitter receptors.
 There are two major classes of receptors: those in which the receptor
molecule is also an ion channel and those in which the receptor and the
ion channel are two separate molecules.
 These receptors give rise to electrical signals by transmitter-induced
opening or closing of the ion channels.

73. CHEMICAL TRANSMISSION – Cont’d
 Whether the postsynaptic actions of a particular neurotransmitter
are excitatory or inhibitory is determined by:
 The ionic permeability of the ion channel affected by the neurotransmitter
and
 By the concentration of the permanent ions inside and outside the
cell
Criteria that Define Neurotransmitters
There are 3 primary criteria been used to confirm that a molecule acts
as a neurotransmitter at a given chemical synapse:
1) The substance must be present within the presynaptic neuron. Moreso,
when enzymes and precursors required to synthesize the substance provide
more evidence. However, presence of glutamate, glycine and aspartate is not
a sufficient evidence.

74. (1) Neurotransmitter presence (2) Neurotransmitter release (3) Postsynaptic presence of specific receptors
Requirements of identifying a neurotransmitter

75. 2) The substance must be released in response to presynaptic
depolarization, and the release must be Ca2+-dependent. This is quite
challenging not only because it may be difficult to selectively stimulate the
presynaptic neuron, but also because enzymes and transporters efficiently
remove the secreted neurotransmitters.
3) Specific receptors for the substance must be present on the postsynaptic
cell/membrane. One way to demonstrate receptors is to show that application
of exogenous transmitter mimics the postsynaptic effect of presynaptic
stimulation.
 A more rigorous demonstration is to show that agonists and antagonists that
alter the normal postsynaptic response have the same effect when the substance
in question is applied exogenously. High resolution histological techniques can
also be used to show that specific receptors are present in the postsynaptic
membrane (by detection of radioactively labeled receptor antibodies).

76. Categories of Neurotransmitters
 More than 100 different agents are known to serve as
neurotransmitters that allow for diverse chemical signaling between
neurons.
 These neurotransmitters are broadly divided into two based on size:
i) Neuropeptides: These are relatively large transmitter molecules
composed of 3 to 36 amino acids.
ii) Small-molecule neurotransmitters: individual amino acids, such as
Glutamate, GABA, Ach, serotonin and histamine are examples.
 Within this category, the biogenic amines such as dopamine,
norepinephrine, epinephrine, serotonin and histamine are often discussed
separately because of their similar properties and postsynaptic actions.

77. NORADRENERGIC TRANSMISSION
Synthesis of Norepinephrine/Epinephrine
 The adrenal medulla that secretes epinephrine/adrenaline and
norepinephrine/noradrenaline, is an important component of the
sympathetic nervous system. As a result, the sympathetic nervous
system and adrenal medulla are often referred to as the
sympathoadrenal system.
 Norepinephrine is one of the five well-established biogenic amine
neurotransmitters: 3 catecholamines (dopamine, norepinephrine
and epinephrine), histamine and serotonin.
 Noradrenaline like the other 2 catecholamines are derived from
tyrosine (which is a product of phenylalanine).

78. Synthesis of Norepinephrine/Epinephrine
 This reaction is catalyzed by phenylalanine hydroxylase in the
liver) in a reaction catalyzed by tyrosine hydroxylase (in the
neuron) requiring O2 as a co-substrate and tetrahydrobiopterin as a
cofactor to form DihydrOxyPhenylAlanine (DOPA).
 Norepinephrine synthesis requires dopamine β-hydroxylase
that catalyzes the production of noradrenaline from Dopamine.
 In the central adrenergic fibers (neurons of the thalamus,
hypothalamus and midbrain) and in the adrenal medulla,
noradrenaline is converted to adrenaline by Phenylethanolamine
-N-methyl Transferase (PNMT).
 This enzyme is not found in the peripheral adrenergic fibers.

79. Synthesis of Norepinephrine/Epinephrine

80. Fate / Degradation of Norepinephrine/epinephrine
 Noradrenaline is the loaded into synaptic vesicles via the Vesicular
MonoAmine Transporter (VMAT) same as with dopamine.
 Norepinephrine is cleared from the synaptic cleft by
Norepinephrine Transporter (NET) mainly in the nerve terminals
which is also capable of taking up dopamine to be recirculated.
 Small amount of Noradrenaline like dopamine is oxidized by
MonoAmine Oxidase (MAO) to inactive products. MAO is found
in nerve terminals and other organs like liver and kidney.
 Some small amount is methylated to inactive products by Catechol
O-Methyl-Transferase (COMT) enzymes found in the many
tissues such as kidney and brain but not in the nerve terminals.
 Epinephrine is mainly methylated in various organs by COMT.

81. Adrenergic Receptors/Adrenoceptors
 Norepinephrine as well as epinephrine, acts on α- and β-adrenergic
receptors that are both G-protein coupled.
 There are two types of α-adrenergic receptors (α1 and α2) and
three β-adrenergic receptors (though 2 are the well known because
of their expression in many types of neurons, β1 and β2).
 Norepinephrine for example excites mainly α receptors but excites
β receptors to a slight extent; while epinephrine excites both types of
receptors almost equally.
 Isoproterenol (a synthetic catecholamine) has strong action on β-
receptors but essentially no action on α-receptors

82. Adrenergic
Drugs/Agonists/Protagonists/Symphatomimietic Drugs
 These are drugs that mimic the actions of norepinephrine or epinephrine
through the following mechanisms:
i) Stimulating the release of the transmitter. Example of these include Amphetamine
and Ephedrine
ii) Inhibiting the action of MAO enzyme. Example, Ephedrine and Hydrazine
iii) Direct stimulation of receptors. Example norepinephrine and epinephrine (α
and β), phenylephrine (α1), clonidine (α2), Dobutamine (β1), Salbutamol (β2) and
isoproterenol (β1 and β2)
 Agonists and antagonists of adrenergic receptors, such as the β blocker
propanolol are used clinically for a variety of conditions ranging from cardiac
arrhythmias to migraine headaches.
 However, most of the actions of these drugs are on smooth muscle receptors
particularly on cardiovascular and respiratory systems.

83. Anti-Adrenergic Drugs/Adrenergic
Blockers/Antagonists/Symphatolytic Drugs
• These are drugs that block the actions of norepinephrine and
epinephrine and they produce their actions via the following
mechanisms:
i) Inhibiting the synthesis of norepinephrine. Example is Aldomet
(that inhibits β-hydroxylase leading to the formation of a false
transmitter).
ii) Preventing the release of the transmitter. Example is Guanethidine
iii) Direct blocking of the receptors. Examples are: Prazosin (α1),
Yohimbine (α2), Phentolamine (α1 and α2), Atenolol (β1),
Butaxamine (β2) and Propranolol (β1 and β2)

84. CHOLINERGIC TRANSMISSION
 Ach is synthesized in nerve terminals from the precursors acetyl
coA and choline in the recation catalyzed by choline acetyl
transferase (CAT)
 Choline is present in plasma at a high concentration (about 10 mM)
and is taken up into cholinergic neurons by a high - affinity
Na+/choline transporter.
 After synthesis in the neuroplasm a vesicular Ach transporter loads
approx 10, 000 molecules of Ach into each cholinergic vesicle.
 In contrast to most other small-molecular neurotransmitters, the
postsynaptic actions of Ach at many cholinergic synapses (the
NMJ in particular) is not terminated by reuptake but by a powerful
hydrolytic enzyme, Acetylcholinesterase (AchE)

85. Electrical synapse Chemical synapse

86. (a) Chemically gated (b) Receptor Enzyme (c) G-Protein coupled
receptor-channel Receptor

87. Functions of Cranial Nerves

88. Classification of Mammalian Nerve Fibers
NB: A and B fibers are myelinated while the C fibers are unmyelinated

89. Relative susceptibility of mammalian A, B, and C nerve fibers to conduction block produced by
various agents

90. Neurotrophins: Trophic Support of Neurons
Proteins necessary for survival and growth of neurons are
called neurotrophins.
Many are products of the muscles or other structures that the
neurons innervate, but others are produced by astrocytes.
These proteins bind to receptors at the endings of a neuron.
They are internalized and then transported by retrograde
transport to the neuronal cell body, where they foster the
production of proteins associated with neuronal development,
growth, and survival.
Other neurotrophins are produced in neurons and transported
in an anterograde fashion to the nerve ending, where they
maintain the integrity of the postsynaptic neuron.

91. The first neurotrophin to be characterized was nerve growth
factor (NGF), a protein that is necessary for the growth and
maintenance of sympathetic neurons and some sensory
neuron.
It is found in many different tissues. NGF is picked up by
neurons and transported in retrograde fashion from the endings
of the neurons to their cell bodies.
It is also present in the brain and appears to be responsible
for the growth and maintenance of cholinergic neurons in the
basal forebrain and striatum.

92. NEUROTRANSMITTERS
Mostly, neurons in the human brain communicate with one
another by releasing chemical messengers called neurotransmitters.
A large number of neurotransmitters are now known and more
remain to be discovered.
Neurotransmitters evoke postsynaptic electrical responses by
binding to members of a diverse group of proteins called
neurotransmitter receptors.
There are two major classes of receptors:
 those in which the receptor molecule is also an ion channel,
which are called ionotropic receptors or ligand gated ion
channels, and give rise to fast postsynaptic responses that
typically last only a few milliseconds; and

94.  those in which the receptor and ion channel are separate
molecules called metabotropic receptors, that produce slower
postsynaptic effects that may endure much longer.
Abnormalities in the function of neurotransmitter systems
contribute to a wide range of neurological and psychiatric disorders.
As a result, many neuropharmacological therapies are based on
drugs that affect neurotransmitter release, binding, and/or removal.
Categories of Neurotransmitters
More than 100 different agents are known to serve as
neurotransmitters.
This large number of transmitters allows for tremendous diversity
in chemical signaling between neurons and are divided into two
broad categories based on size.

95. i) neuropeptides are relatively large transmitter molecules
composed of 3 to 36 amino acids.
ii) small-molecule neurotransmitters are Individual amino
acids, such as glutamate, GABA, acetylcholine, serotonin,
and histamine, are much smaller than neuropeptides
Within the category of small-molecule neurotransmitters, the
biogenic amines (dopamine, norepinephrine, epinephrine,
serotonin, and histamine) are often discussed separately
because of their similar chemical properties and postsynaptic
actions.
The particulars of synthesis, packaging, release, and
removal differ for each neurotransmitter.

96. Acetylcholine
Acetylcholine (ACh) was the first
substance identified as a
neurotransmitter.
Acetylcholine is synthesized in
nerve terminals from the precursors
acetyl coenzyme A (acetyl CoA,
which is synthesized from glucose)
and choline, in a reaction catalyzed
by choline acetyltransferase
(CAT).
Choline is present in plasma at a After synthesis in the cytoplasm
high concentration and is taken up of the neuron, a vesicular Ach
into cholinergic neurons by a high- transporter loads approximately
affinity Na+/choline transporter. 10,000 molecules of ACh into
each cholinergic vesicle.

98. In contrast to most other small-molecule neurotransmitters,
the postsynaptic actions of ACh at many cholinergic synapses
(the neuromuscular junction in particular) is not terminated by
reuptake but by a powerful hydrolytic enzyme,
acetylcholinesterase (AChE).
This enzyme is concentrated in the synaptic cleft, ensuring a
rapid decrease in ACh concentration after its release from the
presynaptic terminal.
The AChE has a very high catalytic activity (about 5000
molecules of ACh per AChE molecule per second) and
hydrolyzes Ach into acetate and choline.
The choline produced by ACh hydrolysis is transported back
into nerve terminals and used to re-synthesize ACh.

99. Among the many interesting drugs that interact with cholinergic
enzymes are the organophosphates that include some potent
chemical warfare agents.
One such compound is the nerve gas “Sarin,” which was made
notorious after a group of terrorists released this gas in Tokyo’s
underground rail system.
Organophosphates can be lethal because they inhibit AChE,
causing Ach to accumulate at cholinergic synapses.
This build-up of ACh depolarizes the postsynaptic cell and
renders it refractory to subsequent ACh release, causing
neuromuscular paralysis and other effects.
The high sensitivity of insects to these AChE inhibitors has
made organophosphates popular insecticides.

100. Acetylcholine Receptors
There are two types of cholinergic receptors:
 Muscarinic
 Nicotinic

101. Glutamate
• Glutamate is the most important transmitter in normal brain
function.
• Nearly all excitatory neurons in the central nervous system are
glutamatergic, and it is estimated that over half of all brain
synapses release this agent.
• Glutamate plays an especially important role in clinical
neurology because elevated concentrations of extracellular
glutamate, released as a result of neural injury, are toxic to
neurons.
• Glutamate is a nonessential amino acid that does not cross the
blood-brain barrier and therefore must be synthesized in neurons
from local precursors.

102. The most prevalent precursor
for glutamate synthesis is
glutamine, which is released by
glial cells.
Once released, glutamine is
taken up into presynaptic terminals
and metabolized to glutamate by
the mitochondrial enzyme
glutaminase.
Glutamate can also be
synthesized by transamination
of 2-oxoglutarate, an intermediate
of the tricarboxylic acid cycle. The glutamate synthesized in
the presynaptic cytoplasm is
Hence, some of the glucose packaged into synaptic
metabolized by neurons can also vesicles by transporters,
be used for glutamate synthesis. termed VGLUT.

103. The glutamate synthesized in the presynaptic cytoplasm is
packaged into synaptic vesicles by transporters, termed
VGLUT.
At least three different VGLUT genes have been identified.
Once released, glutamate is removed from the synaptic cleft
by the excitatory amino acid transporters (EAATs).
Glutamate taken up by glial cells is converted into glutamine
by the enzyme glutamine synthetase; glutamine is then
transported out of the glial cells and into nerve terminals.

104. In this way, synaptic terminals cooperate with glial cells to
maintain an adequate supply of the neurotransmitter.
This overall sequence of events is referred to as the
glutamate-glutamine cycle.
Glutamate Receptors
Several types of glutamate receptors have been identified.
Three of these are ionotropic receptors and are called:
 NMDA (N-methyl-D-aspartate)receptors,
 AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate),
receptors, and
 kainate receptors
These glutamate receptors are named after the agonists that
activate them.

105. All of the ionotropic glutamate receptors are nonselective
cation channels similar to the nAChR, allowing the passage of
Na+ and K+, and in some cases small amounts of Ca2+.
Hence AMPA, kainate, and NMDA receptor activation always
produces excitatory postsynaptic responses.
Like other ionotropic receptors, AMPA/kainate and NMDA
receptors are also formed from the association of several protein
subunits that can combine in many ways to produce a large
number of receptor isoforms.

106. GABA and Glycine
Most inhibitory synapses in the brain and spinal cord use
either γ-Aminobutyric acid (GABA) or glycine as
neurotransmitters.
Like glutamate, GABA was identified in brain tissue during the
1950s.
It is now known that as many as a third of the synapses in the
brain use GABA as their inhibitory neurotransmitter.
GABA is most commonly found in local circuit interneurons,
although cerebellar Purkinje cells provide an example of a
GABAergic projection neuron.
The predominant precursor for GABA synthesis is glucose,
which is metabolized to glutamate by the tricarboxylic acid cycle
enzymes (pyruvate and glutamine can also act as precursors).

107. The predominant precursor for
GABA synthesis is glucose, which
is metabolized to glutamate by the
tricarboxylic acid cycle enzymes
(pyruvate and glutamine can also
act as precursors).
The enzyme glutamic acid
decarboxylase (GAD), which is
found almost exclusively in
GABAergic neurons, catalyzes the
conversion of glutamate to GABA.
Because pyridoxal
phosphate is derived from
GAD requires a cofactor,
vitamin B6, a B6 deficiency
pyridoxal phosphate, for activity. can lead to diminished
GABA synthesis.

108. The significance of this
became clear after a disastrous
series of infant deaths was linked
to the omission of vitamin B6
from infant formula.
This lack of B6 resulted in a
large reduction in the GABA
content of the brain, and the
subsequent loss of synaptic
inhibition caused seizures that in
some cases were fatal.
Once GABA is synthesized, it
is transported into synaptic
vesicles via a vesicular
inhibitory amino acid
transporter (VIATT).

109. The mechanism of GABA removal is similar to that for
glutamate: Both neurons and glia contain high-affinity
transporters for GABA, termed GATs (several forms of GAT
have been identified).
Most GABA is eventually converted to succinate, which is
metabolized further in the tricarboxylic acid cycle that mediates
cellular ATP synthesis.
The enzymes required for this degradation, GABA
transaminase and succinic semialdehyde dehydrogenase,
are mitochondrial enzymes.
Inhibition of GABA breakdown causes a rise in tissue GABA
content and an increase in the activity of inhibitory neurons.
There are also other pathways for degradation of GABA.

110. The most noteworthy of these results in the production of γ-
hydroxybutyrate, a GABA derivitive that has been abused as a
“date rape” drug.
Oral adminis-tration of γ-hydroxybutyrate can cause
euphoria, memory deficits, and unconsciousness.
Presumably these effects arise from actions on GABAergic
synapses in the CNS.
Inhibitory synapses employing GABA as their transmitter can
exhibit three types of postsynaptic receptors, called GABAA,
GABAB, and GABAC.
GABAA and GABAC receptors are ionotropic receptors,
while GABAB receptors are metabotropic.

111. Drugs that act as agonists or modulators of postsynaptic
GABA receptors, such as benzodiazepines and barbiturates,
are used clinically to treat epilepsy and are effective sedatives
and anesthetics.

113. SENSORY SYSTEMS: TOUCH, PAIN, AND TEMPERATURE
Learning Objectives
At the end of this lesson, the students are expected to:
 List common senses and their receptors;
 Explain the terms hyperalgesia and allodynia;
 Explain sensory coding;
 Compare the pathway that mediates sensory input from touch,
proprioceptive, and vibratory senses to that mediating information
from pain and thermoreceptors; and
 Describe mechanisms to modulate transmission in pain
pathways.

114. Information about the internal and external environment
activates the central nervous system (CNS) via sensory
receptors.
These receptors are transducers that convert various forms
of energy into action potentials in neurons.
The somatic sensory system has two major components:
 a subsystem for the detection of mechanical stimuli (e.g.,
light touch, vibration, pressure and cutaneous tension); and
 a subsystem for the detection of painful stimuli and
temperature.
Together, these two subsystems give humans and other
animals the ability to:

115.  identify the shapes and textures of objects;
 monitor the internal and external forces acting on the body at
any moment; and
 Detect potentially harmful circumstances.
Types of Somatic Sensory Receptors
Cutaneous (superficial) receptors for touch and pressure are
mechanoreceptors.
Potentially harmful stimuli such as pain, extreme heat, and
extreme cold are mediated by nociceptors.
Chemoreceptors are stimulated by a change in the chemical
composition of the environment in which they are located.

116. These include receptors for taste and smell as well as
visceral receptors such as those sensitive to changes in the
plasma level of O2, pH, and osmolality.
Photoreceptors are those in the rods and cones in the retina
that respond to light.
Cutaneous Mechanoreceptors
Sensory receptors can be specialized dendritic endings of
afferent nerve fibers and are often associated with non-neural
cells that surround them, forming a sense organ.
Touch and pressure are sensed by four types of mechanoreceptors:

117. i. Meissner’s corpuscles respond to changes in texture and
slow vibrations.
ii. Merkel cells respond to sustained pressure and touch.
iii. Ruffini corpuscles respond to sustained pressure.
iv. Pacinian corpuscles respond to deep pressure and fast
vibration.
Nociceptors and Thermoreceptors
Pain and temperature sensations arise from unmyelinated
dendrites of sensory neurons located around hair follicles
throughout the smooth and hairy skin, as well as in deep tissue.

118. Impulses from nociceptors (pain) are transmitted via two fiber
types:
i. One system comprises thinly myelinated Aδ fibers that
conduct at rates of 12–30 m/s.
ii. The other is unmyelinated C fibers that conduct at low rates of
0.5–2 m/s.
Thermoreceptors also span the following two fiber types:
i. cold receptors are on dendritic endings of Aδ fibers and C
fibers; and
ii. warm receptors are on C fibers.

119. On the other hand, the nociceptors could be categorized
based on stimuli they respond to into:
Mechanical nociceptors respond to strong pressure.
Thermal nociceptors are activated by skin temperatures
above 45°C or by severe cold.
Chemically sensitive nociceptors respond to various agents
such as bradykinin, histamine, high acidity, and
environmental irritants.
Polymodal nociceptors respond to combinations of these
stimuli.

120. The Major Classes of Somatic Sensory Receptors

121. The Major Afferent Pathway for Mechanosensory
Information: The Dorsal Column–Medial Lemniscus System
The action potentials generated by tactile and other
mechanosensory stimuli are transmitted to the spinal cord by
afferent sensory axons traveling in the peripheral nerves.
The neuronal cell bodies that give rise to these first-order
axons are located in the dorsal root (or sensory) ganglia
associated with each segmental spinal nerve.
The dorsal horn in the spinal cord is divided on the basis of
histologic characteristics into laminae I–VII, with lamina I being
the most superficial and lamina VII the deepest.
Lamina II and part of lamina III make up the substantia
gelatinosa, the area near the top of each dorsal horn.

122. Schematic representation of the terminations of the three types of primary afferent neurons in the
various layers of the dorsal horn of the spinal cord

123. Dorsal root ganglion cells are also known as first-order
neurons because they initiate the sensory process.
Depending on whether they belong to the mechanosensory
system or to the pain and temperature system, the first-order
axons carrying information from somatic receptors have:
 different patterns of termination in the spinal cord; and
 define distinct somatic sensory pathways within the central
nervous.
These differences provide for different pathways as follows:

124.  the dorsal column–medial lemniscus pathway that carries
the majority of information from the mechanoreceptors that
mediate tactile discrimination and proprioception; and
 the spinothalamic (anterolateral) pathway mediates pain
and temperature sensation.
The difference(s) in the afferent pathways of these modalities
is one of the reasons of treating the sensations separately.

125. DORSAL COLUMN (MEDIAL LEMNISCAL) PATHWAY
This is the principal direct
pathway to the cerebral
cortex for touch, vibratory
sense, and proprioception
(position sense).
Upon entering the spinal
cord, the major branch of the
incoming axons called the
first-order axons carrying
information from peripheral
mechanoreceptors ascends
ipsilaterally through the
dorsal columns (posterior
funiculi) of the cord.

126. In this column, it goes all
the way to the lower medulla,
where it terminates by
synapsing with the second-
order neurons in the gracile
and cuneate nuclei (together
referred to as the dorsal
column nuclei).
Axons in the dorsal columns
are topographically organized
such that:

127.  the fibers that convey
information from lower limbs
that are in the medial
subdivision of the dorsal
columns, called the gracile
tract; and
 The lateral subdivision,
called the cuneate tract,
which contains axons
conveying information from
the upper limbs, trunk, and
neck.

128. In a cross-section through the
medulla, the medial lemniscal
axons carrying information from
the lower limbs are located
ventrally, whereas the axons
related to the upper limbs are
located dorsally (again, a fact of
some clinical importance).
The second-order neurons
from these nuclei ascend
contralaterally ascend in the
medial lemniscus to end in the
contralateral ventral posterior
lateral (VPL) nucleus and
related specific sensory relay
nuclei of the thalamus.

129. These axons of the medial lemniscus that reach the ventral
posterior lateral (VPL) nucleus of the thalamus are the third-
order neurons of the dorsal column–medial lemniscus system.
The Trigeminal Portion of the Mechanosensory System
As noted, the dorsal column–medial lemniscus pathway
described in the preceding section carries somatic information
from only the upper and lower body and from the posterior third
of the head.
Tactile and proprioceptive information from the face is
conveyed from the periphery to the thalamus by a different route
called trigeminal somatic sensory system.
Low-threshold mechanoreception in the face is mediated by
first order neurons in the trigeminal (cranial nerve V) ganglion.

130. The peripheral processes of
these neurons form the three
main subdivisions of the 10 Somatic
Sensory Cortex
trigeminal nerve:
 the ophthalmic;
 Maxillary; and
 mandibular branches,
• Each of these innervates a
well-defined territory on the
face and head, including the
teeth and the mucosa of the
oral and nasal cavities.

131. The central processes of
trigeminal ganglion cells form
the sensory roots of the 10 Somatic
Sensory Cortex
trigeminal nerve.
They enter the brainstem at
the level of the pons to
terminate on neurons in the
subdivisions of the trigeminal
brainstem complex.
The trigeminal complex has
two major components:
 the principal nucleus  the spinal nucleus
(responsible for processing (responsible for processing
mechanosensory stimuli); and painful and thermal stimuli).

132. Thus, most of the axons
carrying information from low-
0
1 Somatic
threshold cutaneous Sensory Cortex
mechanoreceptors in the face
terminate in the principal nucleus.
In effect, this nucleus
corresponds to the dorsal column
nuclei that relay mechanosensory
information from the rest of the
body.
The spinal nucleus corresponds The second order neurons of the
to a portion of the spinal cord that trigeminal brainstem nuclei give off
axons that cross the midline and
contains the second-order neurons
ascend to the ventral posterior medial
in the pain and temperature system (VPM) nucleus of the thalamus via the
for the rest of the body. trigeminothalamic tract (also called
the trigeminal lemniscus).

133. The Somatic Sensory Components of the Thalamus
Each of the several ascending
somatic sensory pathways
originating in the spinal cord and
brainstem converge on the thalamus.
The ventral posterior complex
(VPL and VPM) of the thalamus,
which comprises a lateral and a
medial nucleus, is the main target of
these ascending pathways.
The VPL nucleus receives
projections from the medial The VPM nucleus receives
lemniscuscarrying all somatosensory axons from the trigeminal
information from the body and lemniscus (that is,
mechanosensory and nociceptive
posterior head.
information from the face).

134. The Somatic Sensory Cortex
The axons arising from
neurons in the ventral posterior
complex of the thalamus project
to cortical neurons located
primarily in layer IV of the
somatic sensory cortex.
The primary somatic sensory
cortex in humans (also called SI),
which is located in the
postcentral gyrus of the Experiments carried out in
parietal lobe, comprises four non-human primates indicate
distinct regions, or fields, known that neurons in areas 3b and 1
as Brodmann’s areas 3a, 3b, 1, respond primarily to cutaneous
and 2. stimuli.

135. The axons arising from
neurons in the ventral posterior
complex of the thalamus project
to cortical neurons located
primarily in layer IV of the
somatic sensory cortex.
The primary somatic sensory
cortex in humans (also called SI),
which is located in the
postcentral gyrus of the
parietal lobe, comprises four Experiments carried out in
distinct regions, or fields, known non-human primates indicate
as Brodmann’s areas 3a, 3b, 1, that neurons in areas 3b and 1
and 2. respond primarily to cutaneous
stimuli.

136. Neurons in 3a respond mainly
to stimulation of proprioceptors;
area 2 neurons process both
tactile and proprioceptive stimuli.
Mapping studies in humans
and other primates show further
that each of these four cortical
areas contains a separate and
complete representation of the
body.
In these somatotopic maps,
the foot, leg, trunk, forelimbs, and
face are represented in a medial
to lateral arrangement.

137. Ventrolateralspinothalamic Tract
Fibers from nociceptors and
thermoreceptors synapse on
neurons in the dorsal horn.
The axons from these neurons
cross the midline and ascend in the
ventrolateral quadrant of the spinal
cord, where they form the lateral
spinothalamic tract.
Fibers within this tract synapse in
the VPL nuclei.
Other dorsal horn neurons that From this pathway,
receive nociceptive input synapse in fibers then project to the
the reticular formation of the brain centrolateral nucleus of
stem (spinoreticular pathway). the thalamus.

138. Positron emission tomographic (PET) and functional
magnetic resonance imaging (fMRI) studies in normal
humans indicate that pain activates cortical areas SI, SII, and
the cingulate gyrus on the side opposite the stimulus.
Also,the mediofrontal cortex and insular cortex are activated.
These technologies were important in distinguishing
two components of pain pathways.
From VPL nuclei in the thalamus, fibers project to SI and SII.
This is called the neospinothalamic tract, and it is
responsible for the immediate awareness of the painful
sensation and the awareness of the location of the noxious
stimulus.

139. The pathway that includes synapses in the brain stem reticular
formation and centrolateral thalamic nucleus projects to the
frontal lobe, limbic system, and insula.
This is called the paleospinothalamic tract, and it mediates
the emotional response to pain.
In the CNS, visceral sensation travels along the same
pathways as somatic sensation in the spinothalamic tracts and
thalamic radiations, and the cortical receiving areas for visceral
sensation are intermixed with the somatic receiving areas.
This likely contributes to the phenomenon called referred
pain.

140. Dorsal Column Medial Lemniscal Pathway Spinothalamic (anterolateral) Pathway

141. PHYSIOLOGY OF PAIN
Pain is defined by the International Association for the
Study of Pain (IASP) as “an unpleasant sensory and emotional
experience associated with actual or potential tissue damage….”
This is different from nociception, which the IASP defines as
the unconscious activity induced by a harmful stimulus applied to
sense receptors.
Pain can be classified mainly into two as:
A) Physiological (or acute) pain
Acute pain typically has a sudden onset and recedes during
the healing process.
It can be considered “good pain” because it serves an
important protective mechanism.

142. The withdrawal reflex is an example of this protective role
of pain.
B) Pathological (Chronic) Pain
Chronic pain can be considered “bad pain” because it
persists long after recovery from an injury and is often refractory
to common analgesic agents, including nonsteroidal anti-
inflammatory drugs (NSAIDs) and opiates.
It can result from nerve injury including diabetic
neuropathy, toxin-induced nerve damage, and ischemia.
Pathological pain can be subdivided into:
i) Inflammatory pain; and
ii) neuropathic pain

143. Hyperalgesia and Allodynia
Pain that is often accompanied by, an exaggerated response
to a noxious stimulus is called hyperalgesia.
Allodynia is a sensation of pain in response to an innocuous
stimulus.
An example of allodynia is the painful sensation from a warm
shower when the skin is damaged by sunburn.
Hyperalgesia and allodynia signify increased sensitivity of
nociceptive afferent fibers.

144. In response to tissue injury Injured cells release
chemical mediators can chemicals such as K+ that
sensitize and activate depolarize nerve terminals,
nociceptors thereby making nociceptors more
contributing to hyperalgesia responsive.
and allodynia.
Injured cells also release
bradykinin and substance P,
which can further sensitize
nociceptive terminals.
Other Chemicals include:
 histamine is released from
mast cells;
 serotonin (5-HT) from
platelets;
Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:
Principles of Neural Science. McGraw-Hill, 2000.

145. calcitonin gene-related peptide All these chemicals
(CGRP) from nerve terminals; and contribute to the
inflammatory process and
prostaglandins from cell activating or sensitizing the
membranes. nociceptors.
Substance P acts on mast
cells to cause degranulation
and release of histamine,
which activates nociceptors
and plasma extravasation
CGRP dilates blood
vessels that together with the
plasma extravasation result
in edema formation.
Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]:
Principles of Neural Science. McGraw-Hill, 2000.

146. The resulting edema causes Some released
additional release of bradykinin. substances act by releasing
another one (e.g., bradykinin
activates both Aδ and C
fibers and increases
synthesis and release of
prostaglandins).
Prostaglandin E2 (a
cyclooxygenase metabolite
of arachidonic acid) is
released from damaged cells
and produces hyperalgesia.
This is why aspirin and
other NSAIDs (inhibitors of
cyclooxygenase) alleviate
Adopted from Kandel ER, Schwartz JH, Jessell TM [editors]: Pain.
Principles of Neural Science. McGraw-Hill, 2000.

147. Sensory Coding
Converting a receptor stimulus to a recognizable sensation is
termed sensory coding.
All sensory systems code for four elementary attributes of a
stimulus: modality, location, intensity, and duration.
Modality is the type of energy transmitted by the stimulus.
The particular form of energy to which a receptor is most
sensitive is called its adequate stimulus.
Location is the site on the body or space where the stimulus
originated.
A sensory unit is a single sensory axon and all its peripheral
branches while the receptive field of a sensory unit is the spatial
distribution from which a stimulus produces a response in that
unit.

148. One of the most important mechanisms that enable
localization of a stimulus site is lateral inhibition.
Activity arising from sensory neurons whose receptors are at
the peripheral edge of the stimulus is inhibited compared to that
from the sensory neurons at the center of the stimulus.
Thus, lateral inhibition enhances the contrast between the
center and periphery of a stimulated area and increases the
ability of the brain to localize a sensory input.
Lateral inhibition underlies the neurological assessment
called the two-point discrimination test, which is used to test
the integrity of the dorsal column (medial lemniscus) system.

149. Intensity is signaled by the response amplitude or frequency
of action potential generation.
Duration refers to the time from start to end of a response in
the receptor.
If a stimulus of constant strength is applied to a receptor, the
frequency of the action potentials in its sensory nerve declines
over time.
This phenomenon is known as adaptation or desensitization;
the degree to which it occurs varies from one sense to another.
Based on this phenomenon, receptors can be classified into:
 rapidly adapting (phasic) receptors; and
 slowly adapting (tonic) receptors.

150. Central Pain Pathways
The pathways that carry information about noxious stimuli to
the brain, as might be expected for such an important and
multifaceted system, are also complex.
It helps in understanding this complexity to distinguish two
components of pain:
 the sensory discriminative component, which signals the
location, intensity, and quality of the noxious stimululation,
 the affective-motivational component of pain—which signals
the unpleasant quality of the experience, and enables the
autonomic activation that follows a noxious stimulus.
The discriminative component is thought to depend on
pathways that target the traditional somatosensory areas of
cortex, while the affective- motivational component is thought to
depend on additional cortical and brainstem pathways.

151. Pathways responsible for the discriminative component of pain
originate with other sensory neurons, in dorsal root ganglia and,
like other sensory nerve cells the central axons of nociceptive
nerve cells enter the spinal cord via the dorsal roots.
When these centrally projecting axons reach the dorsal horn of
the spinal cord, they branch into ascending and descending
collaterals, forming the dorsolateral tract of Lissauer.
Axons in Lissauer’s tract typically run up and down for one or
two spinal cord segments before they penetrate the gray matter
of the dorsal horn.
Once within the dorsal horn, the axons give off branches that
contact neurons located in several of Rexed’s laminae (these
laminae are the descriptive divisions of the spinal gray matter in
cross section).

152. The axons of these second-order neurons in the dorsal horn of
the spinal cord cross the midline and ascend all the way to the
brainstem and thalamus in the anterolateral (also called
ventrolateral) quadrant of the contralateral half of the spinal cord.
These fibers form the spinothalamic tract, the major
ascending pathway for information about pain and temperature.
This overall pathway is also referred to as the anterolateral
system, much as the mechanosensory pathway is referred to as
the dorsal column–medial lemniscus system.
The location of the spinothalamic tract is particularly important
clinically because of the characteristic sensory deficits that follow
certain spinal cord injuries.

153. Since the mechanosensory pathway ascends ipsilaterally in the
cord, a unilateral spinal lesion will produce sensory loss of touch,
pressure, vibration, and proprioception below the lesion on the
same side.
The pathways for pain and temperature, however, cross the
midline to ascend on the opposite side of the cord.
Therefore, diminished sensation of pain below the lesion will be
observed on the side opposite the mechanosensory loss (and the
lesion).
This pattern is referred to as a dissociated sensory loss and
(together with local dermatomal signs) helps define the level of the
lesion.

154. As is the case of the mechanosensory pathway, information
about noxious and thermal stimulation of the face follows a separate
route to the thalamus.
First-order axons originating from the trigeminal ganglion cells
and from ganglia associated with nerves VII, IX, and X carry
information from facial nociceptors and thermoreceptors into the
brainstem.
After entering the pons, these small myelinated and unmyelinated
trigeminal fibers descend to the medulla, forming the spinal
trigeminal tract (or spinal tract of cranial nerve V), and terminate in
two subdivisions of the spinal trigeminal complex:
 the pars interpolari; and
 pars caudalis.

155. Axons from the second-order neurons in these two trigeminal
nuclei, like their counterparts in the spinal cord, cross the midline
and ascend to the contralateral thalamus in the trigeminothalamic
tract.
The principal target of the spinothalamic and trigeminothalamic
pathway is the ventral posterior nucleus of the thalamus.
Similar to the organization of the mechanosensory pathways,
information from the body terminates in the VPL, while information
from the face terminate in the VPM.
These nuclei send their axons to primary and secondary
somatosensory cortex.
The nociceptive information transmitted to these cortical areas
is thought to be responsible for the discriminative component of pain:

156.  identifying the location;
 the intensity; and
 quality of the stimulation.
Consistent with this interpretation, electrophysiological
recordings from nociceptive neurons in S1, show that these
neurons have small localized receptive fields, properties
commensurate with behavioral measures of pain localization.
The affective–motivational aspect of pain is evidently mediated
by separate projections of the anterolateral system to the
reticular formation of the midbrain (in particular the parabrachial
nucleus), and to thalamic nuclei that lie medial to the ventral
posterior nucleus (including the so-called intralaminar nuclei).

157. Studies in rodents show that neurons in the parabrachial
nucleus respond to most types of noxious stimuli, and have large
receptive fields that can include the whole surface of the body.
Neurons in the parabrachial nucleus project in turn to the
hypothalamus and the amygdala, thus providing nociceptive
information to circuits known to be concerned with motivation and
affect.
These parabrachial targets are also the source of projections to
the periaqueductal grey of the midbrain, a structure that plays an
important role in the descending control of activity in the pain
pathway.

158. Nociceptive inputs to the parabrachial nucleus and to the
ventral posterior nucleus arise from separate populations of
neurons in the dorsal horn of the spinal cord.
Parabrachial inputs arise from neurons in the most superficial
part of the dorsal horn (lamina I), while ventral posterior inputs
arise from deeper parts of the dorsal horn (e.g., lamina V).
By taking advantage of the unique molecular signature of these
two sets of neurons, it has been possible to selectively eliminate
the nociceptive inputs to the parabrachial nucleus in rodents.
In these animals, the behavioral responses to the presentation
of noxious stimulation (capsaicin, for example) are substantially
attenuated.

159. Projections from the anterolateral system to the medial thalamic
nuclei provide nociceptive signals to areas in the frontal lobe, the
insula and the cingulate cortex.
In accord with this anatomy, functional imaging studies in
humans have shown a strong correlation between activity in the
anterior cingulate cortex and the experience of a painful stimulus.
Moreover, experiments using hypnosis have been able to tease
apart the neural response to changes in the intensity of a painful
stimulus from changes in its unpleasantness.
Changes in intensity are accompanied by changes in the
activity of neurons in somatosensory cortex, with little change in
the activity of cingulate cortex, whereas changes in
unpleasantness are correlated with changes in the activity of
neurons in cingulate cortex.

160. The cortical representation of pain is the least well documented
aspect of the central pathways for nociception, and further studies
will be needed to elucidate the contribution of regions outside the
somatosensory areas of the parietal lobe.
Nevertheless, a prominent role for these areas in the perception
of pain is suggested by the fact that ablations of the relevant
regions of the parietal cortex do not generally alleviate chronic
pain (although they impair contralateral mechanosensory
perception, as expected).

161. Some Disorders of Sensory System
1. Referred Pain
• There are few, if any, neurons in the dorsal horn of the spinal
cord that are specialized solely for the transmission of visceral
pain.
• The visceral pain is conveyed centrally via dorsal horn
neurons that are also concerned with cutaneous pain.
• As a result of this arrangement, disorder of an internal organ
is sometimes perceived as cutaneous pain.
• This phenomenon is called referred pain.
• The most common clinical example is anginal pain which is
referred to the upper chest wall, with radiation into the left arm
and hand.

162. Other important examples are:
 gallbladder pain referred to the scapular region;
 esophogeal pain referred to the chest wall;
 ureteral pain (e.g., from passing a kidney stone) referred to the
lower abdominal wall;
 bladder pain referred to the perineum; and
 the pain from an inflamed appendix referred to the anterior
abdominal wall around the umbilicus.
Understanding referred pain can lead to an astute diagnosis
that might otherwise be missed.

163. 2. Phantom Limbs and Phantom Pain
Following the amputation of an extremity, nearly all patients
have an illusion that the missing limb is still present.
Although this illusion usually diminishes over time, it persists in
some degree throughout the amputee’s life and can often be
reactivated by injury to the stump or other perturbations.
Such phantom sensations are not limited to amputated limbs
but there could also be:
 phantom breasts following mastectomy;
 phantom genitalia following castration; and
 phantoms of the entire lower body following spinal cord
transection.

164. Phantoms are also common after local nerve block for
surgery and sometimes during recovery from brachial plexus
anesthesia.
These sensory phantoms demonstrate that the central
machinery for processing somatic sensory information is not idle
in the absence of peripheral stimuli.
Apparently, the central sensory processing apparatus
continues to operate independently of the periphery, giving rise
to these bizarre sensations.
The resulting condition is refered to as, a chronic, intensely
painful experience that is difficult to treat with conventional
analgesic medications.

165. Neurogenic Quote
……..from this description, it should be evident that
the full experience of sensory sensations (including
mechanosensation, pain and temperature) involve the
cooperative action of an extensive network of brain
regions whose properties are only beginning to be
understood…….

166. MOVEMENT AND ITS CENTRAL CONTROL
Movements, whether voluntary or involuntary, are produced
by muscular contractions orchestrated by the brain and spinal
cord.
Analysis of these circuits is fundamental to an understanding
of both normal behavior and the etiology of a variety of
neurological disorders.
Ultimately, all movements produced by the skeletal
musculature are initiated by “lower” motor neurons in the spinal
cord and brainstem that directly innervate skeletal muscles.
The innervation of visceral smooth muscles is separately
organized by the autonomic divisions of the visceral motor
system.

167. The lower motor neurons are controlled:
 directly by local circuits within the spinal cord and brainstem
that coordinate individual muscle groups; and
 indirectly by “upper” motor neurons in higher centers that
regulate those local circuits, thus enabling and coordinating
complex sequences of movements.
Especially important of the circuits are in the basal ganglia
and cerebellum that regulate the upper motor neurons, ensuring
that movements are performed with spatial and temporal
precision.
Specific disorders of movement often signify damage to a
particular brain region.

168. Some clinically important and intensively studied
neurodegenerative disorders such as Parkinson’s disease,
Huntington’s disease, and amyotrophic lateral sclerosis
result from pathological changes in different parts of the motor
system.
Knowledge of the various levels of motor control is essential
for understanding, diagnosing, and treating these diseases.

169. Overall organization of neural structures involved in the control of movement

170. Lower and Upper Motor Neurons
• Skeletal (striated) muscle contraction is initiated by “lower”
motor neurons in the spinal cord and brainstem.
• The cell bodies of the lower neurons are located in the
ventral horn of the spinal cord gray matter and in the motor
nuclei of the cranial nerves in the brainstem.
• The cell bodies of upper motor neurons are located either in
the cortex or in brainstem centers, such as the vestibular
nucleus, the superior colliculus, and the reticular formation.
• The axons of the upper motor neurons typically contact the
local circuit neurons in the brainstem and spinal cord, which,
via relatively short axons, contact in turn the appropriate
combinations of lower motor neurons.

171. These neurons (also called α motor neurons) send axons
directly to skeletal muscles via the ventral roots and spinal
peripheral nerves, or via cranial nerves in the case of the
brainstem nuclei.
The spatial and temporal patterns of activation of lower motor
neurons are determined primarily by local circuits located
within the spinal cord and brainstem.
Descending pathways from higher centers comprise the
axons of “upper” motor neurons and modulate the activity of
lower motor neurons by influencing this local circuitry.

172. The local circuit neurons also receive direct input from
sensory neurons, thus mediating important sensory motor
reflexes that operate at the level of the brainstem and spinal
cord.
Lower motor neurons, therefore, are the final common
pathway for transmitting neural information from a variety of
sources to the skeletal muscles.
Neural Centers Responsible for Movement
The neural circuits responsible for the control of movement
can be divided into four distinct but highly interactive
subsystems, each of which makes a unique contribution to
motor control.

173. The first of these subsystems is the local circuitry within the
gray matter of the spinal cord and the analogous circuitry in the
brainstem.
The relevant cells of this subsystem include:
 the lower motor neurons (which send their axons out of the
brainstem and spinal cord to innervate the skeletal muscles of
the head and body, respectively); and
 the local circuit neurons (which are the major source of
synaptic input to the lower motor neurons).
All commands for movement, whether reflexive or voluntary,
are ultimately conveyed to the muscles by the activity of the lower
motor neurons.
Thus these neurons comprise, the “final common path” for
movement.

174. The second motor subsystem consists of the upper motor
neurons whose cell bodies lie in the brainstem or cerebral cortex
Axons of the upper motor neurons descend to synapse with the local
circuit neurons or, more rarely, with the lower motor neurons directly.
The upper motor neuron pathways that arise in the cortex are
essential for the initiation of voluntary movements and for complex
spatiotemporal sequences of skilled movements.
In particular, descending projections from cortical areas in the frontal
lobe, including:
 Brodmann’s area 4 (the primary motor cortex);
 the lateral part of area 6 (the lateral premotor cortex); and
 the medial part of area 6 (the medial premotor cortex)
• Are essential for planning, initiating, and directing sequences of
voluntary movements.

175. Upper motor neurons originating in the brainstem are
responsible for regulating muscle tone and for orienting the eyes,
head, and body with respect to vestibular, somatic, auditory, and
visual sensory information.
Their contributions are thus critical for basic navigational
movements, and for the control of posture.
The third and larger of these subsystems, the cerebellum, is
located on the dorsal surface of the pons.
The cerebellum acts via its efferent pathways to the upper
motor neurons as a servomechanism, detecting the difference,
or “motor error,” between an intended movement and the
movement actually performed.

176. The cerebellum uses this information about discrepancies to
mediate both real-time and long-term reductions in these motor
errors (the latter being a form of motor learning).
As might be expected from this account, patients with
cerebellar damage exhibit persistent errors in movement.
The fourth subsystem, embedded in the depths of the
forebrain, consists of a group of structures collectively referred to
as the basal ganglia.
The basal ganglia suppress unwanted movements and
prepare (or “prime”) upper motor neuron circuits for the initiation
of movements.

177. The problems associated with disorders of basal ganglia, such as
Parkinson’s disease and Huntington’s disease, attest to the
importance of this complex in the initiation of voluntary movements.
Despite much effort, the sequence of events that leads from
volitional thought to movement is still poorly understood.
The picture is clearest, however, at the level of control of the
muscles themselves.
It therefore makes sense to begin an account of motor behavior
by considering the anatomical and physiological relationships
between lower motor neurons and the muscle fibers they innervate.
The third and fourth subsystems are complex circuits with output
pathways that have no direct access to either the local circuit
neurons or the lower motor neurons; instead, they control
movement by regulating the activity of the upper motor neurons.

178. Upper motor neuron and their control of the
Brainstem and the spinal cord
The axons of upper motor neurons descend from higher
centers to influence the local circuits in the brainstem and
spinal cord
This is done by coordinating the activity of lower motor
neurons.
The sources of these upper motor neuron pathways include:
several brainstem centers; and
a number of cortical areas in the frontal lobe.
Upper motor neurons in the Brain Stem
The motor control centers in the brainstem are especially
important in postural control each having a distinct influence:

179. i) the vestibular nuclear complex; and
ii) the reticular formation
The above two have widespread effects on body position.
iii) the red nucleus controls movements of the arms;
iv) the superior colliculus contains upper motor neurons that
initiate orienting movements of the head and eyes.
Upper motor neurons in the Frontal Lobe
Upper motor neurons in the frontal cortex are located in:
i) the motor; and
ii) premotor areas

180. The motor and premotor areas of the frontal lobe are
responsible for the planning and precise control of complex
sequences of voluntary movements.
Most upper motor neurons, regardless of their source,
influence the generation of movements by directly affecting the
activity of the local circuits in the brainstem and spinal cord.
Upper motor neurons in the cortex also control movement
indirectly, via pathways that project to the brainstem motor
control centers, which, in turn, project to the local organizing
circuits in the brainstem and cord.
A major function of these indirect pathways is to maintain the
body’s posture during cortically initiated voluntary movements.

181. Modulation of Movement by the Cerebellum
The efferent cells of the
cerebellum do not project
directly either to the local
circuits of the brainstem and
spinal cord that organize
movement, or to the lower motor
neurons that innervate muscles.
The cerebellum (like the basal
ganglia) influences movements
by modifying the activity
patterns of the upper motor
neurons.
In fact, the cerebellum sends
prominent projections to virtually
all upper motor neurons.

182. Structurally, the cerebellum
has two main components:
a laminated cerebellar cortex;
and
a subcortical cluster of cells
referred to collectively as the
deep cerebellar nuclei.
Pathways that reach the
cerebellum (afferent pathways)
from other brain regions (in
humans, predominantly the
cerebral cortex) project to both
components.

183. The output cells of the cerebellar cortex project to the deep
cerebellar nuclei, which give rise to the main efferent pathways that
leave the cerebellum to regulate upper motor neurons in the
cerebral cortex and brainstem.
Thus, much like the basal ganglia, the cerebellum is part of a vast
loop that receives projections from and sends projections back to
the cerebral cortex and brainstem.
The primary function of the cerebellum is evidently to detect the
difference, or “motor error,” between an intended movement and
the actual movement, and, through its projections to the upper
motor neurons, to reduce the error.
These corrections can be made both during the course of the
movement and as a form of motor learning when the correction is
stored.
When this feedback loop is damaged, as occurs in many
cerebellar diseases, the afflicted individuals make persistent
movement errors whose specific character depends on the location
of the damage.

184. Organization of the Cerebellum
The cerebellum can be
subdivided into three main
parts based on differences
in their sources of input:
1) Cerebrocerebellum, the
largest subdivision in humans.
 It occupies most of the
lateral cerebellar
hemisphere and receives
input from many areas of
the cerebral cortex.
 This region of the cerebellum
is especially well developed
in primates.

185.  The cerebrocerebellum is
concerned with the
regulation of highly skilled
movements, especially the
planning and execution of
complex spatial and temporal
sequences of movement
(including speech).
2) Vestibulocerebellum, the
phylogenetically oldest part of
the cerebellum.
 This portion comprises the
caudal lobes of the
cerebellum that includes:
 the flocculus; and
 the nodulus.

186.  As its name suggests, the
vestibulocerebellum receives
input from the vestibular nuclei
in the brainstem and is primarily
concerned with the regulation of
movements underlying posture
and equilibrium.
3) Spinocerebellum is the last of
the major subdivisions of the
cerebellum.
 The spinocerebellum occupies
the median and paramedian
zone of the cerebellar
hemispheres and is the only part
that receives input directly from
the spinal cord.

187.  The lateral part of the
spinocerebellum is primarily
concerned with movements of
distal muscles, such as the
relatively gross movements of
the limbs in walking.
 The central part, called the
vermis, is primarily concerned
with movements of proximal
muscles, and also regulates eye
movements in response to
vestibular inputs.

188. Connections between Cerebellum and other NS Regions
The connections between the cerebellum and other parts of the
nervous system occur via three large pathways called cerebellar
peduncles.
i) The superior cerebellar peduncle (or brachium conjunctivum)
is almost entirely an efferent pathway.

189. The neurons that give rise to this pathway are in the deep
cerebellar nuclei, and their axons project to upper motor
neurons in the red nucleus, the deep layers of the superior
colliculus, and, after a relay in the dorsal thalamus, the primary
motor and premotor areas of the cortex.

190. ii) The middle cerebellar
peduncle (or brachium pontis)
is an afferent pathway to the
cerebellum.
Most of the cell bodies that
give rise to this pathway are in
the base of the pons, where they
form the pontine nuclei.
The pontine nuclei receive
input from a wide variety of
sources, including almost all
areas of the cerebral cortex and
the superior colliculus.
The axons of the pontine
nuclei, called transverse
pontine fibers, cross the
midline and enter the cerebellum
via the middle cerebellar
peduncle.

191. The pontine nuclei receive
input from a wide variety of
sources, including almost all
areas of the cerebral cortex
and the superior colliculus.
The axons of the pontine
nuclei, called transverse
pontine fibers, cross the
midline and enter the
cerebellum via the middle
cerebellar peduncle.
Each of the two middle
cerebellar peduncles contain
over 20 million axons,
making this one of the largest
pathways in the brain.

192. Most of these pontine axons
relay information from the
cortex to the cerebellum.
iii) The inferior cerebellar
peduncle (or restiform body)
is the smallest but most
complex of the cerebellar
peduncles.
It contains multiple afferent
and efferent pathways:
 Efferent pathways in this
peduncle project to the
vestibular nuclei and the
reticular formation;

193.  the afferent pathways
include axons from the
vestibular nuclei, the spinal
cord, and several regions of
the brainstem tegmentum.

194. Summary diagram of motor modulation by the
cerebrocerebellum
1. The central processing
component, the
cerebrocerebellar cortex,
receives massive input from
the cerebral cortex.
2. It then generates signals that
adjust the responses of
upper motor neurons to
regulate the course of a
movement.
3. Note that modulatory inputs
also influence the processing
of information within the
cerebellar cortex.

195. 4. The output signals from the
cerebellar cortex are relayed
indirectly to the thalamus and
then back to the motor
cortex, where they modulate
the motor commands.

196. BASAL GANGLIA
The term “basal ganglia”
refers to the collection of grey
matter made of cell bodies lying
deep inside the white matter of
the cerebrum, and makes up part
of the midbrain.
It consists of a large and
Anatomy of the Basal Ganglia
functionally diverse set of nuclei
that lie deep within the cerebral
hemispheres.

197. The subset of these nuclei
relevant to motor function
includes:
the caudate;
putamen; and
the globus pallidus.
Two additional structures are:
the substantia nigra in the Components of the Basal Ganglia
base of the midbrain; and
the subthalamic nucleus in the
ventral thalamus.

198. These additional structures are closely associated with the
motor functions of these basal ganglia nuclei.
The components of the basal ganglia, effectively make a
subcortical loop that links most areas of the cortex with upper
motor neurons in the primary motor and premotor cortex and in
the brainstem.
The neurons in this loop respond in anticipation of and during
movements, and their effects on upper motor neurons are
required for the normal course of voluntary movements.

199. On the overall, the basal ganglia receive large amount of input
from the cerebral cortex and after processing send it back to the
cerebral cortex via the thalamus.
This major pathway led to the creation of the popular concept
of cortico-basal ganglia- cortical loops.
When one of these components of the basal ganglia or
associated structures is compromised, the patient cannot switch
smoothly between commands that initiate a movement and those
that terminate the movement.
The disordered movements that result can be understood as a
consequence of abnormal upper motor neuron activity in the
absence of the supervisory control normally provided by the
basal ganglia.

200. The globus pallidus is divided into external and internal
segments (GPe and GPi).
The substantia nigra is divided into pars compacta and pars
reticulata.
The caudate nucleus and putamen are collectively called the
(corpus) striatum.
The putamen and globus pallidus form the lenticular nucleus.
The main inputs (input zone) to the basal ganglia terminate in
the striatum with their neurons being the destinations of
most of the pathway that reach the basal ganglia from other
parts of the brain.

201. The inputs from the cerebral cortex that reach the basal
ganglia found their destinations on the dendrites of the medium
spiny neurons in the corpus striatum.

202. Projections (Input) to the Basal Ganglia
The connections between the
parts of the basal ganglia include:
The striatum projects to both GPe
and GPi.
 a dopaminergic nigrostriatal
projection from the substantia nigra
pars compacta to the striatum; and
 a corresponding GABAergic
projection from the striatum to
substantia nigra pars reticulata.
• GPe projects to the subthalamic
nucleus, which in turn projects to
both GPe and GPi.

203. Projections (output) from the Basal Ganglia
The principal output from the
basal ganglia is from GPi via
the thalamic fasciculus to the:
 ventral lateral;
 ventral anterior, and
 centromedian nuclei of the
thalamus.
From the thalamic nuclei, fibers
project to the prefrontal and
premotor cortex.
The substantia nigra also projects
to the thalamus.

204. The main feature of the
connections of the basal ganglia is
that:
1. the cerebral cortex projects to the
striatum,
2. the striatum to GPi,
3. GPi to the thalamus, and
4. the thalamus back to the cortex,
completing a loop.
The output from GPi to the
thalamus is inhibitory, whereas
the output from the thalamus to
the cerebral cortex is excitatory.

205. Functions of the Basal Ganglia
i. Act by modifying ongoing activity in motor pathways.
ii. Inhibit muscle tone (proper tone – balance the excitatory and
inhibitory inputs to motor neurons that innervate skeletal muscle).
iii. Select and maintain purposeful motor activity while
suppressing unwanted patterns of movement
iv. Monitor and coordinate slow and sustained contractions,
especially those related to posture and support.
v. Regulate attention and cognition
vi. Control timing and switching
vii. Motor planning and learning

206. Circuits within the Basal Ganglia System
A) Direct Pathway
The pathway to the cortex arises primarily in the internal
globus pallidus and reaches the motor cortex after a relay in the
ventral anterior (VA) and ventral lateral (VL) nuclei of the
dorsal thalamus.
These two nuclei directly project to motor areas of the cortex
thus completing a vast loop that originates in multiple cortical
areas and terminates back in the motor areas of the frontal lobe.
In humans for e.g. the corpus striatum contains about 100
million neurons, about 75% of which are medium spiny
neurons.

207. Organization of the Basal Ganglia
(direct pathway)
Substantia nigra
Pars reticulata

208. Chain of Nerve Cells Arranged in a
Disinhibitory Circuit

209. In contrast, the main destination of their axons, the globus
pallidus, comprises only about 700,000 cells.
Thus on the average about 140 medium spiny neurons
innervate each pallidal cell.
The efferent neurons of the internal globus pallidus and
subtantia nigra reticulata together give rise to major pathways
that link the basal ganglia with upper motor neurons in the cortex
and brain stem.
In contrast, the axons from the substantia nigra pars
reticulata synapse on upper motor neurons in the superior
colliculus that command eye movements without relay in the
dorsal thalamus.

210. This difference between in globus pallidus and substantia
nigra pars reticulata is not absolute.
This is because many reticulata axons also project to the
thalamus where they contact relay neurons that project to the
frontal eye fields of the premotor cortex.
Because the efferent cells of both the globus pallidus and the
sustantia nigra pars reticulata are both GABAergic, the main
output of the basal ganglia is inhibitory.
These output zones (in contrast to the inactive medium spiny
neurons) have high levels of spontaneous activity that tend to
prevent unwanted movements by tonically inhibiting cells in the
superior colliculus and thalamus.

211. The net effect of the excitatory inputs that reach the striatum
from the cortex is to inhibit the tonically active inhibitory cells
of the globus pallidus and substantia nigra pars reticulata.
When the pallidal cells are inhibited, the thalamic neurons are
then disinhibited and relay signals from other sources to the
upper motor neurons in the cortex.
This disinhibition is what normally allows the upper motor
neurons to send commands to local circuit and lower motor
neurons that initiate movements.
Conversely, an abnormal reduction in the tonic inhibition as a
result of basal ganglia dysfunction leads to excessive
excitability of the upper motor neurons, and thus to the
involuntary movement syndromes that are characteristic of
basal ganglia disorders such as Huntington’s disease.

212. Chain of Nerve Cells Arranged in a Disinhibitory Circuit

213. Disinhibition in the Direct Pathway

214. B) Indirect Pathway
 This pathway serves to increase the level of tonic inhibition
and provides a second route that links the corpus striatum to
the internal globus pallidus and the subtantia nigra pars
reticulata.
 In this pathway, a population of medium spiny neurons
projects to the external globus pallidus which in turn sends
projections to the internal globus pallidus and to the
subthalamic nucleus of the ventral thalamus.
 The subthalamic nucleus instead of projecting outside the
basal ganglia it projects excitatory neurons backwards into the
internal globus pallidus and the substantia nigra pars reticulata.

215. Organization of the Basal Ganglia (indirect pathway)

216.  The indirect pathway influences the activity of the upper
motor neurons and serves to modulate the disinhibitory actions
of the direct pathway.
 Normally, when the indirect pathway is activated by the
signals from the cerebral cortex the medium spiny neurons
discharge and inhibit the tonically active GABAergic neurons
of the external globus pallidus.
 As, a result, the subthalamic cells become more active and by
virtue of their excitatory synapses with cells of the internal
globus pallidus and sustantia nigra reticulata, they increase the
inhibitory outflow of the basal ganglia.

217.  Thus in contrast to the direct pathway, which when
activated reduces tonic inhibition, the net effect of the
indirect pathway is to increase inhibitory influences on the
upper motor neurons.
 Therefore, the indirect pathway can be regarded as a
“brake” on the normal function of the direct pathway.
 The consequences of imbalances in this fine control
mechanism are apparent in diseases that affect the
subthalamic nucleus.

218.  These disorders remove a source of excitatory input to
the internal globus pallidus and substantia nigra pars
reticulata, and thus abnormally reduce the inhibitory
outflow of the basal ganglia.
 A basal ganglia syndrome called the hemiballismus,
which is characterized by violent, involuntary movements
of the limbs is the result of damage to subthalamic
nucleus.
 The involuntary movements are initiated by abnormal
discharges of the upper motor neurons that are receiving
less tonic inhibition from basal ganglia.

219. Neurotransmitters of the Basal Ganglia
 Corticostriatal projections are glutamatergic (excitatory)
 Projections from caudate, putamen, GPi, Gpe, and SNpr
are all GABAergic (inhibitory)
 Subthalamic nucleus projections to GPi are glutamatergic
(excitatory)
 Nigrostriatal projections are dopaminergic (either
excitatory or inhibitory, depending on striatal cell type)

221. Basal Ganglia Associated Neurodegenerative Disorders
Parkinson’s Disease
 Age of onset >65 years old
 Uncommon before 40 years old
 Estimated 1.5% of population affected over 65 years old,
2.5% over 85 years old.
 Loss of dopamine producing neurons in the substantia
nigra (50-60%)
 80% loss of striatal DA
 Etiology unknown
 Very recent discovery of several familial forms

222.  On striatal MSNs of the direct pathway, dopamine
exerts an excitatory influence because these cells
express D1 receptors, which are positively linked to cAMP
formation and cell excitability.
 On striatal MSNs of the indirect pathway, dopamine
exerts an inhibitory influence because these cells express
D2 receptors, which are negatively coupled to cAMP
formation and cell excitability.

225. Parkinson’s Disease Symptoms
 Resting tremor
 Impairment of balance and coordination
 Muscle rigidity (cogwheel)
 Difficulty initiating movement
 Micrographia (shrinking handwriting)
 Decreased facial expression
 Late stages include depression, fatigue, sleep
disorders, hallucinations, psychosis and dementia
 Loss of DA to the striatum causes increased activity of
the indirect pathway and decreased activity in direct
pathway (D1, D2 receptors)

226. Cognitive Impairments in Parkinson’s Disease
 Bradyphrenia: slowing of thought processes
 Memory, specifically retrieving information in
nonstructured situations/spatial working memory
 Emotional functioning: depression is common
 Decrease in executive functioning

227. Some Parkinson’s Treatments
• L-DOPA: Dopamine
precursor allows more
dopamine to be made by
remaining cells.
• Subthalamic nucleus
stimulation.
• Dopamine transplants-
Stem cells.

228. Huntington disease (HD)
 It is heritable
 Progressive, untreatable, decreased function and
dementia
 Genetic defect in gene called huntington
 Autosomal dominant
– gene defect on chromosome 4
– CAG repeats
• 70-100 - HD as juveniles
• >40 – anticipation

229.  Choreiform movements leading to severe impairment;
death within 15 years
 Loss of about 90% of striatal neurons, especially of
indirect pathway: overactivity of direct pathway:
uncontrolled movements.
Five characteristic features of HD
 Heritability
 Chorea
 Behavioral/psychiatric disturbances
 Dementia
 Death within 15-20 years of onset

231. Mechanism of Huntington Disease
 Striatal neurons giving
rise to indirect pathway
are selectively lost
 In advanced HD, loss
of striatal neurons
projecting to internal
pallidum

232. Hemiballismus
 It is usually characterized by involuntary flinging
motions of the extremities.
 The movements are often violent and have wide
amplitudes of motion.
 Some of the symptoms include:
• Involuntary movements on one side of the body
• Involuntary muscle spasms on one side of the body
• Violent movements involving one side of the body
• Usually arms are more affected than the legs

233. PHYSIOLOGY OF LEARNING AND MEMORY
Learning Objectives
 Describe the various types of long-term memory.
 Define synaptic plasticity, long-term potentiation, long-term
depression, habituation, and sensitization, and their roles in
learning and memory.
 List the parts of the brain that are involved in memory and
their role in memory processing and storage.
 Describe the abnormalities of brain structure and function
found in Alzheimer disease.

234. Introduction
A revolution in our understanding of brain function has been
brought about by the development and widespread availability
of techniques of assessing the brain function.
Today, we have more than a dozen techniques that are
rapidly evolving toward greater precision and a broader range of
application.
The most widely used methods are EEG, positron emission
tomography (PET), magnetic resonance imaging (MRI),
functional MRI (fMRI), and magnetoencephalography (MEG).
Positron emission tomography is often used to measure local
glucose metabolism, which is proportionate to neural activity,
and fMRI is used to measure local amounts of oxygenated
blood.

235. These techniques make it possible to determine the activity in
various parts of the brain in healthy subjects and in those with
various diseases.
They have been used to study not only simple responses, but
also complex aspects of learning, memory, and perception.
An example of the use of PET scans to study the functions of
the cerebral cortex in processing words is shown in figure (next
slide).
Different portions of the cortex are activated when a person is
hearing, seeing, speaking, or generating words.

236. Images of active areas of the brain in a male (left) and female (right) during a language task. Note that
males use only one side of the brain whereas females use both sides of the
brain when language is being processed (Adapted from Medical Physiology: a Systems Approach by
Hershel and Michael. McGraw-Hill Company, 2011).

237. Definitions
Learning is acquisition of
information that makes it
possible to alter behavior on
the basis of experience, and
memory is the retention and
storage of that information.
The two are obviously
closely related and should be
considered together.
From a physiologic point of Areas concerned with encoding explicit memories. The
prefrontal cortex and the parahippocampal cortex of the
view, memory is divided into brain are active during the encoding of memories (Adapted
from Rugg (1998);. Memories are made of this. Science.
explicit and implicit forms. 281(5380):1151–1152.)

239. A) Explicit or Declarative
Memory
It is associated with
consciousness (or at least
awareness).
It is dependent on the
hippocampus and other parts
of the medial temporal lobes
of the brain for its retention.
Areas concerned with encoding explicit memories. The
Explicit memory is prefrontal cortex and the parahippocampal cortex of the
brain are active during the encoding of memories (Adapted
subdivided into: from Rugg (1998);. Memories are made of this. Science.
281(5380):1151–1152.)

240.  episodic memory for events; and
 semantic memory for facts (e.g., words, rules, and
language).
Explicit memories initially required for activities such as riding
a car can become implicit once the task is thoroughly learned.
B) Implicit or Non-declarative Memory
It does not involve awareness, and its retention does not
usually involve processing in the hippocampus.

241. Implicit memory is subdivided into four types : (P2AN)
 Procedural memory that includes skills and habits, which,
once acquired, become unconscious and automatic.
 Priming which means facilitation of recognition of words or
objects by prior exposure to them. An example is improved
recall of a word when presented with the first few letters of it.
 Non associative learning in which a person (one) learns
about a single stimulus.
 Associative learning, one learns about the relation of one
stimulus to another.
Explicit memory and many forms of implicit memory are
subdivided into short term and long term memories

242. Types of Memory
1. Short term memory which lasts seconds to hours, during
which processing in the hippocampus and elsewhere leads to
long-term changes in synaptic strength.
During short term memory, the memory traces are subject to
disruption by trauma and various drugs.
 Working memory is a form of short-term memory that
keeps information available, usually for very short periods, while
the individual plans action based on it.
2. Long term memory, which stores memories for years and
remarkably resistant to disruption.

243. Physiologic Mechanism of Learning and Memory
(Synaptic Plasticity)
The key to memory is alteration in the strength of selected
synaptic connections referred to as Synaptic Plasticity.
In all but the simplest of cases, the alteration involves
activation of genes and protein synthesis.
This occurs during the change from short term working
memory to long term memory.
If an intervention occurs too soon after a training session,
acquisition of long term memory is impaired.
This is exemplified by the loss of memory for the events
immediately preceding brain concussion or electroshock
therapy (retrograde amnesia).

244. Short term and long term changes in synaptic function can
occur as a result of the history of discharge at a synapse.
This means that synaptic conduction can be strengthened or
weakened on the basis of past experience.
These changes, which can be presynaptic or postsynaptic, are
of great interest because they represent forms of learning and
memory.
One form of plastic change is post tetanic potentiation, the
production of enhanced postsynaptic potentials in response to
stimulation.
This enhancement lasts up to 60 seconds and occurs after a
brief (tetanizing) train of stimuli in a presynaptic neuron.

245. The stimulation causes Ca2+ to accumulate in the
presynaptic neuron to such a degree that the intracellular
binding sites that keep cytoplasmic Ca2+ low are overwhelmed.
Habituation is a simple form of learning in which a stimulus
is repeated many times.
The first time it is applied it is novel and evokes a reaction
(the “what is it?” response); however, it evokes less and less
electrical response as it is repeated.
Eventually, the subject becomes habituated to the stimulus
and ignores it.
This is associated with decreased release of neurotransmitter
from the presynaptic terminal because of decreased
intracellular Ca2+.

246. The decrease in intracellular Ca2+ is due to a gradual
inactivation of Ca2+ channels.
It can be short term, or it can be prolonged if exposure to the
benign stimulus is repeated many times.
Habituation is a classic example of non associative learning.
Sensitization is the prolonged occurrence of augmented
postsynaptic responses after a stimulus to which one has
become habituated is paired once or several times with a
another stimulus.
It is due to presynaptic facilitation and may occur as a
transient response.

247. Concept of Long Term Potentiation (LTP)
The LTP is a rapidly developing persistent enhancement of
the postsynaptic potential response to presynaptic stimulation
after a brief period of rapidly repeated stimulation of the
presynaptic neuron.
It resembles post tetanic potentiation but is much more
prolonged and can last for days.
Unlike post tetanic potentiation, LTP is initiated by an
increase in intracellular Ca2+ in the postsynaptic rather than
the presynaptic neuron.
It occurs in many parts of the CNS but has been studied in
greatest detail in the hippocampus.

248. If it is reinforced by additional pairings of the stimulus and
the initial stimulus, it can exhibit features of short term or long
term memory.
The short-term prolongation of sensitization is due to a Ca2+-
mediated change in adenylyl cyclase that increases production
of cAMP.
The LTP involves protein synthesis and growth of the
presynaptic and postsynaptic neurons and their connections.

249. There are two forms of LTP:
a) Mossy fiber LTP, which is presynaptic and independent of
N-methyl-d- aspartate (NMDA) receptors
b) Schaffer collateral LTP, which is postsynaptic and NMDA
receptor- dependent.
The hypothetical basis of the latter form is summarized in the
following figure (next slide).

250. Production of long-term potentiation (LTP) in Schaffer collaterals in the hippocampus (Courtesy of R.
Nicoll)

252. Production of Long Term Potentiation (LTP) in Schaffer
Collaterals in the Hippocampus
Glutamate (Glu) released from the presynaptic neuron binds
to α-amino-3-hydroxyl-5- methyl-4-isoxazole-propionate
(AMPA), N-methyl-d-aspartate (NMDA) and Kainate (recently
found) receptors in the membrane of the postsynaptic neuron.
The depolarization triggered by activation of the AMPA
receptors relieves the Mg2+ block in the NMDA receptor
channel, and Ca2+ enters the neuron with Na+.
The increase in cytoplasmic Ca2+ activates calmodulin
(CaM), which in turn activates Ca2+/calmodulin kinase II
(CaM kII).

253. The kinase phosphorylates the AMPA receptors (P),
increasing their conductance, and moves more AMPA receptors
into the synaptic cell membrane from cytoplasmic storage sites.
In addition, a chemical signal (PS) may pass to the
presynaptic neuron, producing a long-term increase in the
quantal release of glutamate.

254. Working Memory
Working memory areas are
connected to the hippocampus
and the adjacent parahippocampal
portions of the medial temporal
cortex.
Bilateral destruction of the
ventral hippocampus, or Alzheimer
disease (described below) and
similar disease processes that
destroy its CA1 neurons, causes
striking defects in short-term
memory.
Individuals with such destruction Their implicit memory
have intact working memory and processes are generally
remote memory. intact.

256. Working memory areas are
connected to the hippocampus
and the adjacent parahippocampal
portions of the medial temporal
cortex.
Bilateral destruction of the
ventral hippocampus, or Alzheimer
disease and similar disease
processes that destroy its CA1
neurons, causes striking defects in
short-term memory.
Individuals with such destruction
have intact working memory and
remote memory. Their implicit memory
processes are generally
intact.

257. The hippocampus is closely associated with the overlying
parahippocampal cortex in the medial frontal lobe.
When subjects recall words, activity in their left frontal lobe
and their left parahippocampal cortex increases, but when they
recall pictures or scenes, activity takes place in their right
frontal lobe and the parahippocampal cortex on both sides.
The connections of the hippocampus to the diencephalon
are also involved in memory.
Some people with alcoholism related brain damage develop
impairment of recent memory, and the memory loss correlates
well with the presence of pathologic changes in the mamillary
bodies, which have extensive efferent connections to the
hippocampus via the fornix.

258. The mamillary bodies project to the anterior thalamus via
the mamillothalamic tract.
From the thalamus, the fibers concerned with memory project
to the prefrontal cortex and from there to the basal forebrain.
From the basal forebrain, a diffuse cholinergic projection
goes to all of the neocortex, the amygdala, and the
hippocampus from the nucleus basalis of Meynert.
Severe loss of these fibers occurs in Alzheimer disease.
The amygdala is closely associated with the hippocampus
and is concerned with encoding and recalling emotionally
charged memories.

259. During retrieval of fearful memories, the theta rhythms of the
amygdala and the hippocampus become synchronized.
In healthy subjects, events associated with strong emotions
are remembered better than events without an emotional
charge, but in patients with bilateral lesions of the amygdala,
this difference is absent.

260. Long Term Memory
While the encoding process for short-term explicit memory
involves the hippocampus, long-term memories are stored in
various parts of the neocortex.
Various parts of the memories—visual, olfactory, auditory,
etc. are located in the cortical regions concerned with these
functions.
These parts are tied together by long term changes in the
strength of transmission at relevant synaptic junctions so that all
the components are brought to consciousness when the
memory is recalled.
Once long-term memories have been established, they can
be recalled or accessed by many different associations.

261. For example, the memory of a vivid scene can be evoked not
only by a similar scene, but also by a sound or smell associated
with the scene.
Thus, each stored memory must have multiple routes, and
many memories have an emotional component.

262. Some Learning/Memory (Neurodegenerative) Disorders
Alzheimer disease is the most common age-related
neurodegenerative disorder.
Memory decline initially manifests as a loss of episodic memory,
which impedes recollection of recent events.
Loss of short-term memory is followed by general loss of
cognitive and other brain functions, the need for constant care,
and, eventually, death.
The cytopathologic hallmarks of the disease are intracellular
neurofibrillary tangles, made up in part of hyperphosphorylated
forms of the tau protein that normally binds to microtubules.

263. Comparison of a normal neuron (A) and one with abnormalities associated with Alzheimer disease
(B) (Adapted from Kandel et al., (2000). Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

264. The Aβ peptides are products of a normal protein, amyloid
precursor protein (APP), a transmembrane protein that
projects into the extracellular fluid (ECF) from all nerve cells.
This protein is hydrolyzed at three different sites by α-, β-,
and γ-secretase, respectively. When APP is hydrolyzed by α-
secretase, nontoxic peptide products are produced.
However, when it is hydrolyzed by β- and γ-secretase,
polypeptides with 40–42 amino acids are produced; the actual
length varies because of variation in the site at which γ-
secretase cuts the protein chain.
These polypeptides are toxic, the most toxic being Aβσ1–42.
The polypeptides form extracellular aggregates, which can
stick to and Ca2+ ion channels, increasing Ca2+ influx.

265. Another pathology is the extracellular senile plaques, which
have a core of β-amyloid peptides (Aβ) surrounded by altered
nerve fibers and reactive glial cells.
They also initiate an inflammatory response, with production
of intracellular tangles and the damaged cells eventually die.
An interesting finding that may have broad physiologic
implications is that frequent effortful mental activities slow the
onset of cognitive dementia due to Alzheimer disease and
vascular disease.
The explanation for this “use it or lose it” phenomenon is as
yet unknown, but it certainly suggests that the hippocampus
and its connections have plasticity like other parts of the brain.

266. PHYSIOLOGY OF LANGUAGE AND SPEECH
Memory and learning are functions of large parts of the brain.
On the other hand, centers controlling some of the other
“higher functions of the nervous system,” particularly the
mechanisms related to language, are more or less localized to
the neocortex.
Human language functions depend more on one cerebral
hemisphere than on the other. This is called the dominant
hemisphere and is concerned with categorization and
symbolization.
The other hemisphere is not less developed “non-dominant”;
instead, it is specialized in the area of spatiotemporal relations.

267. It is this hemisphere that is concerned, for example, with the
identification of objects by their form and plays a primary role in
the recognition of faces.
This contributes to the concept of complementary
specialization of the hemispheres, one for sequential-analytic
processes (the categorical hemisphere) and one for
visuospatial relations (the representational hemisphere).
The categorical hemisphere is concerned with language
functions. Lesions in the categorical hemisphere produce
language disorders.
In contrast, lesions in the representational hemisphere lead
to astereognosis, the inability to identify objects by feeling
them.
Hemispheric specialization is related to handedness.

268. In 96% of right-handed individuals, who constitute 91% of
the human population, the left hemisphere is the dominant or
categorical hemisphere, and in the other 4%, the right
hemisphere is dominant.
In 70% of left-handers, the left hemisphere is also the
categorical hemisphere; in 15%, the right hemisphere is the
categorical hemisphere; and in 15%, there is no clear
lateralization.
Learning disabilities such as dyslexia (an impaired ability to
learn to read) are 12 times as common in left-handers as they
are in right-handers, possibly because some fundamental
abnormality in the left hemisphere led to a switch in
handedness early in development.

269. The spatial talents of lefthanders may be well above average
as a disproportionately large number of artists, musicians, and
mathematicians are left-handed.
Some anatomic differences between the two hemispheres
may correlate with the functional differences.
The planum temporale, an area of the superior temporal
gyrus that is involved in language-related auditory processing,
is regularly larger on the left side than the right.
Imaging studies show that other portions of the upper surface
of the left temporal lobe are larger in right-handed individuals,
the right frontal lobe is normally thicker than the left, and the left
occipital lobe is wider and protrudes across the midline.

270. In patients with schizophrenia, a disorder characterized by a
distorted sense of reality, MRI studies show reduced volumes of
gray matter on the left side in the anterior hippocampus,
amygdala, parahippocampal gyrus, and posterior superior
temporal gyrus.
The degree of reduction in the left superior temporal gyrus
correlates with the degree of disordered thinking in the disease.
There are also apparent abnormalities of dopaminergic
systems and cerebral blood flow in this disease.

271. SPINAL REFLEXES
Learning Objectives
At the end of the following lesson, it is expected that the student
can:
 Describe the components of a reflex arc.
 Describe the muscle spindles and their role in the stretch reflex.
 Describe the functions of the Golgi tendon organs as part of a
feedback system that maintains muscle force.
 Define reciprocal innervation, inverse stretch reflex, and clonus.
 Describe the short- and long-term effects of spinal cord injury
on spinal reflexes.

272. INTRODUCTION
The basic unit of integrated reflex activity is the reflex arc.
This arc consists of a sense organ, an afferent neuron,
synapses within a central integrating station, an efferent neuron,
and an effector organ.

273. The afferent neurons enter the central nervous system (CNS)
via the spinal dorsal roots or cranial nerves and have their cell
bodies in the dorsal root ganglia or in the homologous ganglia
for the cranial nerves.
The efferent fibers leave the CNS via the spinal ventral roots
or corresponding motor cranial nerves.

274. Activity in the reflex arc starts in a sensory receptor with a
generator potential whose magnitude is proportional to the
strength of the stimulus.
This generates all-or-none action potentials in the afferent
nerve, the number of action potentials being proportional to the
size of the generator potential.

275. In the CNS, the responses are again graded in terms of
excitatory postsynaptic potentials (EPSPs) and inhibitory
postsynaptic potentials (IPSPs) at the synaptic junctions.
The postsynaptic potentials (PSPs) are either:
 excitatory postsynaptic potentials (EPSPs), if their effect is
to make the postsynaptic cell more likely to respond with an
action potential; or
 inhibitory postsynaptic potentials (IPSPs), if they make the
postsynaptic cell less likely to fire an action potential.
All-or-none responses are generated in the efferent nerve.

276. Activity within the reflex arc is modified by the multiple inputs
converging on the efferent neurons or at any synaptic station
within the reflex loop.
The simplest reflex arc is one with a single synapse between
the afferent and efferent neurons.
Such arcs are monosynaptic, and reflexes occurring in them
are called monosynaptic reflexes.
Reflex arcs in which one or more interneuron is interposed
between the afferent and efferent neurons are called
polysynaptic reflexes.
There can be anywhere from two to hundreds of synapses in a
polysynaptic reflex arc.

277. It is evident that reflex activity is stereotyped and specific in
terms of both the stimulus and the response; a particular
stimulus elicits a particular response.
The Stretch Reflex
This reflex is an example of monosynaptic reflex.
When a skeletal muscle with an intact nerve supply is
stretched, it contracts.
The sense organ (receptor) is a small encapsulated
spindlelike or fusiform shaped structure called the muscle
spindle, located within the fleshy part of the muscle.
The impulses originating from the spindle are transmitted to
the CNS by fast sensory fibers (group Ia) that pass directly to the
motor neurons that supply the same muscle.

278. The stretch reflex is the best-known and studied monosynaptic
reflex and is typified by the knee-jerk reflex.
The stimulus that initiates the reflex is stretch of the muscle,
and the response is contraction of the same muscle.
The Withdrawal Reflex
The withdrawal reflex is a typical polysynaptic reflex that
occurs in response to a painful stimulation of the skin or
subcutaneous tissues and muscle.
The response is flexor muscle contraction and inhibition of
extensor muscles, so that the body part stimulated is flexed and
withdrawn from the stimulus.

279. When a strong stimulus is applied to a limb, the response
includes not only flexion and withdrawal of that limb, but also
extension of the opposite limb.
This crossed extensor response is part of the withdrawal
reflex.