2013

Veterinary

Neurobiology
(CVM 6120)

Class Notes

by

Alvin J. Beitz, PhD

Thomas F. Fletcher, DVM, PhD
Lucy Vulchanova, PhD
 CONTENTS
1: Introductory Lecture ..................................................... 3

2: Neurohistology ................................................................ 9

3: Cellular Neurobiology .................................................. 21

4: Neuroembryology ......................................................... 30

5: Spinal Cord Organization............................................ 43

6: Spinal Reflexes .............................................................. 49

7: Nociception I ................................................................. 58

8: Nociception II ................................................................ 67

9: Cranial Nerves .............................................................. 72

10: Vestibular System ......................................................... 79

11: Auditory System ........................................................... 84

12: Visual System ................................................................ 92

13: Posture and Movement .............................................. 102

14: Cerebral Hemisphere and Cortex ............................. 110

15: Cerebellum .................................................................. 116

16: Diencephalon and Hypothalamus .............................. 121

17: Olfaction and Limbic System ..................................... 127

APPENDIX
Initial Neuroanatomy Vocabulary
CVM 6120 Syllabus
CVM 6120 Schedule
Lecture 1

Veterinary Neurobiology - Introductory

Lecture
Objectives:
1. To go over the course syllabus and schedule
2. Given the information presented in lecture the student will be able to describe the
basic organizational plan of the nervous system and its functional relevance
3. Given the information presented in lecture the student will be able to describe the
major components of the central nervous system, relate these components to their
function and list some of the clinical signs observed following damage to each region.

I. Course Goals and Objectives -- Knowledge:

When the student successfully completes the course, she/he will have developed an
understanding of how the nervous system of domestic mammals is organized, in terms of
relationships among the major components comprising the nervous system and how these
components contribute to nervous system function. The student will also develop an appreciation
for the clinical signs and altered behavior that occurs following damage to or disorders of
nervous system components. This course provides a fundamental knowledge base for learning
more detailed information regarding the physiology, pharmacology and pathology of the nervous
system and for understanding clinical diagnosis and treatment, which will be taught in later
coursework in the curriculum.

II. Concept of the nervous system: why is it important?

The nervous system is the master controller of the body and regulates all body systems. In
addition to gathering critical information about the environment via the eyes, ears, nose and skin,
the central nervous system receives internal information from sensors that monitor heart rate,
blood pressure, levels of oxygen and the contents of the stomach and intestines. It processes this
information about the state of the organism and its environment and then responds via motor
systems to organize and generate appropriate actions (body movement, alterations in autonomic
function, etc.). It also participates in higher-level functions including reasoning, planning,
speech, and problem solving. Finally, it controls the organs of the immune system, and therefore
can regulate the immune responses that you will learn about in your Host Defense course.

Key Concept #1: The brain is the body’s most complex organ. There are billions of neurons
in the mammalian brain all of which are in use. This complex organ can malfunction in
many ways leading to disorders that manifest themselves through a variety of clinical signs
and symptoms.

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Key Concept #2: Sensory circuits (sight, touch, hearing, smell, taste) bring information to
the nervous system to make the animal aware of the environment, whereas motor circuits
send information from the brain and spinal cord to muscles and glands to produce a
response (e.g. movement or secretion).

III. Aims of a Neurological Exam:

Does the animal have a neurological problem?
Where is the disease process, what part(s) of the nervous system is affected?
What is the nature of the disease (is it infectious, it is caused by a tumor, is it autoimmune,
is it a metabolic disease)? What is the underlying cause of the animal symptoms?

Key Concept #3: The principles of the neurological examination are based on knowledge of
the anatomy and physiology of the central nervous system (CNS) and the peripheral nervous
system (PNS).

IV. Organization of the Nervous System:

A. Definition: The nervous system includes the brain, spinal cord and all the nerves that
communicate between tissues and the brain and spinal cord.

B. Cellular Components: The peripheral and central nervous systems are comprised of
two types of specialized cells:
1. Neurons: the specialized cells of nervous tissue that can conduct electrical signals
and transmit information from one part of the nervous system to another or to
peripheral targets such as muscle.
2. Glia: the supporting cells of the nervous system; they have a broad range of
function as you will learn later.

NN

Figure 1: A. Photomicrograph of a neuron from

the brain (red arrow); B. Image of a section from
the spinal cord showing a large neuron (N) and
A many small glial cells (arrows).

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Key Concept #4: Neurons communicate using both electrical and chemical signals. Action
potentials are electrical signals carried along the axons of neurons. Synapses are chemical
or electrical junctions that allow electrical signals to pass from one neuron to the next or
to a target cell like a muscle.

C. Anatomical Divisions:
1. The central nervous system, which is composed of the brain and the spinal cord
and is housed inside the cranial cavity and vertebral canal, respectively.
2. The peripheral nervous system, which is composed of ganglia and peripheral
nerves that lie outside the brain and spinal cord.

Figure 2: Schematic diagram of the canine nervous system illustrating the central and
peripheral components,

Key Concept #5: Understanding the differences in anatomy and function of the PNS
versus the CNS is helpful in clinical diagnosis of neurological disease or injury.

V. Central Nervous System Components:

A. CEREBRUM (telencephalon);, the largest part of the brain, it controls learning

and behavior, is involved with interpreting sensation, gives an animal its personality and
is associated with higher-level functions. Divided into frontal, parietal, temporal and
occipital lobes based on the bones of the calvaria under which these areas lie. (See Fig. 3)

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 B. BRAIN STEM- The brain stem connects the brain to the spinal cord and is
responsible for basic functions of life including heart rate, breathing and swallowing. An
exact line of demarcation between the brain stem and spinal cord is not evident, but
roughly occurs at the level of the foramen magnum. It is divided into 4 major parts:
1. Diencephalon (thalamus, hypothalamus, etc.): the most rostral portion of the brain
stem. Function: Coordinates and regulates all functional activity of the cerebral cortex;
integration center of the autonomic nervous system; vision, hearing.
Clinical Signs following damage: altered levels of consciousness; endocrinopathies,
behavioral abnormalities, disorders of thirst, appetite and temperature regulation.

Figure 3: Schematic Diagram of the canine central nervous system as seen from top (dorsal),
lateral and medial views. Note the 4 lobes of the brain and the 4 major components of the
brainstem (diencephalons, midbrain, pons and medulla). The spinal cord extends from the
medulla caudally within the vertebral canal.

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 2. Midbrain: located between the pons caudally and diencephalons rostrally, site of exit of
cranial nerves 3 and 4.
Function: Visual reflexes; Hearing reflexes; Eye Movement; Body Movement.
Clinical Signs following damage: decreased states of consiousness, loss of papillary light
reflex, pupils dilated, extensor rigidity in all 4 limbs; contralateral paralysis or weakness
with unilateral lesions

3. Pons: located between the medulla and midbrain, just underneath the cerebellum.
Function: It gives rise to the trigeminal nerve and thus controls jaw opening and receives
sensation from the head and face. It also has parts that are important for the level of
consciousness and for sleep.
Clinical Signs following damage: Hopping and placing deficits, muscle atrophy of the
head, loss of facial sensation, vital sign changes.

4. Medulla: this structure forms the caudal-most part of the brain stem and is located
between the spinal cord and the pons.
Function: It is responsible for maintaining vital body functions, such as breathing and heart
rate, it also plays a role in pain modulation. Several cranial nerves exit from the medulla.
Clinical Signs following damage: Head tilt, facial paralysis, difficulty swallowing,
atrophy of the tongue, regurgitation, vital sign changes, vestibular signs, nystagmus.

C. CEREBELLUM: a structure located dorsal to the pons and medulla and connected to
these structures by the cerebellar peduncles.
Function: The cerebellum processes input from other areas of the brain, spinal cord and
sensory receptors to provide precise timing for coordinated, smooth movements of the skeletal
muscular system.
Clinical Signs following damage: Ataxia of all four limbs and head, intention tremors,
vestibular signs

D. SPINAL CORD: forms the caudal part of the CNS, it is the most important part of the
CNS from a Veterinary clinical standpoint
Function: It connects much of the peripheral nervous system to the brain. Sensory
information (nerve impulses) reaching the spinal cord primary afferent neurons is transmitted to
higher brain regions. Signals arising in the motor areas of the brain travel back down to the cord
to affect motor neurons and influence muscle contraction.
Clinical Signs following damage: cervical/upper thoracic- Ataxia; tetraparesis;
ipsilateral hemiplegia; hopping, placing and proprioceptive deficits; hyperactive spinal reflexes;
neck pain. Lumbosacral- ataxia rear limbs; paraparesis; paraplegia; hopping, placing and
proprioceptive deficits; depressed or absent rear limb spinal reflexes; deep pain alterations.

Key Concept #6: Each part of the central nervous system (spinal cord, cerebellum, etc.) is
anatomically distinct and is associated with different functions. Thus damage to different
brain regions will result in different functional deficits and clinical signs.

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 5, White Matter versus Gray Matter:
Both the spinal cord and the brain consist of:
A. White matter = bundles of axons (many have a covering of myelin which gives
the white matter a “white” appearance in freshly dissected brain).
B. Gray matter = comprised of neuronal cell bodies, dendrites and glial cells
In the spinal cord, the white matter is at the surface, the gray matter inside. In the
brain of mammals, this pattern is reversed. However, the brains of "lower"
vertebrates like fishes and amphibians have their white matter on the outside of
their brain as well as their spinal cord.

Figure 4: Coronal section through the dog brain at the level of the diencephalon and
cerebrum showing gray matter (comprised of neuronal cell bodies) and white matter
(comprised primarily of axons)

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Lecture 2

Neurohistology:
Cells and General Features

Objectives, be able to:

• understand the histological components of nervous tissue
• recognize the morphological features of neurons
• differentiate myelinated from non-myelinated axons
• be able to diagram or describe the connective tissue sheaths of peripheral nerves
• be able to describe the three layers of the meninges and the concept of meningitis
• explain how receptors are classified.

I. Histological components

A. Neurons (nerve cells)— neurons are the structural and functional units of
the nervous system; they are specialized to conduct electrical signals.

Morphological features of neurons (see Figure 1 below)

1. Cell body — the expanded portion of the neuron that contains the nucleus.
Neuronal nuclei are very large and leptochromatic (stains lightly due to active
transcription of many genes). Cytoplasm stains basophilically due to the abundance of
RER and polyribosomes. These clumps of RER and polyribosomes detected in stained
tissue sections are referred to as Nissl Bodies.

2. Dendrites — one to many extensions of the cell body specialized to receive

input from other neurons. They contain Nissl bodies in their proximal parts and thus the
initial portions of dendrites stain basophilically. Dendrites often have small protrusions,
called dendritic spines that expand the dendritic surface area and serve as sites of synaptic
contact.

3. Axon — Axons are neuronal processes that project to and synapse with
dendrites or cell bodies of other neurons or with non-neuronal targets (e.g. muscle). An
axon is an extension of the cell body that is specialized for conducting regenerative, all or
none, electrical impulses called action potentials. There is typically one axon per neuron.
Swellings, termed axonal varicosities/boutons, are found along the axon or at its terminal
branches and are typically the sites where synapses occur. Axons are either myelinated or
non-myelinated. Axons lack Nissl bodies and do not stain and with routine histological
stains.

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Figure 1: Diagram of a neuron

4. Synapse - a specialized point of functional

contact between neurons or between a neuron and a
target organ (i.e., muscle) that allows neurons to
communicate with one another or with their target
cells.

Definitions
1. Ganglion — a collection of neuron cell bodies
situated in the PNS
2. Nucleus — this term is used in a special sense in
neurobiology to describe a collection of neuronal
cell bodies in the CNS (accumulation of gray matter)
3. Nerves — bundles of axons that extend out from
the brain as cranial nerves
and from the spinal cord as spinal nerves
(surrounded by connective tissue sheaths)
4. Tract — a bundle of axons (nerve fibers) within
the CNS. Connective tissue is absent around nerve
fibers in the CNS.

Figure 2: Types of neurons

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Neuronal Classification

Anatomically, by number of processes (see Figure2 on the right)

1. Unipolar (pseudounipolar) — Neuron has one process that bifurcates; the cell
body of this neuronal type is found in spinal and cranial ganglia.
2. Bipolar Neuron — Neuron has 2 processes (relatively rare; retina of eye and
certain cranial ganglia).
3. Multipolar Neuron — Neuron has many processes, typically 1 axon and 2 or
more dendrites. The most common type of neuron

By Function
1. Motor (Efferent) — related to innervation of muscle and glands; activation of
these neurons leads to some motor event (i.e., contraction of a muscle).
2. Sensory (Afferent) — related to the transfer of sensory information (i.e., pain,
touch, pressure, etc.); e.g., neurons of spinal (dorsal root) ganglia.
3. Interneurons — neither motor or sensory (e.g., neurons responsible for the
various spinal reflexes).

B. Glial cells.
These are non-neuronal cells that provide support and protection for neurons.
Glial cells outnumber neurons 10:1. The CNS has four types of glial cells and the PNS
has one type.
CNS Glial cells
1. Astrocytes — star-shaped cells with relatively large leptochromatic (lightly
stained) nuclei that play an active role in brain function :

a) influencing the activity of neurons;

b) contacting blood vessels and controlling local blood flow in the CNS, and thus
contributing to the integrity of the blood-brain barrier.

2. Oligodendrocytes — responsible for forming myelin sheaths around brain and

spinal cord axons. Myelin is composed primarily of lipids and serves as an electrical
insulator that allows for rapid transmission of action protentials. Oligodendrocytes have
relatively small round pachychromatic (darkly stained) nuclei.

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 3. Microglia-- the smallest of glial cells. They represent the intrinsic immune
effector cells of the CNS and underlie the inflammation response that occurs following
damage to the central nervous system and the invasion of microorganisms. Microglia are
sometimes referred to as brain macrophages. They represent only about 4% of the glial
cell population under normal circumstances.

4. Ependymal cells— are columnar epithelial cells that make up the ependyma
which lines the cerebrospinal fluid (CSF) filled ventricle system of the brain and the
central canal of the spinal cord. Their apical surfaces contain cilia that help to circulate
CSF throughout the central nervous system, and also contain microvilli which absorb
CSF. Modified ependymal cells associated with capillaries in the ventricles make up the
choroid plexus that produces CSF.

PNS Glial cells—Lemmocytes (Schwann cells)

1. Lemmocytes are the supporting cells of the PNS. They are associated with all
peripheral nerve fibers. In myelinated nerves, they are responsible for forming the myelin
sheath, analogous to olidendrocytes in the central nervous system.

Note: Glial cells are capable of reproduction, and when control over cell division is lost,
primary brain tumors result. Astrocytomas and glioblastomas are amongst the most
deadly or malignant forms of cancer

II. Myelinated and Non-myelinated Axons

A. MYELINATED AXONS (>1 µm; fast conducting)
1. Myelinated axons are invested with a membranous, lipid sheath (making them
the largest and fastest conducting nerve fibers).
2. Myelin is a highly organized multilamellar structure formed by the plasma
membrane of oligodendrocytes in the CNS and lemmocytes (Schwann cells) in the PNS.

PNS Myelin - Myelination occurs when an axon attains a diameter > 1 µm. A
chain of lemmocytes is required to provide myelin for one axon in the PNS. In the PNS, a
typical myelinated axon has the following structure: axon, surrounded by lemmocyte
myelin sheath, surrounded by lemmocyte cytoplasm, surrounded by basal lamina,
surrounded by endoneurium. The lemmocyte wraps around the nerve fiber (axon) several
times producing a membranous sheath that varies in thickness depending on the number
of times the lemmocyte wraps around the axon.

CNS Myelin - The myelin sheath is produced by oligodendrocytes. A single

oligodendrocyte will provide myelin for multiple axons, and each axon is myelinated by
multiple oligodendrocytes. In the CNS, myelinated axons lack a basal lamina and
endoneurium. Unlike in the PNS, axons in the CNS do not regenerate following injury. In

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part, this is due to the fact that CNS myelin contains several proteins that inhibit axonal
regeneration. (CNS myelin has more glycolipid and less phospholipid than PNS myelin.)
3. Myelin is an electrical insulator that allows increased speed of conduction along
an axon. Myelinated axons located in the PNS differ from those in the CNS both in
chemical composition and in the cell type that produces the myelin.
4. Under the light microscope, the myelin sheath appears as a tube surrounding the
axon. In H & E or Triple-stained sections, myelin appears like spokes of a wheel around
the axon; this appearance is actually artifactual in that tissue processing (dehydration in
alcohols and clearing in xylene) dissolves lipid components of the myelin leaving
non-lipid components.

Nodes of Ranvier --The nodes are breaks in the continuity of the myelin sheath that
occur regularly in both the peripheral and central nervous systems. They represent the
intervals between adjacent segments of myelin and occur at the junction of two
lemmocytes in the PNS or two oligodendrocytes in the CNS. The nodes appear as
constrictions along the nerve fiber. See illustration in Figure 3 and Figure 4 below.

Fig. 3. Peripheral nerve tissue (light

microscopy).

Top. Longitudinal illustration of a myelinated

axon (myelin is gray; cytoplasm is black).
Lemmocytes form myelin sheaths around one
axon. Adjacent lemmocytes (myelin sheaths)
are separated by nodes. Cytoplasm filled clefts
are sometimes evident in myelin sheaths.

Right. Myelin sheaths appear as individual

black rings in a transverse section through a
nerve fascicle.

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Figure 4. Myelin Node of Ranvier

Figure 5: Schematic
diagram illustrating the
different phases of myelin
formation in peripheral
nerves.

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 B. NON-MYELINATED AXONS (<1 µm; slow conducting)

1. PNS— Non-myelinated axons are embedded in infoldings of the plasma

membrane of a chain of lemmocytes. Each lemmocyte typically encloses 5-20
axons (see Fig. 6). Axoplasm clumps and stains poorly with routine histological
stains. A group of axons and associated lemmocytes are surrounded by basal
lamina and endoneurium.

2. CNS — Non-myelinated axons are not associated with

oligodendrocytes but run free without any type of ensheathment. They are
separated from one another by astrocytic processes.

Figure 6. Diagram showing features of myelinated and non-myelinated nerve fiber

development.

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 C. CLINICAL CORRELATION

Demyelination - Demyelination refers to the destructive removal of myelin.

When axons become demyelinated, they transmit the nerve impulses 10 times slower
than normal myelinated fibers and in some cases they stop transmitting action potentials
altogether. A number of clinical diseases are associated with the breakdown and
destruction of myelin sheaths surrounding axons in the brain, spinal cord or peripheral
nerves. Degenerative myelopathy, for instance, is a progressive disease of the spinal cord
in older dogs.

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III. Receptors

Receptor = a specialized region located on a peripheral terminal branch of an axon of a

primary afferent neuron, that can serve as a transducer—converting environmental
energy (sensory stimuli) into depolarizing ionic current (nerve signals). The number of
receptors per neuron ranges from several (small receptive field) to several dozen (large
receptive field).

vs.

Sense organ = an organized collection of receptor cells, with which the dendritic zones
of afferent neurons synapse. The excitability of receptor cells is modified by
environmental energy, i.e., the receptor cells act as transducers.

The sense organs are: retina, cochlea, vestibular apparatus, taste buds, and olfactory
epithelium. Neurons that synapse on receptor cells are SSA or SVA in type and
commonly bipolar rather than unipolar.

Classification of receptor populations

A. Receptor classification based on Morphology
1. Free nerve endings—terminal branches ramifying among epithelial cells, very
common especially in the skin (mediate pain sensation, itch thermal sensations).
2. Tactile discs—consists of a terminal expansions of an afferent axon which are joined
to modified epidermal cells (found in skin and mucous membranes).
3. Encapsulated—each receptor is encapsulated by lemmocytes and perineural
epithelium (examples: Pacinian corpuscles, tactile corpuscles, muscle spindles).

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 B. Receptor classification based on Location:
1. Exteroceptors—associated with skin and subcutaneous tissue (GSA)
2. Proprioceptors—associated with muscles, tendons and joints (GSA)
3. Interoceptors—located in viscera (GVA)

C. Receptor and sense organ classification based on modality (energy

sensitivity):
1. Mechanoreceptors—detect mechanical deformation (touch, pressure, vibration)
2. Thermoreceptors—detect changes in temperature (some detect warmth, some - cold)
3. Nociceptors—detect damage to tissue (pain receptors); also detect itch
4. Electromagnetic—detect light on the retina of the eye
5. Chemoreceptors—detect chemical molecules, including: taste receptors, olfactory
receptors, arterial oxygen receptors in the aortic arch and carotid bodies, blood osmolarity
in the hypothalamus and blood glucose and fatty acid receptors in the hypothalamus.

Schematic diagram illustrating various types of peripheral receptors:

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IV. Connective tissue coating axons in the PNS:

A. Endoneurium-- surrounds each myelinated axon, or a group of non-myelinated

axons.

B. Perineurium— surrounds each nerve fascicle (a bundle of axons); consists of a

perineural epithelium and associated collagenous connective tissue. The perineurium
participates in forming a blood-nerve barrier that limits the passage of water-soluble
substances and proteins from blood into the endoneurial compartment. (The integrity of
this barrier is altered in certain neuropathies and following nerve trauma.)

C. Epineurium— surrounds the entire nerve

V. Meninges: protective connective tissue sheaths

surrounding the brain and spinal cord.

A. There are three layers of meninges:

1. Dura Mater— the outermost layer consisting of coarse, irregular connective tissue;
composed of collagen and elastic fibers.

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2. Arachnoid— middle layer
of the meninges; it consists of a
distinct membrane and numerous
fibrous trabeculae on its inner
surface. This trabecular network
forms the structural framework
for the subarachnoid space,
which lies between the arachnoid
proper and the underlying pia
mater. The subarachnoid space
contains cerebrospinal fluid
(CSF). At certain points the
subarachnoid space is dilated
and forms “cisterns”. The
cisterna magna and lumbar
cisterns are important clinically
because that is where CSF taps
are performed. Note: CSF is a
clear colorless fluid that
surrounds and permeates the
entire central nervous system. It functions to protect, support and nourish the CNS.

3. Pia Mater—from the Latin term meaning “tender mother” is the innermost layer of
the meninges. It forms a thin protective membrane that adheres to the surface of the
brain and spinal cord. It consists of flattened fibrocytes superficial to elastic and collagen
fine fibers that extend into the numerous depressions and fissures on the surface of the
brain and cord. It is very vascular.

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Lecture 3

Cellular Neurobiology

Overall Objectives:
• understand the basic mechanisms of neuronal signaling (action potential
generation and propagation, synaptic transmission)
• To be able to describe the anatomical and functional organization of the synapse
• To be able to explain the concept of axonal transport

I. Overview
The mechanisms of neuronal signaling are based on excitability, functional
polarity, and specific connectivity. These properties are determined, in part, by ion
channels and receptors within the plasma membrane of neurons and by signaling
messengers (neurotransmitters) released from neurons.
Clinical relevance: The channels and receptors involved in neuronal signaling are
important drug targets. Understanding the basic mechanisms of neuronal signaling
enables understanding of the rationale and mechanisms of action of clinically used drugs.

II. Conduction of electrical signals

A. Resting membrane potential

• There is a separation of charge

across the membrane, which
creates an electrical potential.
At rest the membrane potential is ~ -60 to -70 mV.
• Ions (K+, Na+, Ca2+, Cl-) are unevenly distributed across the membrane.
• The membrane has channels that allow movement of ions across it, generating
current.

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• Channel: a transmembrane protein that
forms a pore in the membrane; can be
gated or non-gated.
• By convention, the direction of the
current is the same as the direction of
movement of positive ions:
+ ions out = outward current
+ ions in = inward current
• What determines if ions are flowing in or out of the cells?
Ionic movement across the membrane is determined by a chemical
driving force (concentration gradient) and an electrical driving force (potential
difference). For any ion, the potential at which the chemical driving force equals
the electrical driving force is defined as Equilibrium potential (calculated by
Nernst equation, see box below for details). Ions move in the direction, which
drives the membrane potential closer to their equilibrium potential. For example,
if the membrane potential is -60 mV and the equilibrium potential of K+ is -90
mV, K+ ions will be flowing out of the cell (outward current), making it
hyperpolarized; in contrast, Na+ ions will be flowing into the cells, making it
depolarized and driving the membrane potential towards the equilibrium potential
of Na+ (~ +60 mV).
• At rest the only channels, that are open are resting K+ channels (leak channels).

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The Nernst and Goldman Equations with the Squid Giant Axon

The Nernst equation is used to calculate the equilibrium potential (Ex) of an ion (X),
based on its intracellular and extracellular concentration.

RT [ X ]o 58 [ X ]o
EX = ln = log Nernst equation
zF [ X ]i z [ X ]i

Equilibrium potential for K+ in the squid giant axon:

58 [20]
EK+ = log = -75 mV
1 [400]

Equilibrium potential for Na+ in the squid giant axon:

58 [440]
ENa+ == log = +55 mV
1 [50]

But at rest permeability (P) for K+ >>>> permeability for Na+ (more K+ resting channels).
For squid giant axon at rest, PK:PNa:PCl = 1:0.04:0.45

The Goldman equation is used to calculate the membrane potential based on the
electrochemical driving force for all permeant ions as well as on the membrane
permeability for individual ions.

RT PK [ K + ]o + PNa [ Na + ]o + PCl [Cl − ]i

Vm = ln Goldman equation
F PK [ K + ]i + PNa [ Na + ]i + PCl [Cl − ]o
Resting membrane potential of the squid giant axon:
1x 20 + 0.04 x 440 + 0.45 x52
Vr = 58 log = -60 mV
1x 400 + 0.04 x50 + 0.45 x560

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 B. Action potential: a membrane depolarization that propagates along the axon
and conducts the electrical signal from the cell body to the axon terminals.
The “threshold” for action potential generation is the depolarization, at which
voltage-gated Na+ channels are activated.

• Suprathreshold depolarization of • Voltage-gated (VG) channels are

the membrane initiates an action at the basis of the action potential.
potential.

• Activation of VG • VG Na+ channels

• V m returns to Vr
Suprathreshold Na+ channels inactivate
• Influx of Na+ • VG K+ channels
• Na+K+ATPase
depolarization restores chemical
• V m approaches open
gradients
ENa+ • Influx of K+

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Clinical correlations:
• Use-dependent blockers of voltage-gated Na+ channels are used as anti-epileptic
drugs (phenytoin, carbamazepine, lamotrigine)
• In demyelinating disorders, voltage-gated K+ channels are redistributed along the
internodes of the axons, causing conduction abnormalities; channel blockers are
under development.

III. The Synapse

A. Definition

The synapse is a specialized point of

functional contact between neurons
or between a neuron and a target
organ (i.e., muscle) that allows
neurons to communicate with one
another or with their target cells.
The synapse is a site of apposition
between a presynaptic element of
one neuron and a postsynaptic
membrane of a target neuron (or an
effector organ); where, typically, a
presynaptic axon enlargement
releases transmitter molecules that
diffuse across a synaptic cleft and
bind to receptor channels in the
postsynaptic membrane. Figure from http://en.wikipedia.org/wiki/Synapse

B. Synaptic ultrastructure: synapses

are comprised of three elements:
1. Presynaptic nerve terminal: The
presynaptic enlargement (bouton,
varicosity, or end plate) contains
synaptic vesicles filled with
neurotransmitters (20 nm diameter),
clustered around an electron dense
active zone (protein-rich plasma
membrane). Vesicles are anchored in
place by actin microfilaments and fuse
with the plasma membrane upon
stimulation.

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 2. Synaptic Cleft: Pre- and
postsynaptic plasma membranes
are separated by a synaptic cleft
(20 nm wide) into which
neurotransmitter molecules are
released. The cleft contains
glycoprotein linking material and
is surrounded by glial cell
processes.
3. Postsynaptic element: a
dendrite, a cell body, or a target
cell receiving the synaptic input.
Receptor proteins (typically
ligand-gated channels) are
embedded in the postsynaptic
plasma membrane and bind to
neurotransmitter molecules bind.
The postsynaptic plasma
membrane may appear
unremarkable or thickened
(electron dense).

C. Common presynaptic arrangements:

1. Axon terminal branches have terminal enlargements (called boutons or bulbs)
2. Axon terminal branches feature varicosities (for synapses “in passing”)
3. Neuromuscular synapse: axon branches have terminal ramifications that form
motor end plates on skeletal muscle fibers.

D. Classification of synaptic types:

1. Axodendritic — axon terminal branch (presynaptic element) synapses on a dendrite
2. Axosomatic — axon terminal branch synapses on a soma (cell body)
3. Axoaxonic — axon terminal branch synapses on another axon terminal branch (for
presynaptic inhibition) or beside the initial segment of an axon
4. Dendrodendritic — dendrite synapsing on another dendrite (very localized effect).

26
IV. Synaptic Physiology
A. Presynaptic events:
1. In the resting state, the presynaptic membrane is polarized. When an action potential
arrives at the end of the axon, the presynaptic membrane is passively depolarized
(toward zero transmembrane potential). This triggers voltage-gated Ca++ channels to
open resulting in an influx of Ca++ (driven by [Ca++] gradient).
2. Elevated [Ca++] triggers vesicle mobilization and docking with the plasma
membrane where a number of vesicles fuse with presynaptic plasma membrane and
release neurotransmitter molecules (about 5,000 per vesicle) by exocytosis.
Neurotransmitter molecules are released in proportion to the amount of Ca++ influx,
in turn proportional to the amount of presynaptic membrane depolarization.
3. Transmitter molecules diffuse across the cleft & bind with postsynaptic receptor
proteins
4. Neurotransmitter molecules are eliminated from synaptic clefts via uptake by
presynaptic or glial processes and/or via enzymatic degradation at the postsynaptic
membrane. The molecules are recycled.
5. Subsequently, presynaptic plasma membrane repolarizes and synaptic vesicles are
recycled.

B. Postsynaptic events
1. Arriving neurotransmitter molecules bind briefly/repeatedly to ligand-gated receptors,
which opens ion channels directly or by means of second messengers.
Neurotransmitter binding results in a proportional ion flux across the postsynaptic
membrane. The particular excitability effect depends on the nature of the ion flux
which depends on the nature of the ion channels in the particular postsynaptic
membrane, i.e., in the resting state, postsynaptic plasma membrane is polarized
(resting K+ channels dominate conductance).
a. Activation of [Na+ & K+]
channels —> leads to
depolarization toward zero
potential
b. Activation of Cl-or K+ channels
—> hyperpolarization of
postsynaptic membrane.
2. A postsynaptic potential (PSP) results
from altered membrane conductance.
PSPs constitute electrotonic conduction,
a passive voltage spread (in contrast to
the regenerative conduction of which
axons are capable). PSPs decay
exponentially, over distance and with

27
 time. The magnitude of a PSP depends on the number of open ion channels which, in
turn, depends on the amount of neurotransmitter released.
a. EPSP = Excitatory PSP = depolarization toward zero potential, excites the
postsynaptic cell
b. IPSP = Inhibitory PSP = hyperpolarization (serves to cancel EPSPs), inhibits
the postsynaptic cell
3. Following the removal/degradation of neurotransmitter molecules, the postsynaptic
membrane is re-polarized (K+ channel conductance again dominates).
4. Integration of PSP: Neurons receive thousands of synapses. The changes in
membrane potential at active synapses sum together in space and time. An action
potential is generated if the summed change in membrane potential is suprathreshold.

C. Types of synaptic transmission.

Time
Effect on Membrane Potential
Course
Fast excitatory Depolarization ms
Fast inhibitory Hyperpolarization ms
Slow excitatory Depolarization / ↑ excitability s
Slow inhibitory Hyperpolarization / ↓ excitability s

1. Fast transmission is mediated by ligand-gated ion channels (ionotropic receptors).

2. Slow transmission is mediated by G-protein coupled receptors (GPCR, metabotropic
receptors).

Receptor: A protein that transmits a signal upon the binding of a ligand.

D. Additional Comments
1. Synaptic transmission is unidirectional (vesicles are located on only one side).
2. Glutamate is the major excitatory neurotransmitter in the nervous system; GABA
and glycine are the major inhibitory neurotransmitters.
3. Synaptic transmission is slower than axonal conduction; each synapse introduces
delay into a neural pathway (at least 0.5 msec/synapse).
4. Synapses are more susceptible to fatigue, hypoxia, and drug effects than are axons
(generally pathways fail first at synapses).
5. Different kinds of drugs (tranquilizers, anesthetics, narcotics, anticonvulsants,
muscle relaxants, etc.) work by modifying activity selectively among the different
kinds of chemical synapses.
6. Certain diseases are manifestations of selective synaptic dysfunction; e.g.,
Parkinson’s disease, tetanus, myasthenia gravis, various intoxications, etc.

28
7. Extrasynaptic transmission: neuropeptides (e.g. opiod peptides, the neurokinin
Substance P) are released from large-dense core vesicles (rather than small synaptic
vesicles) outside of the synaptic cleft. They modulate the excitability of the
postsynaptic cells through activation of extrasynaptic G-protein coupled receptors.
Release of neuropeptides requires stronger presynaptic depolarization than release
of small synaptic vesicles. Extrasynaptic transmission also occurs between neurons
and adjacent glial cells (astrocytes, microglia).

E. Astrocytes support synaptic transmission

1. Recycle neurotransmitters
2. Secrete neurotrophic factors (e.g., neural growth factor) that stimulate the growth
and maintenance of neurons
3. Dictate the number of synapses formed on neuronal surfaces and modulating
synapses in adult brain
4. Maintain the appropriate ionic composition of extracellular fluid surrounding
neurons, by absorbing excess potassium and other larger molecules

V. Axonal Transport – the net movement of substances along the axon

A. Two rates:
1. Fast Axonal Transport—100-500 mm/day
2. Slow Axonal Transport—1-10 mm/day

B. Two directions

1. Anterograde Transport—transport of materials down the axon away from the cell
body; important for renewing proteins along the axon and thus maintaining the axon.

2. Retrograde Transport—transport from the axon terminal toward the cell body.
Important mechanism by which some viruses (rabies) and neurotoxins (tetanus
toxin) gain access to the CNS. Note: Tetanus and Botulinum toxins are proteases
which cleave neuronal SNARE-proteins.

29
Lecture 4

Development of the Nervous System

Objectives:
• describe the embryonic origin of the nervous system
• explain how different regions of the CNS originate and differentiate
• account for the embryonic origins of the various cells that comprise the PNS
• describe how the three meningeal layers arise in the embryo

I. Neurulation:
The notochord induces overlaying ectoderm to become neuroectoderm and form a neural tube.
The following stages of neural tube formation are evident:
• neural plate—ectodermal cells overlaying the notochord become tall columnar,
producing a thickened neural plate (in contrast to surrounding ectoderm that produces epidermis of
skin).
• neural groove—the neural plate is transformed into a neural groove.
• neural tube—the dorsal margins of the neural groove merge medially, forming a neural
tube composed of columnar neuroepithelial cells surrounding a neural cavity.
In the process of separating from overlaying ectoderm, some neural plate cells become
detached from the tube and collect bilateral to it, forming neural crest.

Note: • Neural tube becomes central nervous system (CNS), which consists of
the brain and spinal cord. The cavity of the tube (neural cavity) becomes
the ventricles of the brain and central canal of the spinal cord.
• Neural crest cells become neurons of peripheral nervous system (PNS)
that have their cell bodies located in ganglia. They also become
neurolemmocytes (Schwann cells) of the PNS. Additionally, neural crest cells
become adrenal medulla cells, melanocytes of skin, and a variety of structures in the face.

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II. Sculpting Neuronal Circuits:
Sculpting – removing excess material to achieve a desired effect

To ensure that all targets get sufficient innervation, initial neural development produces an
excessive number of neurons along with a profuse, random growth of neuronal processes.

Neurons that fail to contact an appropriate target will degenerate and disappear (because they do
not receive sufficient neurotrophic molecules). For the same reason, processes of surviving
neurons will undergo degeneration if they fail to contact an appropriate target (selective
pruning). Neurotrophic molecules are released by target cells to nurture neurons (and are
released by neurons to modify target cells).

The selective degeneration of neurons and neuronal processes is a consequence of functional

competition for neural targets. Neural targets that lead to more excitation/conduction and more
neurotransmitter release are preferred by neurons. Thus developmental remodeling is driven by
neuronal activity, related to experiences/behavior. “Survival of the successful” is the neural
theme.

Experiences drive nervous system remodeling throughout life. Selective growth and
pruning of neuronal synapses is the most common remodeling event in the adult.

For example . . .
1) Embryonic Neuromuscular Innervation
Initially, individual neurons innervate an excessive number of muscle fibers and individual
muscle fibers are innervated by a number motor neurons. Ultimately, motor neurons will innervate
only about 10% of their initially innervated muscle fibers (90% of terminal branches will
degenerate). Individual muscle fibers will retain only a single neuromuscular synapse in the adult.
The surviving neuromuscular synapses (winners) released more neurotrophic molecules than
the degenerated synapses (losers). Neurons having fewer branches were able to release more
neurotrophic molecules per terminal branch, giving them a competitive advantage over neurons with
excessive processes. The neurotrophic consequences of synaptic excitation drives process pruning.

2) Neonatal Cortex
In human prefrontal cortex, synaptic density peaks during the first year of age
(80K/neuron). The adult has half that synaptic density (and synaptic spine density). Only innervation
successful neurons survive. (Note: different studies show different timelines for degeneration.)

Above. Drawings of a neuron developing over time. Initially three processes went in search of innervation targets.
After two days, only one process has flourished and the other two processes have degenerated.

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III. Central Nervous System:
Formation of neurons and glial cells from neuroepithelium:
Neuroepithelium represents stem cells that give rise to neurons,
glial cells, and ependymal cells. Additionally, the CNS contains
blood vessels and microglial cells derived from mesoderm.
Neuroepithelial cells have processes which contact the inner and outer
surfaces of the neural tube; they undergo mitotic division in the following
manner:
— the nucleus (and perikaryon) moves away from the neural cavity for
interphase (DNA synthesis);
— for mitosis, the nucleus moves toward the neural cavity, the cell
becomes spherical and looses its connection to the outer surface of the neural
tube. This inward-outward nuclear movement is repeated at each cell
division.

Some stem cell divisions are differential, producing neuroblasts

which give rise to neurons or glioblasts (spongioblasts) which
give rise to glial cells (oligodendrogliocytes and astrocytes).
Neuroblasts and most glioblasts lose contact with surfaces of the
neural tube and migrate toward the center of the neural tube wall
where they accumulate in a mantle layer. (Some glial cells retain
surface contacts to guide neuroblast migrations.)

Note: Microglial are derived from mesoderm associated with

invading blood vessels.

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Layers and plates of the neural tube:
Accumulated neuroblasts and glioblasts form the mantle layer, a zone of high cell density
within the wall of the nerual tube. Cells that remain lining the neural cavity are designated
ependymal cells; they form an ependymal layer. Surrounding the mantle layer, a cell-sparse zone
where only axons and some glial cells are present is designated the marginal layer. The mantle
layer becomes gray matter and the marginal layer becomes white matter of the CNS.
The wall of the neural tube is divided into regions (plates). A bilateral indentation evident in the
neural cavity (the sulcus limitans) serves as a landmark to divide each lateral wall into an alar
plate (dorsal) and a basal plate (ventral). Midline regions dorsal and ventral to the neural cavity
constitute, respectively, the roof plate and the floor plate.
The basal plate contains efferent neurons that send axons into the PNS.
The alar plate contains neurons that receive input from the PNS.
In general, neurons are incapable of cell division, so all neurons must be formed from stem cells
during nervous system development. However, in hippocampus and olfactory bulb, some stem
cells or neuroblasts persist and can give rise to a small number of new neurons postnatally.
Note: • A typical neuron has a cell body (perikaryon) and numerous processes emanating from the
cell body. One process, the axon, is generally long and often encased in a myelin sheath
formed by glial cells. Unstained myelin has a white “color”.
• White matter refers to CNS regions that have a high density of myelinated axons.
• Gray matter has sparse myelinated axons and generally a high density of neuron cell bodies.

Regions of the Central Nervous System:

The cranial end of the neural
tube forms three vesicles
(enlargements) that further
divide into the five primary
divisions of the brain. Caudal
to the brain the neural tube
develops into spinal cord.

Flexures: During development, the

brain undergoes three flexures which
generally disappear (straighten out)
in domestic animals.
The midbrain flexure occurs at
the level of the midbrain.
The cervical flexure appears at
the junction between the brain and
spinal cord (it persists slightly in
domestic animals).
The pontine flexure is concave
dorsally (the other flexures are
concave ventrally).

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 Adult CNS Structures Derived From Embryonic Brain Divisions

Note: The portion of brain remaining after the cerebrum and cerebellum are removed is referred to as the brain
stem.

Spinal cord development:

— the neural cavity becomes central canal, which

is lined by ependymal cells;
— growth of alar and basal plates, but not roof
and floor plates, results in symmetrical right and left
halves separated by a ventral median fissure and a
dorsal median fissure (or septum);
— the mantle layer develops into gray matter, i.e., dorsal and ventral gray columns separated by
intermediate gray matter (in profile, the columns are usually called horns); cell migration from the basal plate
produces a lateral gray column (horn) at thoracic and cranial lumbar levels of the spinal cord (sympathetic
preganglionic neurons);
— the marginal layer becomes white matter (which is subdivided bilaterally into a dorsal funiculus,
a lateral funiculus, and a ventral funiculus ). [Note: funiculus = L. slender rope]

Enlargements of spinal cord segments that innervate limbs (cervical and lumbosacral
enlargements) are the result of greater numbers of neurons in those segments. Neurons are
more numerous in enlargement segments because those segments underwent less
neuronal degeneration, compared to segments that did not innervate limbs and thus
offered fewer targets for developing neurons.

34
Hindbrain: Medulla Oblongata and Pons
— alar plates shift laterally and the cavity of the
neural tube expands dorsally forming a fourth ventricle;
the roof of the fourth ventricle (roof plate) is stretched and reduced
to a layer of ependymal cells covered by pia mater; a choroid
plexus develops bilaterally in the roof of the ventricle and secretes
cerebrospinal fluid;
— the basal plate (containing efferent neurons
of cranial nerves) is positioned medial to the alar plate
and ventral to the fourth ventricle;
— white and gray matter (marginal & mantle layers) become intermixed (unlike spinal
cord); cerebellar development adds extra structures.

Hindbrain: Cerebellum
NOTE: • Adult cerebellum features surface gray matter, called cerebellar cortex, and three pair of
cerebellar nuclei, located deep within the cerebellar white matter. The cerebellum connects to the
brain stem by means of three pair of cerebellar peduncles, each composed of white matter fibers.
• Cerebellar cortex is composed of three layers: a superficial molecular layer which is relatively
acellular; a middle piriform (Purkinje) cell layer consisting of a row of large cell bodies; and a deep
granular (granule cell) layer composed of numerous very small neurons.
• The cerebellum functions to adjust muscle tone and coordinate posture and movement so they are
smooth and fluid vs. jerky and disunited.

Bilateral rhombic lips are the first evidence of cerebellar development; the lips are expansions of
the alar plate into the roof plate; the rhombic lips merge medially, forming a midline isthmus (the lips form
the two cerebellar hemispheres and the isthmus forms the vermis of the cerebellum);
Cellular migrations:
• superficial and deep layers of neurons are
evident within the mantle layer of the future
cerebellum; the deep cells migrate (pass the more
superficial cells) toward the cerebellar surface and
become Purkinje cells of the cerebellar cortex;
meanwhile, neurons of the superficial layer migrate
deeply and become cerebellar nuclei;

• neuroblasts located laterally in the rhombic lip migrate along the outer surface of the
cerebellum, forming an external germinal layer (which continues to undergo mitosis);
subsequently, neurons migrate deep to the Purkinje cells and form the granule cell layer of the
cerebellar cortex;
• some alar plate neurons migrate to the ventral surface of the pons, forming pontine nuclei which send
axons to the cerebellum.

Migration of neuron populations past one another allows connections to be

established between neurons of the respective populations. Neurons that fail to
connect are destined to degenerate. Connections are made by axons that
subsequently elongate as neurons migrate during growth.

35
Midbrain
— the neural cavity of the midbrain becomes mesencephalic
aqueduct. The aqueduct is not a ventricle because it is completely
surrounded by brain tissue and thus it lacks a choroid plexus, formed by
ependyma and pia mater.
— alar plates form two pairs of dorsal bulges which become rostral
and caudal colliculi (associated with visual and auditory reflexes);
— the basal plate gives rise to oculomotor (III) and trochlear (IV)
nerves which innervate muscles that move the eyes.
Note: The midbrain is the rostral extent of the basal plate (efferent neurons).

Forebrain: Diencephalon and Telencephalon (derived entirely from alar plate)

Diencephalon:
— the neural cavity expands dorsoventrally and becomes the narrow third ventricle. The roof plate
stretches and choroid plexuses develop bilaterally in the roof of the third ventricle and secrete cerebrospinal
fluid.
— the floor of the third ventricle gives rise to the neurohypophysis (neural lobe of pituitary gland);
— the mantle layer of the diencephalon gives rise to thalamus, hypothalamus, etc. The thalamus
enlarges such that right and left sides meet at the midline and obliterate the center of the third ventricle.
— the optic nerve and retina develop as an outgrowth of the wall of the diencephalon.

36
Telencephalon (cerebrum):
— bilateral hollow outgrowths become right and left cerebral hemispheres. The cavity of each
hemisphere becomes a lateral ventricle that communicates with the third ventricle via an
interventricular foramen. A choroid plexus develops in the wall of each lateral ventricle. The plexus is
continuous with a choroid plexus of the third ventricle via an interventricular foramen);

— at the midline, the rostral end of the telencephalon forms the rostral wall of the third
ventricle (the wall is designated lamina terminalis);
— the mantle layer surrounding the lateral ventricle in each hemisphere gives rise to basal
nuclei and to cerebral cortex;
— cellular migrations that form cerebral cortex:
• from the mantle layer, cells migrate radially to the surface of the cerebral hemisphere,
guided by glial cells that extend from the ventricular surface to the outer surface of the cerebral
wall (thus each locus of mantle gives rise to a specific area of cerebral cortex);
• migration occurs in waves; the first wave (which becomes the deepest layer of cortex)
migrates to the surface of the cortex; the second wave (which forms the next deepest layer of
cortex) migrates to the cortical surface, passing through first wave neurons which are displaced
to a deeper position; the third wave . . . etc. (the cerebral cortex has six layers).

Cell connections are established within the cerebral cortex as waves of newly
arriving neurons migrate through populations of neurons that arrived earlier.

NOTE: Carnivores are born with a nervous system that does not mature until about six weeks
postnatally (mature behavior is correspondingly delayed). In herbivores, the nervous
system is close to being mature at birth.

IV. Peripheral Nervous System:

NOTE: • The peripheral nervous system (PNS) consists of cranial and spinal nerves. Nerve
fibers within peripheral nerves may be classified as afferent (sensory) or efferent
(motor) and as somatic (innervating skin and skeletal muscle) or visceral (innervating
vessels and viscera). The visceral efferent (autonomic) pathway involves two neurons:
1] a preganglionic neuron that originates in the CNS and 2] a postganglionic neuron
located entirely in the PNS. The glial cell of the PNS is the neurolemmocyte (Schwann
cell).
• All afferent neurons are unipolar and have their cell bodies in sensory ganglia, either
spinal ganglia on dorsal roots or ganglia associated with cranial nerves. Somatic
efferent and preganglionic visceral efferent neurons have their cell bodies located in the
CNS, but their axons extend into the PNS. Postganglionic visceral efferent neurons
have their cell bodies in autonomic ganglia.

— neurolemmocytes (Schwann cells) arise from neural crest and migrate throughout the PNS,
ensheathing and myelinating axons and forming satellite cells in ganglia;

37
— afferent neurons originate from
neural crest as bipolar cells that
subsequently become unipolar. In the
case of the vestibulocochlear cranial nerve,
afferent neurons remain bipolar. The
neurons originate from placodes (localized
thickening of ectoderm in the head).

— postganglionic visceral efferent

neurons arise from neural crest.
Neuroblasts migrate to form
autonomic ganglia in the head, or
beside vertebrae (sympathetic trunk
ganglia), or near the aorta, or within
the gut wall (the latter are
parasympathetic terminal ganglia).

— somatic efferent neurons and preganglionic visceral efferent neurons arise from the basal plate
of the neural tube; their cell bodies remain in the CNS and their axons join peripheral nerves.

Peripheral nerves establish contact early with the nearest somite, somitomere,
placode, or pharyngeal arch and innervate derivatives of these embryonic
structures.
Innervation continuity is retained even when the embryonic targets are widely displaced or when
other structures obstruct the pathway. The early establishment and maintenance of an innervation
connection is essential, which explains why some nerves travel extended distances and including
detours to reach distant inaccessible targets. (The foremost example is the recurrent laryngeal nerve which
courses from the brainstem to the larynx via the thorax. Necessary because the heart migrates from the neck to the
thorax pulling the nerve with it.)

Note: Cranial nerves innervate specific pharyngeal arches and their derivatives:
trigeminal (V) - innervates first pharyngeal arch (muscles of mastication)
facial (VII) - innervates second pharyngeal arch (muscles of facial expression)
glossopharyngeal (IX) - innervates third pharyngeal arch (pharyngeal muscles)
vagus (X) - 4 & 6 pharyngeal arches (muscles of pharynx, larynx, & esophagus)

V. Formation of Meninges:
Meninges surround the CNS and the roots of spinal and cranial nerves.
Three meningeal layers (dura mater, arachnoid, and pia mater) are formed as follows:
— mesenchyme surrounding the neural tube aggregates into two layers;
— the outer layer forms dura mater;
— cavities develop and coalesce within the inner layer, dividing it into arachnoid and pia mater.
The cavity between them becomes subarachnoid space (which contains cerebrospinal fluid).

38
 Development of Special Senses

I. Formation of the Eye:

Both eyes are derived from a single field of the neural plate. The single field separates into
bilateral fields associated with the diencephalon. The following events produce each eye:
— a lateral diverticulum from the diencephalon forms an optic vesicle attached to the
diencephalon by an optic stalk;
— a lens placode develops in the surface ectoderm where it is contacted by the optic vesicle;
the lens placode induces the optic vesicle to invaginate and form an optic cup while the placode
invaginates to form a lens vesicle that invades the concavity of the optic cup;
— an optic fissure is formed by invagination of the ventral surface of the optic cup and optic
stalk, and a hyaloid artery invades the fissure to reach the lens vesicle;

NOTE: • The optic cup forms the retina and contributes to formation of the ciliary
body and iris. The outer wall of the cup forms the outer pigmented layer of
the retina, and the inner wall forms neural layers of the retina.
• The optic stalk becomes the optic nerve as it fills with axons traveling
from the retina to the brain.
• The lens vesicle develops into the lens, consisting of layers of lens fibers
enclosed within an elastic capsule.
• The vitreous compartment develops from the concavity of the optic cup,
and the vitreous body is formed from ectomesenchyme that enters the
compartment through the optic fissure.

39
— ectomesenchyme (from neural crest) surrounding the optic cup condenses to form inner and
outer layers, the future choroid and sclera, respectively;
— the ciliary body is formed by
thickening of choroid
ectomesenchyme plus two layers
of epithelium derived from the
underlying optic cup; the
ectomesenchyme forms ciliary muscle
and the collagenous zonular fibers that
connect the ciliary body to the lens;

— the iris is formed by choroid

ectomesenchyme plus the
superficial edge of the optic cup;
the outer layer of the cup forms
dilator and constrictor muscles
and the inner layer forms
pigmented epithelium; the
ectomesenchyme of the iris
forms a pupillary membrane that
conveys an anterior blood supply
to the developing lens; when the
membrane degenerates following
development of the lens, a pupil
is formed;
— the cornea develops from two sources: the layer of ectomesenchyme that forms sclera is
induced by the lens to become inner epithelium and stroma of the cornea, while surface ectoderm
forms the outer epithelium of the cornea; the anterior chamber of the eye develops as a cleft in
the ectomesenchyme situated between the cornea and the lens;
— the eyelids are formed by upper and lower folds of ectoderm, each fold includes a
mesenchyme core; the folds adhere to one another but they ultimately separate either prenatally
(ungulates) or approximately two weeks postnatally (carnivores); ectoderm lining the inner
surfaces of the folds becomes conjunctiva, and lacrimal glands develop by budding of
conjunctival ectoderm;
— skeletal muscles that move the eye (extraocular eye mm.) are derived from rostral
somitomeres (innervated by cranial nerves III, IV, and VI).

Clinical considerations:
• The ungulate retina is mature at birth, but the carnivore retina does not fully mature until about 5
weeks postnatally.
• Retinal detachment occurs between the neural and outer pigmented layers of the retina (inner and
outer walls of the optic cup) which do not fuse but are held apposed by pressure of the vitreous body.
• Coloboma is a defect due to failure of the optic fissure to close.
• Microphthalmia (small eye) results from failure of the vitreous body to exert sufficient pressure for
growth, often because a coloboma allowed vitreous material to escape.
• Persistent pupillary membrane results when the pupillary membrane fails to degenerate and produce a
pupil.

40
Formation of the Ear
The ear has three
components: external ear,
middle ear, and inner ear.
The inner ear contains sense
organs for hearing (cochlea)
and detecting head
acceleration (vestibular
apparatus), the latter is
important in balance.
Innervation is from the cochlear
and vestibular divisions of the VIII
cranial nerve. The middle ear
contains bones (ossicles) that
convey vibrations from the
tympanic membrane (ear
drum) to the inner ear. The
outer ear channels sound
waves to the tympanic
membrane.
Inner ear:
— an otic placode develops in surface ectoderm adjacent to the hindbrain; the placode
invaginates to form a cup which then closes and separates from the ectoderm, forming an
otic vesicle (otocyst); an otic capsule, composed of cartilage, surrounds the otocyst;
— some cells of the placode and vesicle become neuroblasts and form afferent neurons of the vestibulocochlear
nerve (VIII);
— the otic vesicle undergoes differential growth to form the cochlear duct and semicircular
ducts of the membranous labyrinth; some cells of the labyrinth become specialized receptor cells found
in maculae and ampullae;
— the cartilagenous otic capsule undergoes similar differential growth to form the osseous
labyrinth within the future petrous part of the temporal bone.

41
Middle ear:
— the dorsal part of the first pharyngeal pouch forms the lining of the auditory tube and
tympanic cavity (in the horse a dilation of the auditory tube develops into the guttural pouch);
— the malleus and incus develop as endochondral bones from ectomesenchyme in the first
pharyngeal arch and the stapes develops similarly from the second arch (in fish, these three bones
have different names; they are larger and function as jaw bones).

Outer ear:
— the tympanic membrane is formed by apposition of endoderm and ectoderm where the
first pharyngeal pouch is apposed to the groove between the first and second pharyngeal
(pharyngeal) arches;
— the external ear canal (meatus) is formed by the groove between the first and second
pharyngeal arches; the arches expand laterally to form the wall of the canal and the auricle
(pinna) of the external ear.

Taste buds
Taste buds are groups of specialized (chemoreceptive) epithelial cells localized principally on
papillae of the tongue. Afferent innervation is necessary to induce taste bud formation and
maintain taste buds. Cranial nerves VII (rostral two-thirds of tongue) and IX (caudal third of tongue) innervate
the taste buds of the tongue.

Olfaction
Olfaction (smell) involves olfactory mucosa located caudally in the nasal cavity and the
vomeronasal organ located rostrally on the floor of the nasal cavity. Olfactory neurons are
chemoreceptive; their axons form olfactory nerves (I).
— an olfactory (nasal) placode appears bilaterally as an ectodermal thickening at the
rostral end of the future upper jaw; the placode invaginates to form a nasal pit that develops into
a nasal cavity as the surrounding tissue grows outward; in the caudal part of the cavity, some
epithelial cells differentiate into olfactory neurons;
— the vomeronasal organ develops as an outgrowth of nasal epithelium that forms a blind
tube; some epithelial cells of the tube differentiate into chemoreceptive neurons.

42
Lecture 5

Spinal Cord Organization

Objectives:
• identify macroscopic and microscopic anatomical features of the spinal cord
• describe the types of neurons located within the gray matter of the spinal cord
• explain the purposes and features of selective ascending and descending pathways

I. Introduction and Gross Anatomy:

The spinal cord . . .
• communicates with the brain, by
means of ascending and
descending pathways that form
tracts in spinal white matter;
• connects with spinal nerves,
through afferent & efferent
axons in spinal roots; and
• gives rise to spinal reflexes, pre-
determined by interneuronal
circuits.

Gross anatomy of the spinal cord:

The spinal cord is a cylinder of CNS. The spinal cord exhibits subtle cervical and
lumbosacral enlargements produced by extra neurons within segments that innervate limbs. The
region of spinal cord caudal to the lumbar enlargement is the conus medullaris. Caudal to this, a
nonfunctional terminal filament of glial tissue extends into the vertebral canal of the tail.

A spinal cord segment = a portion of spinal

cord that gives rise to a pair (right & left) of
spinal nerves. Each spinal nerve is attached to
the spinal cord by means of dorsal and ventral
roots composed of rootlets. Spinal segments,
spinal roots, and spinal nerves are all identified
numerically by region, e.g., 6th cervical (C6)
spinal segment.
Sacral and caudal spinal roots (surrounding
the conus medullaris and terminal filament and
streaming caudally to reach corresponding
intervertebral foramina) collectively constitute
the cauda equina.

Both the spinal cord (CNS) and spinal roots (PNS) are enveloped by meninges within the
43
vertebral canal. Spinal nerves (which are formed in intervertebral foramina) are covered by
connective tissue (epineurium, perineurium, & endoneurium) rather than meninges.

II. Spinal Cord Histology:

Central canal (derived from embryonic neural cavity) is lined by ependymal cells & filled
with cerebrospinal fluid. It communicates with the IV ventricle and ends in a dilated region (terminal
ventricle).

Gray matter (derived from embryonic mantle layer) is butterfly-shaped. It has a high density
of neuron cell bodies & gliocytes, a high capillary density, and sparse myelinated fibers. Gray
matter regions include: dorsal horn, ventral horn, and intermediate substance — the latter
features a lateral horn (sympathetic preganglionic neurons) in thoracolumbar spinal segments.
White matter (derived from embryonic marginal layer) is superficial to gray matter. It is
composed of concentrated myelinated fibers, gliocytes, and low capillary density. White matter
regions include: dorsal funiculus; ventral funiculus; lateral funiculus; and white commissure.

Gray matter organization:

Two schemes have evolved for organizing neuron cell bodies
within gray matter. Either may be used according to which works
best for a particular circumstance.
1] Spinal Laminae—spinal gray matter is divided into ten
laminae (originally based on observations of thick sections in a neonatal cat).
The advantage is that all neurons are included. The disadvantage
is that laminae are difficult to distinguish.
2] Spinal Nuclei—recognizable clusters of cells are identified
as nuclei [a nucleus is a profile of a cell column]. The advantage
is that distinct nuclei are generally detectable; the disadvantage is
that the numerous neurons outside of distinct nuclei are not
included.

44
III. Types of spinal neurons:
All neurons found in spinal cord gray matter have multipolar cell bodies. Based on axon
destination, spinal neurons can be divided into three major types, each of which has subtypes:
1] Efferent neurons (embryologically derived from basal plate) send axons into the ventral root.
Cell bodies of efferent neurons are located in ventral horn (somatic efferents) or in intermediate
substance (visceral efferents).
• somatic efferent (SE) neurons (somatotopically arranged in the ventral horn):
alpha motor neurons— innervate ordinary skeletal muscle fibers (motor units);
(neuron size is proportional to motor unit size);
gamma motor neurons—innervate intrafusal muscle fibers (within muscle spindles);
• visceral efferent (VE) neurons: preganglionic sympathetic and parasympathetic neurons.
2] Projection neurons send axons into spinal white matter to travel to the brain (or to a
distant part of the spinal cord). The axons form tracts associated with ascending spinal pathways
that have different functions.
Projection neurons may be categorized according to the types of stimulation that ultimately
excites them: Some projection neurons respond specifically to thermal or mechanical mild or noxious stimuli;
however, many projection neurons respond non-specifically to both mild and noxious stimuli (they function to
maintain alertness). Some projection neuron respond only to somatic stimuli (exteroceptors or proprioceptors);
others respond to both somatic and visceral stimuli. The latter are the basis for the phenomenon of referred pain.
3] Interneurons have axons that remain within spinal gray matter. Interneurons are
interposed between spinal input (from peripheral nerves or brain) and spinal output (efferent
neurons). By establishing local circuits, interneurons "hardwire" input to output and thus
determine the inherent reflex responses of the spinal cord (spinal reflexes).

IV. Spinal Pathways:

Primary Afferent Neuron = the first neuron in a spinal reflex or ascending spinal pathway.
Primary afferent neurons have their unipolar cell bodies in spinal ganglia. Receptors are
found at the peripheral terminations of their axons. Their axons traverse dorsal roots, penetrate
the spinal cord (at the dorsolateral sulcus) and bifurcate into cranial and caudal branches which
extend over several segments within white matter of the dorsal funiculus.
Collateral branches from the cranial and caudal branches enter the gray matter to synapse on
interneurons and projection neurons (or directly on efferent neurons for the myotatic reflex).
In some cases (e.g., discriminative touch), the cranial branches of incoming axons ascend
directly to the brainstem where they synapse on projection neurons of the pathway.

45
Ascending Spinal Pathways:
Chains of neurons carrying information from peripheral receptors to the brain.
Neuronal sequence: primary afferent neurons synapse on projection neurons typically
located in spinal gray matter. The axons of projection neurons join ascending tracts and
synapse on neurons in the brain. In the case of conscious sensation, the pathway leads to
thalamic neurons that project to the cerebral cortex.
Note: The function of a particular pathway is determined by: 1] the primary afferent
neurons that are excited by the environmental energy (stimulus); 2] the particular
projection neurons that are synaptically excited by the primary afferent neurons; and 3]
where the projection neurons synapse in the brain. Thus projection neurons not only form
the anatomical tracts, they are critical in determining the physiological response.

In general, pathways may be categorized into three broad functional types:

1] Conscious discrimination/localization (e.g., pricking pain, warmth, cold,
discriminative touch, kinesthesia) requires a specific ascending spinal pathway to the
contralateral thalamus which, in turn, sends an axonal projection to the cerebral cortex. Generally
there are three neurons in the conscious pathway and the axon of the projection neuron
decussates and joins a contralateral tract (see the first two pathways on the following page; the third
pathway is the one exception to the general rule).

2] Affective related (emotional & alerting behavior) information involves ascending

spinal pathways to the brainstem. Projection neurons are non-specific. They receive synaptic
input of different modalities and signal an ongoing magnitude of sensory activity, but they
cannot signal where or what activity.
3] Subconscious sensory feedback for posture/movement control involves ascending
spinal pathways principally to the cerebellum or brainstem nuclei that project to the cerebellum.
Generally there are only two neurons in a subconscious pathway and the axon of the projection
neuron joins an ipsilateral tract (see the last pathway on the following page).

Note: Pathway = sequence (chain) of neurons synaptically linked to convey

excitability changes from one site to another.

46
47
Descending Spinal Pathways:
Axons of brain projection neurons travel in descending tracts in spinal white matter. They
arise from various locations in the brain and synapse primarily on spinal interneurons.

By synapsing on interneurons, descending tracts regulate:

1] spinal reflexes (which utilize the same interneurons);
2] excitability of efferent neurons (for posture and movement); and
3] excitability of spinal projection neurons, i.e., the brain is able to regulate sensory
input to itself. In some cases, descending tracts affect axon terminals of primary afferent
neurons, blocking release of neurotransmitter (presynaptic inhibition).

48
Lecture 6

Spinal Reflexes & Neuronal Integration

Objective:
• define reflexes and the roles that interneurons, afferent, and efferent neurons play in reflexes
• describe the clinical significance of the withdrawal-crossed extensor reflex and its circuitry
• list components of the muscle spindle and its relationship to other proprioceptors
• explain the myotatic reflex and its functional role in posture & moverment
• explain the significance of neuronal integration in regard to lower motor neurons

I. Reflexes:
Reflex = an inherent, subconscious, relatively consistent responses to a particular stimulation.
In contrast . . .
Reaction = an inherent, subconscious, relatively consistent responses to a particular
stimulation, involving the cerebellum and cerebral cortex; e.g., hopping reaction & tactile placing
reaction.

Examples of brainstem reflexes include:

— eyelids close when the cornea is touched (corneal reflex)
— lip moves in response to a noxious stimulation (pin prick)

Examples of spinal reflexes, involving spinal nerves and the spinal cord, include:
— withdrawal reflex: limb flexes to withdraw from a noxious stimulus
— myotatic reflex: muscle stretch is resisted by reflex contraction of the muscle
— panniculus reflex: pricking skin triggers contraction of cutaneus trunci (panniculus) m.
— extensor thrust: paw proprioceptors trigger limb extension

NOTE:
Reflex responses are determined by interneurons which “hard-wire”
afferent input to efferent output. Interneurons organize efferent neurons (motor
units) into meaningful movement components, which can be utilized by either
spinal input or descending pathways.
Also, interneurons form pattern generators for repetitive movements.
Locomotor pattern generators exist in the spinal cord (e.g., on a treadmill, hind
limbs exhibit stepping even in a cat that has its spinal cord transected in the
thoracic region, i.e., isolated from the brain).
Since "voluntary movement" and "involuntary reflex/reaction" compete
for control of the same interneurons circuits, they cannot be independent of one
another. Thus, brain activity will influence spinal reflex responses, introducing
variation and making clinical reflex evaluation an interpretive art.

49
II. Withdrawal Reflex:

Withdrawal Reflex = Flexor (Crossed Extensor) Reflex

Features of the reflex (diagrammed above) include . . .
— primary afferent neuron (1) participates in both reflexes (2) and ascending pathways (3);
— divergent interneuronal circuit propagates to several segments and right and left sides (B);
— positive feedback prolongs the reflex beyond the time of the stimulus (A);
— individual interneurons are either excitatory or inhibitory (black cells) in their effect;
— antagonists are inhibited while agonists are excited (reciprocal innervation) (D);
— descending pathways (C) modify reflex circuit (reflex is not independent of brain control).
NOTE: • As the reflex is tested clinically, the crossed extension component disappears after
the first 3 weeks of age because descending pathways mature and inhibit
extension. But, later in life, the normally inhibited crossed extension reappears if
“upstream” damage to descending fibers removes the inhibition (crossed extension
is abnormal).
• The withdrawal reflex is often elicited to assess depth of anesthesia (the more
synapses a reflex has, are more vulnerable it is to suppression by anesthesia).

50
 BACKGROUND INFORMATION ABOUT PROPRIOCEPTION
Proprioceptors are mechanoreceptors, located in muscles/tendons & joint capsules/ligaments.
Proprioceptors provide:
• subconscious feedback about the status of muscles & joints,
• conscious kinesthesia (sense of position & movement), and
• pain
Joint receptors:
• free nerve endings that respond to extreme movement or inflammation (pain)
• encapsulated receptors:
— tonic: signal joint position
— phasic: respond to rate of change in joint position (largely subconscious)
Muscle & tendon proprioceptors:
free nerve endings: pain
(Golgi) tendon organs: located in series with muscle fibers (tension detector)
muscle spindles: located in muscle belly (length detector)

III. Muscle Spindle:

A. Muscle spindles are: Muscle & Tendon Receptors
• elaborate proprioceptors positioned in
parallel with muscle fibers;
• designed to signal muscle length
• about 3mm long & 0.5 mm wide.
Morphologically, a muscle spindle consists
of a connective tissue capsule enclosing:
— two kinds of mechanoreceptors,
— two kinds of intrafusal muscle fibers,
— two kinds of gamma efferent neurons.
B. Intrafusal muscle fibers:
(vs. typical extrafusal muscle fibers)
• very small, anchored in endomysium
• do not contribute at all to whole muscle
tension
• center of each fiber is packed with
nuclei & lacks myofilaments
• polar regions are striated and
innervated by gamma neurons
• two kinds of intrafusal muscle fibers:
nuclear bag fibers — central region is
dilated; fiber extends beyond the capsule;
nuclear chain fibers — smaller, central Types of nerve fibers found
region contains chain of nuclei. in a muscle nerve

51
C. Mechanoreceptors within muscle spindle :
They are activated by stretch of the central region, which is stretched either
1) by contraction of polar regions of intrafusal muscle fibers, or
2) by passive stretch of the whole muscle (including the intrafusal fibers)
There are two types of mechanoreceptors:
1] primary (annulospiral) endings — 2] secondary endings —
— spiral around central (nuclear) regions; — "flower-spray" formations adjacent to
— endings of large nerve fibers (type IA); nuclear chain regions;
— initially AP frequency reflects rate of stretch; — endings of type II nerve fibers;
— then steady AP frequency reflects degree of — AP frequency is proportional to degree
stretch of stretch.

IV. Myotatic Reflex:

Clinically, a myotatic reflex is elicited by abruptly tapping a tendon (e.g., the patellar tendon).
Suddenly deforming/displacing a tendon effectively stretches the associated muscle.
When a whole muscle is suddenly stretched (as a result of tendon deformation), annulospiral
receptors in muscle spindles are simultaneously excited, triggering a volley of action potentials
in IA afferent axons. Within the CNS, the axons activate excitatory synapses on alpha motor
neurons that innervate the muscle that was stretched. Also, alpha motor neurons to antagonistic
muscles are inhibited via interneurons. As a result, the stretched muscle immediately contracts.
Thus, the myotatic reflex functions to oppose muscle stretch. Since interneurons are
by-passed in eliciting the contraction, the response is rapid, localized, and relatively resistant to
hypoxia, fatigue, drugs, etc.

A. Reflex sensitivity:
Sensitivity of the myotatic reflex (the extent to which a muscle can be stretched before it reflexly
contracts) is determined ultimately by the contractile state of the polar regions of the intrafusal
muscle fibers—because the degree of contraction of the polar regions determines the pre-existing
bias (degree of stretch of intrafusal central regions) when the whole muscle is stretched.
Thus, since gamma neurons innervate intrafusal polar regions, sensitivity of the myotatic reflex
is set by the frequency of AP's in axons of gamma neurons, and gamma neuron excitability is
controlled by descending tracts from the hindbrain (reticulospinal tracts & vestibulospinal
tracts).

52
B. Functions of the myotatic reflex:
1. Muscle tone = the resistance muscles offer when being stretched (lengthened)
= the resistance encountered when a limb is manipulated clinically
Muscle tone is set by: brain ——> descending pathways ——> gamma neuron firing rate.
Normal tone is variable, but appropriate to the animal’s current behavioral state.
vs. hypertonia (spasticity) = fixed excessive tone, i.e., excess resistance to manipulation
— due to excessive gamma neuron excitation (rate of firing)
or hypotonia ("weakness") = fixed deficient tone, e.g., “rag-doll” appendages
— the result of insufficient gamma neuron excitation.
2. Posture maintenance under changing conditions of load & fatigue
By using myotatic reflexes, the brain is able to set muscle lengths and fix joint position
(i.e., posture) without concern for load and fatigue. The brain sets lengths of intrafusal muscle
fibers to correspond to desired whole-muscle lengths.
Any muscle that is longer than the desired length will have its spindle receptors activated
and the resultant myotatic reflex will persist until the muscle has shortened to the proper length.
After posture is set, motor neurons will receive a burst of excitatory synaptic input whenever a
muscle becomes stretched and they will lose that excitation once the muscle shortens
sufficiently.

53
 By analogy, this is a servosystem, e.g., one sets a thermostat [the brain sets gamma
neuron excitation] to control a furnace [myotatic reflex] to maintain a desired temperature
[posture].
3. Voluntary movement
Posture can be sequentially adjusted to produce movement, e.g., hindlimb scratching the
flank; learning any new movement sequence; etc. Also, gamma neurons (myotatic reflexes) must
be inhibited in antagonistic muscles as agonists are excited.
During voluntary movements, the brain co-activates alpha & gamma neurons to maintain
spindle sensitivity while muscles shorten. If a load is excessive for a given amount of initial apha
activity, myotatic activity can kick in to boost alpha neuron excitability to levels sufficient for
the particular load. Thus the servosystem mentioned for posture works for movement as well, via
co-activation of alpha & gamma neurons.

Clinical Considerations
A clinician taps a tendon in order to :
1) verify the integrity of local peripheral nerves and spinal cord segments; and
2) evaluate brain control and the integrity of descending tracts,
looking particularly for evidence of fixed hypertonia or hypotonia.

IV. Neuronal Integration:

A typical multipolar neuron in the CNS receives many thousands of synaptic inputs
(excitatory/inhibitory; axosomatic/axodendritic; from interneurons/projection neurons; etc.).
How does a neuron integrate all of its diverse synaptic input?
How does it make "sense" of the diversity and "fire" appropriately to effectively
influence other neurons in its circuit?
The answer — neuronal integration.

A. Synaptic inputs — predominantly on dendrites & soma (receptive zone):

axosomatic excitatory synapses — depolarize entire soma (cell body) surface. The
cell body acts like a sphere (charges/ions distribute evenly over a spherical surface).
Although each EPSP affects the whole soma, a single EPSP has a very limited effect.

axodendritic excitatory synapses — depolarize preferentially toward the soma.

The EPSP is passively conducted preferentially toward lower resistance
(asymmetrical diameter = asymmetrical resistance).
NOTE:
Inhibitory synapses behave like excitatory
ones, except that they produce IPSPs, which
hyperpolarize the soma and cancel EPSPs.

54
B. Neuronal output:
• an action potential (AP) originates at the initial segment of the axon where high density of
voltage-gated Na+ channels are present;
• the initial segment is greatly influenced by the massive soma adjacent to it, i.e., the soma
continually depolarizes or hyperpolarizes the initial segment at each instant of time;
• whenever the initial segment reaches threshold depolarization, it generates an AP that
travels along the entire axon.
Thus, the soma membrane of each neuron integrates total synaptic
input at each moment of time! Integration is the result of algebraic
summation of synaptic activity (EPSPs and IPSPs). The floating soma
membrane potential reflects the net excitatory and inhibitory synaptic
input to a particular neuron at a particular time.
C. Factors influencing synaptic effectiveness:
• for a given competing input source, impact on a target neuron depends on:
1) number of source synapses on the target neuron;
2) locations of source synapses on the target neuron.
• for an individual synapse, effectiveness is related to synaptic location on the target neuron
most effective {axon hillock >> soma >> proximal dendrite >> distal dendrite} least
effective
• a given amount of synaptic input will have more effect in a small (vs. large) neuron cell body;
thus, within a neuronal pool, small neurons are recruited first, large neurons last.
• synaptic effect is increased by repetitive firing (temporal summation);
• synaptic effect is increased by collaborative firing of different sources (spatial summation).

NOTE
It is significant that a given amount of synaptic input will have a greater effect
in a small neuron cell body than it would have in a large cell body. Consequently,
small neurons are recruited first and large neurons require more intense synaptic
input.
Small neurons innervate:
— relatively few muscle fibers per neuron (small motor units)
— slow twitch, fatigue-resistant muscle fibers (Type I muscle fibers).
Large neurons innervate:
— many muscle fibers per neuron (large motor units)
— fast-contacting larger, more powerful myocytes (Type II muscle fibers)
Thus, the force of muscle output is related to the intensity of synaptic input to
the particular neuronal pool that innervates the muscle(s). Fatigue-resistant muscle
fibers are naturally recruited first and most often; large muscle fibers are recruited
subsequently as more strength is needed.

55
D. Temporal summation: repeated synaptic input can sum to produce an increased effect, when
subsequent PSPs arrive before previous PSPs completely decay

E. Spatial summation: synaptic input from a second source can sum with that of a primary
source to produce an increased effect..

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 ADDENDUM
Neuronal Integration Scenario

A. Final common pathway neuron:

anatomically = ventral horn neuron or neuron cranial nerve motor nucleus
electrophysiologically = alpha motor neuron
clinically = lower motor neuron (as opposed to upper motor neuron)
A final common pathway (FCP) neuron innervates skeletal muscle. The neuron and the skeletal muscle fibers
it innervates constitute a motor unit. The nervous system controls skeletal muscles by controlling FCP neurons.
A given FCP neuron receives thousands of synapses, mostly from interneurons. Some of the neuronal inputs
are excitatory, others are inhibitory. Some of the input originates in the brain, other from receptors and primary
afferent neurons. Some of the sources of input have a major effect on the neuron, other inputs provide merely
background excitation.

B. Typical inputs to a FCP motor neuron innervating an extensor muscle:

A. Background excitation — (axodendritic synapses; merely predispose neurons to fire)
1. reticulospinal axons = muscle activity for standing
2. vestibulospinal tract = balance and muscle activity for standing
3. propriospinal axons = intersegmental reflexes
B. Major excitatory inputs — (axosomatic synapses; excite neurons to fire APs)
4. commissural interneurons = crossed-extensor reflex
5. rubrospinal tract = voluntary movement
6. primary muscle spindle afferent axon (IA) = stretch (myotatic) reflex
C. Inhibitory inputs — (inhibitory axodendritic or axosomatic synapses; cancel excitatory synapses)
7. pain afferent axon = inhibits extensor muscles
8. pyramidal tract axon = controls distal muscles (inhibits extensor muscles)

C. Clinical note: Damage to FCP neurons (or axons in peripheral nerves) results in flaccid
paralysis of skeletal muscles (neither voluntary movement nor reflex activity is present).

57
Lecture 7

Nociception I
Overview of Pain
OBJECTIVE: Given the information provided in this lecture, the student will be
able to define basic pain terminology, determine how to recognize pain in animals,
describe how pain pathways are organized and apply this information to understand
how damage to a pain pathway affects pain transmission.

I. Some Basic Terminology:

A. Pain—an unpleasant sensory and emotional experience associated with actual or potential tissue
damage. It is a protective mechanism for the body and causes a human or animal to react to
remove the painful or “noxious” stimulus

B. Nociceptor—a primary afferent neuron that is preferentially sensitive to a noxious stimulus.

C. Nociception—the detection of tissue damage by specialized transducers (nociceptors) attached to

“A delta” and “C” peripheral nerve fibers. It refers to the transmission of nociceptive information
to the brain without reference to the production of emotional or other types of response to the
noxious stimulus .

D. Algesic—pain producing vs. Analgesic—pain preventing

E. Hyperalgesia—increased pain sensation elicited by a noxious stimulus (bump an injured toe)

F. Allodynia—a pathological condition in which pain is produced by a stimulus that is normally

innocuous (sunburn).

100
Hyperalgesia
80
Pain Sensation

60
Injury
40

Allodynia Normal
20

0
Innocuous Noxious
STIMULUS INTENSITY
Figure 1: Graph of the relationship between pain sensation and stimulus intensity. Increased
pain sensation (hyperalgesia) occurs when a mild painful stimulus is applied to injured
tissue.

58
Key Concept #1: Tissue damage, injury or inflammation causes the tissue area to be
more sensitive to both innocuous and noxious stimuli leading to increased pain
sensation. Thus, just touching the area around a surgical incision can be painful
(allodynia), whereas touching normal skin would not be painful.

II. How to Recognize Pain in Animals (how do you know when an animal hurts):
1) Is there situational evidence that pain exists, i.e., a recent injury?
2) Are there altered behavioral responses—increased aggressiveness, avoidance behavior,
reluctance to be touched, decreased appetite, decreased activity, lethargy, vocalization—
crying/ yelping or quieter than normal; lameness, adopting an unusual posture?
3) Are there physiological changes—altered autonomic function—increased heart rate,
increased blood pressure, increased respiratory rate (increased panting), increased sweating,
shivering, salivation?
4) Are there biochemical changes— increases in cortisol or adrenaline in the blood?

Key Concept #2: All animals can feel pain and will alter their behavioral responses
according to the type and intensity of the pain. Learn to recognize these altered
behaviors and to minimize pain wherever possible (see last page of handout).

III. Pain Transmission and Pain Pathways:

*All somatosensory pathways begin at a peripheral receptor that converts environmental
energy into an electrical signal. This signal is conveyed via specific neural pathways to
the thalamus and cerebrum where the animal can detect and localize the sensation.

Fig. 2: Schematic overview of the three-neuron spinothalamic pain pathway.

59
 Mother Nature’s Design of a Pain Pathway
A. Peripheral Transmission: Pain or nociception is initiated when the peripheral terminals
(receptors) of a subgroup of sensory neurons (nociceptors) are activated by noxious
chemical, mechanical or thermal stimuli.

1. Receptors — free nerve endings - non-myelinated terminals of peripheral axons that

contain synaptic vesicles. Those that specifically respond to potentially damaging or
painful stimuli are called nociceptors and they send information back to the spinal cord
or brain stem via peripheral or cranial nerves.

Pain Receptors =

Figure 2: Diagram illustrating free nerve ending which respond to noxious stimuli, tissue
damage or injury and send electrical signals to the spinal cord.
Damage to tissue causes the release of a large number of mediators that activate nociceptor
free nerve endings. These mediators include ATP from damaged cells and bradykinin
from blood as well as many other substances that may cause pain (see Fig. 3).



Fig. 3: Diagram of mediators released at site of injury and effects on nociceptor.

60
Injury: Following injury a variety of mediators are secreted by blood vessels and other cells in the
region which activate pain terminals by increasing conductance of sodium (gNA) or calcium
(gCa2+) channels or by activating second messenger systems (adenylate cyclase, AC, etc.). Once
activated pain terminals then conduct an electrical signal to the spinal cord.

Key Concept #3: Tissue damage or repetition of a noxious stimulus causes nociceptors to
become sensitized and they exhibit a reduction in their threshold for activation leading to an
increase in their response to a given stimulus or to the development of spontaneous activity.
This is the mechanism that underlies hyperalgesia.

2. Peripheral nociceptors have their cell body or soma in a spinal or a cranial nerve ganglia.
The cell body gives rise to: 1) a peripheral process or primary afferent axon that inner- vates skin,
muscle, viscera, etc. as a free nerve ending and 2) a central process that terminates in the spinal cord
dorsal horn or in the brain stem.

Fig. 4: Diagram illustrating the termination sites of nociceptive fibers in

the marginal nucleus and nucleus proprius of the spinal cord.

3. Noxious information is transmitted from nociceptive receptors by two types of axons:

(1) A-delta fibers—lightly myelinated, conduct at velocities of 2-30 M/sec (1st pain)
(2) C-fibers—non-myelinated, conduct at velocities of less than 2 M/sec (2nd pain).

4. Primary Response Characteristics (code intensity of stimulus):

Mechanical Stimulation:
action potentials:

innocuous innocuous light hard

brushing pressure pinch pinch

Thermal Stimulation:
action potentials:

50 C
45 C
40 C
30 C
Response characterstics of a nociceptive fiber in a peripheral nerve
61
 B. Central Transmission: Pain is transmitted from Primary Afferent Axons (axons from cell
bodies in a spinal ganglion) —> the spinal cord dorsal horn (marginal nucleus or nucleus
proprius) —> thalamus —> cerebral cortex

Key Concept #4: Pain sensation is conveyed from the spinal cord by several central nervous
system pathways, the two most important in animals are: (1) the Spinothalamic Pathway and
(2) the Spinocervicothalamic Pathway.

1. The Spinothalamic Pathway—this pathway is classically considered to be the major pain relay
system in mammals. The organization of the spinothalamic pathway can be summarized as follows:
(A). 1st Order Neuron—Cell body located in a spinal (dorsal root) ganglion; its
peripheral process is associated with the receptor, while its central process enters the gray matter
of the cord to synapse in the marginal nucleus (lamina I), substantia gelatinosa (lamina II) and
deeper laminae [Fig. 4].

(B). 2nd Order Neuron—cell body located in the marginal nucleus and the nucleus
proprius. The axons of second order neurons cross the midline (decussate) and join other axons
that also carry pain sensation. These axons collectively form a tract in the ventral part of the
lateral funiculus called the Spinothalamic Tract (Fig. 5). The axons of 2nd order neurons in this
pain pathway travel through the brain stem to terminate in the thalamus.

(C). The axons of 2nd order neurons synapse on 3rd order neurons in the thalamus. The
thalamus is the crucial relay for the reception and processing of nociceptive information en route
to the cortex. Axons terminating in the lateral thalamus mediate discriminative aspects of pain.
Axons terminating in the medial thalamus mediate the motivational-affective aspects of pain (e.g.,
relationship between emotion [mood] and pain; attention to and memory of pain).
62
 (D). These 3rd order neurons in the thalamus in turn send their axons to the cerebral
cortex.
Note: An animal becomes aware of painful stimuli at the level of the thalamus, the cerebral
cortex is required for localization of the pain to a specific body region.

Figure 5: Diagram of the Spinothalamic Pathway illustrating its origin from the
spinal cord and its termination in the thalamus and cortex.

63
Fig.6: Diagram of the spinocervicothalamic pathway illustrating the additional neuron in the
lateral cervical nucleus and the crossing of the pathway at the rostral most spinal cord

2. The Spinocervicothalamic (Spinocervical) Pathway--this pathway appears to play an equally

important role in pain transmission in carnivores (it is less well developed in humans and in other
domestic animals). It differs from the spinothalamic pathway in that it has an additional neuron
located in the lateral cervical nucleus and the pathway crosses at the level of the rostral spinal
cord/lower brainstem.

A. Receptors: Free nerve endings

64
 B. 1st order neurons: Dorsal Root Ganglion

C. 2nd order neurons: Marginal Nucleus or Nucleus Proprius

D. Axons of these 2nd order neurons ascend ipsilaterally to the upper cervical spinal cord to
synapse on 3rd order neurons located in the Lateral Cervical Nucleus (see Fig 1 below).

E. Axons from 3rd order neurons in the lateral cervical nucleus cross the midline and ascend to
the contralateral thalamus where they terminate on 4th order neurons.

F. The axons of these 4th order neurons project to the somatosensory area of the cerebral
cortex.

Note: The major difference between the spinocervical pathway (4 neuron pathway) and the
spinothalamic pathway (3 neuron pathway) is the presence of an additional neuron (located
in the Lateral Cervical Nucleus of the cervical spinal cord) in the pathway.
Below is another way to look at these two pathways diagrammatically:

Spinothalamic Pathway (pain & temperature)

Spinothalamic Tract
Dorsomarginal Nuc.
midline

Spinal Cord BRAIN

Pelvic limb neuron Thoracic limb neuron

Spinocervicothalamic Pathway (touch and pain)

Spinal Cord
Dorsal horn Spinocervicothalamic Tract BRAIN
midline Medial
lemniscus
to thalamus
C-1,2

Lateral Cervical Nuc.

Pelvic limb neuron Thoracic limb neuron

Fig.7: Diagrams of the spinothalamic and spinocervical pathways.

65
Addendum: How to recognize Pain in Cats:
Cats can feel pain just like people. All animals have specialized nerve endings called nociceptors that,
when activated, send signals to the central nervous system, which then generates pain.
Trust Your Instincts. If you think a cat is in pain, it probably is. Minimizing animal pain, wherever
possible, is important both ethically and legally.

Signs to Look for:

Some Changes in Appearance
• Apprehensive facial expression
• Creased forehead
• Ungroomed appearance

Some Changes in Behavior

• Crying, yowling, growling, or hissing if approached or made to move
• Hiding or separating itself from other cats
• Seeming unusually quiet
• Incessant licking
• Lack of appetite

Some Changes in Posture or Movement

• Limping or holding up a limb with no attempt to use it
• Stiff and abnormal posture, varying with the site of pain:
• Pain in the head or ears can cause a cat to tilt its head toward the affected side.
• Generalized pain in the chest and abdomen might cause a cat to appear crouched or hunched.
• If the pain is in the chest, a cat might extend its head, neck, and body.
• A cat with abdominal or back pain might stand or lie on its side with its back arched or walk
with a stilted gait.
How to Recognize Pain in Your Cat
.
For more information about pain in pets, farm animals, and laboratory animals, visit:
http://nas.edu/pain
This factsheet is based on the National Research Council report Recognition and Alleviation of Pain in
Laboratory Animals (2009), which helps scientists, veterinarians, and animal care staff understand the
basis of animal pain, recognize its presence and evaluate its severity, and appreciate the means by
which pain can be minimized or abolished.

66
  
Lecture 8  
 
 
  Nociception II
Objectives:
1. To understand and be able to explain the mechanisms underlying peripheral versus central sensitization and how
this contributes to increased pain sensation.
2. Be able to define the different types of pain.
3. To understand and be able to explain the concept of the endogenous analgesia system.
4. To recognize and explain how pain is accessed in animals.
 

III. Mechanisms underlying the development of allodynia and hyperalgesia

A. Peripheral Sensitization: Changes occur in peripheral nociceptors that lead to
sensitization of these pain receptors. Thus the tissue site “hurts more” in response to
mechanical, thermal or chemical stimuli. This process is diagrammed below:

Injury,(Inflamma,on,(Tissue(damage(

Release(of(endogenous(mediators8(inflammatory(soup(
bradykinin,(prostaglandins,(etc(

Bind(to(bradykinin,(prostaglandin(receptors(on(nociceptors(

Ac,va,on(of(intracellular(second(messengers((

Changes(in(sensi,vity(of(ion(channels((sodium,(calcium)(((

Nociceptors(become(more(sensi,ve(to(thermal,(chemical,(mechanical(s,muli(((

 
 
 
Figure  1:  Diagram  illustrating  the  steps  associated  with  the  process  of  peripheral  sensitization  
 
 
 

Figure 2. Peripheral Sensitization is associated with the release of sensitizing stimuli like bradykinin
and prostaglandins that activate receptors on nociceptors leading to increased second messenger
signaling and increased ion channel conductance.

  67  
Note: Data is accumulating indicating a crucial role for ion channels in pain pathways, and many
ion channels have already become candidates for therapeutics and drug development.

B. Central Sensitization: Changes also occur in the spinal cord that contribute to the
development of acute and chronic pain. Spinal cord nociceptive neurons exhibit increased excitability
following peripheral injury or inflammation. Central sensitization is produced by release of various
transmitters (glutamate), neuropeptides (substance P), growth factors (BDNF) and mediators
(prostaglandin E2) that modulate the activation of neurons in the spinal cord. Again this occurs by
activating second messenger systems in spinal neurons leading to changes in ion channel sensitivity.

Figure 3: Summary of the events leading to central sensitization. Peripheral injury or

inflammation lead to increased release of glutamate and substance P as well as the
neurotrophin, BDNF from primary afferent C fibers. This leads to sensitization of the
glutamate receptors, NMDA and AMPA leading to increased influx of sodium and calscium
ions which increases the excitability of spinal nociceptive neurons. As the firing activity of
these neurons increase, additional signals are sent via pain pathways to the brain indicating
“increased pain. In addition there are increases in signaling kinases that lead to long-term
alterations in gene expression, which underlie the development of more chronic pain states.
 
Key Concept #1: Persistent pain and chronic pain are maintained by the processes of peripheral
and central sensitization. Peripheral or central sensitization may result in increased nociceptive
input to the brain and also changes the processing of nociceptive information within the brain.
There is evidence that in patients with chronic pain, structural brain changes may occur, which
contribute to the continued chronic pain state.
 

  68  
  
THE ENDOGENOUS ANALGESIA (Pain Suppression) SYSTEM:
Reynolds was the first to demonstrate in 1969 that potent analgesia could be produced by
electrical stimulation of the midbrain in freely moving animals. We now know that narcotic
drugs (e.g. morphine), acupuncture, certain types of hypnosis and electrical stimulation in
selected brain regions will activate this endogenous analgesia system resulting in a profound
reduction in pain sensation.
 
Major Components:
 
1. Midbrain Periaqueductal Gray (PAG)—the region surrounding the mesencephalic
aqueduct. It contains a high density of opiate receptors and has direct connections with the
spinal cord, the locus coeruleus, and the nucleus raphe magnus. Activation of this region
by an opiate drug, acupuncture or direct stimulation activates a descending pathway that
excites neurons in the nucleus raphe magnus and consequently inhibits spinothalamic and
spinocervicothalamic neurons in the spinal cord.

2. Nucleus Raphe Magnus—located in the midline of the rostral medulla. The neurons that
comprise this nucleus contain high levels of the indoleamine neurotransmitter, serotonin and
they send their axons to the spinal cord dorsal horn, where they synapse on projection neurons
in the marginal nucleus and nucleus proprius. Release of serotonin causes inhibition of pain
transmission neurons in these nuclei of the dorsal horn.

3. Nucleus Locus Coeruleus—located in the caudal pons near the floor of the fourth
ventricle. The neurons here contain the monoamine transmitter, norepinephrine and their
axons also synapse on neurons in the dorsal horn of the spinal cord and cause inhibition of
pain transmission neurons. These components are summarized in Figure 4 below.
 

 
Figure 4: Diagram showing the location of the periaqueductal gray (midbrain), locus coeruleus (pons)
  and raphe magnus (medulla). These are key components of the endogenous analgesia system. 69  
  

Endogenous Pain Activation System:

There also appears to be an endogenous pain activation system that actually enhances pain.
This pain enhancement system appears to help maintain chronic pain status. We are just
beginning to learn about this system, which also is centered in the brainstem.
 
Pain Assessment In Animals:
* Pain assessment should always be part of a routine examination
 
You should recognize the importance of pain assessment as part of daily patient
evaluation; obtain a pain score as a fourth vital sign [Temperature, Pulse,
Respiratory Rate, Pain].
 
In addition to the owners assessment, your own behavioral assessment and the
assessment of physiologic measures (heart rate, respiratory rate, epinephrine,
norepinephrine, and cortisol) as indications of pain, you should also utilize a
scoring system for pain. For instance you can utilize a visual analog scale (VAS)
to evaluate pain (as well as successful pain management). A VAS is a scale that
goes from “no pain” to “worst pain ever”, based on a numeric scale from 0-100
mm.

  70  
  
Pain Relief in Animals:
Animals have pain — Treat it!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Classes of Pain Medications
• Local anesthetics [Carbocaine, lidocaine, bupivacaine]-nerve blocks
• Corticosteroids [Prednisone]
• Non-steroid anti-inflammatory drugs [Apirin, Rimadyl (carprofen inject-
able), deracoxib oral, tepoxalin oral]

• Alpha agonists [xylazine, detomidine, medetomidine]

2

• Opioids [Buprenex Injectable (buprenorphine hydrocloride)]

Acupuncture — The effects of acupuncture on the central and peripheral nervous system
include activation of the body’s endogenous pain modulatory systems, causing a release
of norepinephrine, opioid substances and other neurotransmitters, thereby altering
nociceptive processing and perception. (For additional information, see the review by
Mittleman and Gaynor, JAVMA 217:1201, 2000 and the review by Koski, MA, Vet Clin
North Am Exot Anim Pract. 2011 Jan;14(1):141-54).

  71  
Lecture 9

Cranial Nerves
Objectives:
1. To understand and be able to explain why the anatomical organization of the brain stem
is so complex.
2. To understand and be able to explain the general organizational pattern of cranial nerve
nuclei.
3. To appreciate and be able to explain the main function of each cranial nerve
4. To appreciate and be able to explain the main clinical signs observed in animals with
damage or lesions of the cranial nerves or their nuclei of origin.

I. Factors Responsible for Complex Internal Organization of Brain Stem:

A. Development of the Fourth Ventricle
1. Medulla Oblongata and Pons are ventral to the fourth ventricle
2. Alar Plate is displaced lateral to Basal Plate.

B. Cranial nerve nuclei form discontinuous cell columns rather than continuous cell columns as
seen in the spinal cord.

C. Some cranial nerve nuclei migrate from their primitive embryonic positions (e.g., nuclei of
nerves V & VII).

D. Special senses (hearing, balance, taste and vision) develop in association with the brain stem
(SVA & SSA).

E. Development of the cerebellum and its connections adds additional components.

Figure 1: Schematic Diagram of the developing brainstem, showing how the development
of the fourth ventricle displaces the alar plates lateral to the basal plates.

Key Concept: The development of the 4th ventricle, the development of cranial nerve
nuclei associated with the special senses and the development of the cerebellum lead
to a complex organization of the brain stem compared to the simple structure of the
spinal cord.
72
II. Cranial Nerve Nuclei:
A nucleus is a profile of a column of neuron cell bodies. Efferent nuclei are composed of cell bodies
of alpha and gamma motor neurons (SE) or preganglionic parasympathetic neurons (VE). Afferent
nuclei consist of cell bodies of projection neurons and interneurons upon which primary afferent
axons synapse in connection with ascending pathways or reflex activity.

III. Motor Efferent Nuclei (Basal Plate Derivatives):

Figure 2: Comparison of the four major cell columns in the spinal cord with the more
complicated picture seen in the brainstem. Note the location of motor nuclei (basal plate
derivatives) in the ventromedial part of the brainstem, while sensory nuclei (alar plate
derivatives) are positioned in the dorsolateral part of the brainstem.

III. MOTOR EFFERENT NUCLEI (basal plate derivatives):

A. SE (Somatic Efferent) Nuclei: SE neurons form two longitudinally oriented but discontinuous
columns of cell bodies in the brain stem. The neurons that comprise these columns are responsible for
innervating all of the skeletal musculature of the head. Refer to the diagram on page 46 for the location
of brain stem nuclear columns.

1. Oculomotor, Trochlear, Abducent and Hypoglossal Nuclei — are formed by a column of cells
located near the dorsal midline of the brainstem. The nuclei innervate muscles of the tongue and eye
which are derived from somites. Damage or lesions to these nuclei or their nerves (III, IV, VI, and XII)
result in the following clinical signs:

a) Oculomotor, trochlear or abducent (cranial nerves III, IV, &VI): Abnormalities

in eye movement, deviation of the eyes (strabismus).

b) Hypoglossal (XII): Paralysis and atrophy of tongue muscles; deviation of

tongue toward the side of damage, problems chewing & swallowing.

2. Motor Nucleus of the Trigeminal N. (cranial nerve V), Facial Nucleus (cranial nerve VII) and
Nucleus Ambiguus (cranial nerves IX & X)— are formed by a column of cells located in the
73
ventrolateral brainstem. This location results from the ventrolateral migration of the cell column during
development. These neurons innervate muscles derived from somitomeres in pharyngeal arches.

Damage or lesions involving these nuclei or their nerves result in the following clinical signs:

a) Motor nucleus of the Trigeminal N.: innervates muscles of mastication and

damage to it or the trigeminal nerve results in paralysis of these muscles
and associated muscle atrophy (bilateral damage results in dropped jaw).

b) Facial nucleus: Innervates muscles of facial expression (ears, eyelids, nose

& lips); damage to the nucleus or facial nerve results in facial paralysis.

c) Nucleus Ambiguus: innervates muscles of the soft palate, larynx, and

pharynx (involved with speech, coughing, swallowing & gag
reflexes); damage results in swallowing and vocalization difficulties.

Key Concept: Damage to SE brainstem motor nuclei or the nerves arising from these nuclei
results in paralysis of specific muscle groups innervated by these nerves. For example, damage
to the facial nucleus or nerve causes paralysis of the muscles of facial expression.

B. VE (Visceral Efferent) Nuclei: Represent the cranial portion of the parasympathetic division of
the autonomic nervous system (preganglionic parasympathetic neurons). Four nuclei are recognized,
but only two are important to remember: the parasympathetic nucleus of the vagus nerve and the
parasympathetic nucleus of the oculomotor nerve.

The parasympathetic nucleus of the vagus innervates cervical, thoracic and abdominal viscera while
the parasympathetic nucleus of III innervates pupillary constrictor muscle and the ciliary body
muscle of the eye:
1. Parasympathetic nucleus of III — damage causes loss of pupillary constriction in response to
light in the eye on the side of the lesion.

2. Parasympathetic nucleus of X — damage results in accelerated heart rate, increased blood

pressure, and disturbances of gastrointestinal activity.

Key Concept: Damage to parasympathetic autonomic nuclei of the brainstem effects

autonomic nervous system control of papillary constriction and cardiovascular function

Key Concept: Lesions or damage to the ventral or medial portions of the brainstem will affect
motor nuclei and thus will cause motor or autonomic dysfunction. Knowing where specific
cranial nerve nuclei are found in the brainstem can be correlated with the results of a
neurological exam and this information is helpful in localizing where clinical lesions occur in
the brainstem.

74
IV. Sensory Afferent Nuclei (Alar Plate derivatives):

A. GSA (General Somatic Afferent) Nuclei: Represented by the sensory trigeminal complex which is
located quite laterally in the brain stem. The complex is composed of the following three major
subdivisions:

1. Nucleus of the spinal trigeminal tract (spinal trigeminal nucleus)—located in the medulla;
associated predominately with pain and temperature sensation from the face and oral cavity; damage to
this nucleus results in loss of pain and temperature sensation from half the face.

2. Pontine nucleus of the trigeminal nerve (principal sensory nucleus)—located in the pons; associated
with touch and pressure sensation from the face and oral cavity; damage result in loss of touch and
pressure sensation from the face.

3. Mesencephalic nucleus of the trigeminal nerve: unipolar neurons located in the midbrain; their
peripheral processes innervate muscle spindles of masticatory muscles and thus they receive
proprioceptive information. Their central processes innervate the motor nucleus of the trigeminal nerve
and they function to help control the force of the animalʼs bite.

B. GVA (General Visceral Afferent) Nucleus: Located lateral to the GVE column and comprised of a
single nucleus termed the nucleus of the solitary tract (nucleus solitarius). The GVA portion of this
nucleus is associated with cranial nerves IX and X. It mediates visceral sensation from the pharnyx,
larynx and portions of the esophagus.

The nuclei of Special Senses:

C. SVA (Special Visceral Afferent) Nuclei:

1. Taste: There is a taste SVA component in the nucleus of the solitary tract. Taste is associated with
cranial nerves VII, IX and X which convey taste from the tongue and pharynx. Lesions or damage to the
nucleus solitarius will disrupt taste sensation.

2. Smell: The olfactory nerve is associated with olfactory SVA sensation. This nerve however is not
foundf in the brainstem; rather, olfaction is conducted directly to the piriform lobe of the telencephalon.
Lesions or damage to the olfactory nerve will interrupt olfaction.

D. SSA (Special Somatic Afferent) Nuclei: These brain stem nuclei relate to the sense of vision (lateral
geniculate nucleus), the sense of hearing (cochlear nuclei) and the ability to maintain balance (vestibular
nuclei).

1. Hearing: The medullary SSA column related to hearing and balance is located dorsally and laterally
in the brain stem and is related to cranial nerve VIII.

2. Vision: The SSA nucleus related to vision is located in the thalamus and is associated with the optic
nerve/tract input. Obviously damage to cranial nerves II or VIII or their associated nuclei will have
profound effects on the animalʼs ability to see or hear, respectively.

75
 Sensory nuclei Motor nuclei

Figure 3: Location of Sensory (left side of each figure) and Motor (right side of each
figure) Cranial Nerve Nuclei in the Brainstem

76
Table Summarizing Cranial Nerves and Their Functions:

Name and Brain Region Function Clinical Symptom

Number Associated (Functional Examination Seen
With Components) After Injury
Olfactory - I Cerebrum Smell (SVA) Owner’s Anosmia
Observations (Loss of
Smell)
Optic - II Diencephalon Vision (SSA) Menace Anopsia
Response (Loss of
Vision)
Oculomotor - Midbrain Eye Movement Horizontal Eye Strabismus:
III (SE, VE) Movement; eye
Pupil- deviated down
lary Light &
Reflex out. Large
Pupil
Trochlear - IV Midbrain Eye Movement Extend head Cat: dorsal
(Dorsal Oblique and aspect
Muscle: SE) look for dorso- of vertical
lateral pupil
strabismus deviated
laterally
Trigeminal - V Pons Masticatory Move- Jaw movement Bilateral
ments, sensation Eye blink reflex damage =
from face (SE, Dropped jaw,
GSA) Asymmetric
chewing,
atrophy
Abducens - VI Medulla Eye Movement Lateral Eye Double vision;
(Lateral Rectus Movement Strabismus:
Muscle; SE) eye
deviated
medially
Facial - VII Medulla Facial Movement; Facial Facial
Taste, rostr. tongue Movement paralysis,
(SE, SVA, VE) drooling
Vestibuloco- Medulla Hearing and Horizontal and Deafness,
chlear Balance (SSA) Vertical Eye Head tilt,
- VIII Movement nystagmus
Glossopharyn- Medulla Tongue and Pharyngeal gag Choking,
geal Pharynx (GVA, reflexes Swallowing
- IX VE, SVA) Difficulty
Vagus - X Medulla Pharynx, Larynx, Gag reflexes, Hoarseness,
Heart, Viscera Blood Pressure, Inspiratory
(SE, VE, GVA, ...) Heart Rate dyspnea
Spinal Medulla Trapezius, + three. Neck movement Weakened
Accessory neck mm. (SE) turning of neck
- XI
Hypoglossal - Medulla Tongue Muscles Tongue Deviation of
XII (SE) movement Tongue toward
Side of lesion

77
Figure 4: Diagram showing cranial nerves I-VIII and the target
tissues that they innervate.

Figure 5. Position of
the eyes in a normal
cat and appearance of
the eyes in cats with a
lesion of cranial nerve
3, 4 or 6.

78
Lecture 10

Vestibular System
Objectives:
• describe the anatomy of the inner ear (labyrinth) and components of the vestibular apparatus
• explain how receptor cells are stimulated and signals are conducted in vestibular nerves
• describe connections of vestibular nerves and vestibular nuclei within the CNS
• explain vestibular reflexes and interpret clinical vestibular syndromes, including nystagmus

I. Introduction:
The vestibular system is responsible for maintaining normal position of the eyes and head as
external forces tend to displace the head from its “normal” position. Located within the inner ear,
the vestibular apparatus is the sense organ that detects linear and angular accelerations of the
head and relays this information to brainstem nuclei that elicit appropriate postural and ocular
responses.
Note: Because [force = mass • acceleration ] and because head mass is constant,
detecting head acceleration is equivalent to detecting external force to the head, e.g., the
force exerted by gravity.

II. Inner Ear Anatomy:

The inner ear is called the labyrinth because it consists of channels and chambers hollowed
out within the temporal bone. The labyrinth has osseous and membranous components:

A. Osseous Labyrinth — tubes and chambers in the petrous part temporal bone that contain
perilymph fluid and house the membranous labyrinth. The three osseous components are:
1) Cochlea — a spiral chamber that is related to hearing and will be discussed later
2) Vestibule — a large chamber adjacent to the middle ear
3) Semicircular Canals — three semicircular channels in bone, each semicircular canal
is orthogonal to the other two

Schematic diagram of the osseous labyrinth containing the membranous labyrinth. The
macula relationship (left) and the crista ampullaris relationship (right) are shown.

79
B. Membranous Labyrinth — consists of interconnected tubes and sacs filled with
endolymph, a fluid high in potassium. (Fluid outside the membranous labyrinth is perilymph,
which is low in potassium and high in sodium like typical extracellular fluids.)

The membranous labyrinth, which contains the sense

organ receptor cells, consists of the following
components:
1) Cochlear Duct — related to hearing (will be
discussed later).
2) Utricle — the larger of two sacs located within the
vestibule; contains a macula and otolith membrane.
3) Saccule — the smaller of two sacs located within
the vestibule; contains a macula and otolith
membrane.
4) Three Semicircular Ducts — each duct is located
within one of the semicircular canals. Each duct has
an enlargement called an ampulla which contains a
crista ampullaris (crest bearing sensory receptor cells)
and a cupula (gelatinous membrane).

III. Vestibular Apparatus:

Vestibular apparatus is a collective term for sensory areas within the membranous labyrinth that
are responsible for detecting linear acceleration (including gravity) and angular acceleration of
the head.
The vestibular apparatus (sense organ) consists of:
1) macula of the utricle — the sensory area (spot) located in the wall of the utricle; it is
horizontally oriented and detects linear acceleration in the horizontal plane (side to side).
2) macula of the saccule — the sensory spot in the wall of the saccule; it detects linear
acceleration in the vertical plane (up and down).
3) crista ampullaris — one per semicircular duct ampulla; each detects angular acceleration
directed along the plane in which the duct is positioned.

Schematic illustration of a macula, including neurons of the vestibular nerve. Two types of receptor
(hair) cells are shown. Each has stereocilia that extend into the overlying otolith membrane.

80
IV. Signal Transduction:
All components of the vestibular apparatus (each
macula & crista ampullaris) have the same kind of
sensory epithelium, composed of supporting cells and
receptor cells (hair cells). From the apical surface of
each hair cell, stereocilia protrude into an overlying
membrane.
Movement of the overlying membrane results in
deflection of stereocilia. Deflection toward the
kinocilium mechanically opens ion channels. This
allows potassium ions to flow from the endolymph
into the hair cell, thus depolarizing the receptor cell
membrane.
The depolarization (receptor potential) of the
receptor cell enables Ca++ influx and release of
glutamate from synaptic vesicles which are located
along the basolateral region of the receptor cell. The
gluatamate neurotransmitter triggers action potentials
in afferent axons of the vestibular nerve.
Deflection away from the kinocilium closes ion
channels and ultimately reduces glutamate release.

A. Crista Ampullaris:
Stereocilia are embedded in a gelatinous membrane called a cupula, which is moved by
fluid inertia when the head rotates in the plane of a semicircular duct. The direction of head
rotation is signaled to the brain by the relative amounts of activity from the three semicircular
ducts.

B. Macula:
Stereocilia are embedded in a gelatinous otolith membrane, so called because it contains
calcium concretions (“ear stones”). Being denser than surrounding endolymph, the otolith
membrane has more inertia than the endolymph fluid and it lags during linear acceleration or
deceleration of the head.

C. Additional comments:
1) Receptor cells are spontaneously active and vestibular nerve axons continually conduct
action potentials to the brainstem. Thus, movement of sterocilia results in an increase or
decrease in the rate of spontaneous activity.
2) Vestibular organs of each side are mirror images, a shift toward the kinocilia on one side
results in a shift away from the kinocilia on the other side. Thus, spontaneous activity, which is
bilaterally balanced under normal postural conditions, is quickly imbalanced during head
acceleration.

81
V. CNS Connections:
Vestibular nerve fibers (axons from neuron cell bodies of the vestibular ganglion) travel
from the inner ear to the brain. They synapse in vestibular nuclei of the brainstem and in the
nodulus or flocculus of the cerebellum.

A. Vestibular nuclei:
Four vestibular nuclei are located bilaterally in the medulla oblongata and pons. The
nuclei receive input from the vestibular nerve and project to:
1) cerebellum (flocculo-nodular lobe)
2) reticular formation
3) spinal cord via the lateral vestibulospinal tract
(which activates limb extensor muscles via alpha and gamma neurons)
4) neurons controlling eye (3, 4, and 6 cranial nerves) and neck (cervical spinal cord)
muscles via the medial longitudinal fasciculus (also called medial vestibulospinal tract in the
ventral funiculus of the cervical spinal cord).

82
VI. Vestibular Reflexes:

A. Effects on Eyes:
The eyes are shifted in a direction opposite to the direction that the head is accelerated, in
order to maintain a stable visual field.
For example, head rotation to the right produces increased AP frequency in the right
vestibular nerve and decreased frequency in the left. Vestibular nuclei on the right side dominate
activity in the left abducens nucleus & right oculomotor nucleus, causing both eyes to move left.
In general, vestibular nuclei push the eyes contralaterally. When nuclear activity is
balanced on each side the push is balanced and eyes are not shifted.

B. Effects on Neck and Limbs:

Analogous to eye control, the head is maintained in a normal posture by means of
vestibular reflex control of neck muscles.
Vestibular nuclei influence extensor muscles in the limbs; extensor muscles are
contracted on the side toward which the head is accelerating (to preclude falling).

Note: Neck reflexes, which adjust body posture so it is aligned with head position, are available
to counteract vestibular reflexes. These reflexes are triggered by cervical proprioceptors. Neck
reflexes are most obvious when the forebrain is removed (decerebrate animal).

C. Clinical considerations:
Lesions affecting the middle ear, vestibular apparatus, vestibular nerve, or vestibular nuclei are
common. Such lesions produce imbalanced neural activity which leads to a vestibular syndrome.

1. Vestibular syndrome:
• head tilt — the lesion is typically located on the “down ear” side
• stumbling, falling, rolling — direction is toward the lesion side
• nystagmus (oscillatory eye movement which are abnormal when the animal is not rotating)
— slow phase of nystagmus is directed toward the side of the lesion

Note: You should be capable of diagnosing which side has the destructive lesion. The
normal (undamaged) side is more active than the lesioned (damaged) side. This
imbalance causes reflexes to be expressed as if there were an “acceleration” toward
the normal side, but there is no acceleration so the animal is thrown off balance.

2. Nystagmus = eyes continuously shift: slowly to one side, then quickly back to center.
• vestibular nystagmus — is generated reflexly by vestibular nuclei in response to
angular acceleration;
• opticokinetic nystagmus — is generated by cerebral cortex when focusing on moving
objects, e.g., train passenger focussing on telephone poles.

83
Lecture 11

Cochlea and Auditory Pathways

Objectives:
• the organization of the middle ear, the cochlea and the spiral organ
• the mechanism of transduction of sound waves to neural activity and the encoding of sound pitch,
volume and direction
• the anatomy of the auditory pathway and main functions of selected nuclei

I. Anatomy of the ear

A. External ear:
The external auditory meatus (canal) is formed by auricular and annular cartilages, plus a short contribution from the
temporal bone.

B. Middle ear:
1. Structure
Air-filled tympanic cavity (including a ventrally expanded bulla) that features:
- four openings (three sealed by membranes):
• auditory tube opening (not sealed) connects middle ear to the nasopharynx;
• tympanic membrane (ear drum) separates tympanic cavity from external auditory meatus;
• oval (vestibular) window separates the tympanic cavity from perilymph in the vestibule;
• round (cochlear) window separates tympanic cavity from perilymph in the scala tympani;
- three ossicles, malleus, incus, and stapes, transmit tympanic membrane movements to
the membrane of the oval window;
- two muscles reflexly dampen ossicle movement, to suppress forceful low frequencies:
• stapedius muscle, innervated by facial nerve, pulls the stapes away from oval window;
• tensor tympani muscle, innervated by trigeminal nerve, pulls malleus thus tensing the tympanic membrane.

84
2. Function
The middle ear increases the efficiency of sound transmission. Pressure oscillations
in air (sound waves) are very inefficiently converted to pressure waves in fluid (only 0.1%
of the force is normally transmitted.) Middle ear components convert large amplitude, low force
input into low amplitude, high force output (the middle ear matches low impedance input
to high impedance output). The tympanic membrane occupies a large area and undergoes
a large excursion, offering low resistance to being vibrated (by air pressure waves). The
membrane of the oval window has a small area and makes small excursions against high
resistance load (it must push against incompressible perilymph fluid and the round
window. The ossicles form a lever system that collects energy from the large tympanic
membrane and focuses it on the small oval window membrane (yielding a 60-fold force gain).

C. Inner ear:
1. Cochlea and cochlear duct
The inner ear consists of the cochlea and vestibular
apparatus. The cochlea is a component of osseous
labyrinth that contains perilymph and the cochlear
duct. The cochlear duct is a component of membranous
labyrinth and contains endolymph.
The cochlea makes 3.25 turns in the dog (2.5 in man) around
a core of bone (called the modiolus) through which the cochlear
nerve passes. The entire complex resembles a snail’s shell
(whence the term cochlea is derived).

Within the cochlea, the cochlear duct (scala media) separates two perilymph chambers: the
scala vestibuli, which contacts the oval window membrane, and the scala tympani, which
contacts the round window
membrane. Perilymph can flow from one
scala to the other through an opening
(helicotrema) at the apex of the cochlea.
The helicotrema is non-functional with
respect to the physiology of hearing, it
merely precludes perilymph stagnation.

The cochlear duct (scala media)

is triangular in cross-section. A thin
vestibular membrane separates
cochlear duct from scala vestibuli,
presenting an ionic barrier between
perilymph & endolymph. Vestibular
membrane can be ignored in regard
to the mechanics of hearing.

An osseous spiral lamina and

basilar membrane separate cochlear
duct from the scala tympani. The
basilar membrane is critical in the physiology of hearing. It consists of radial fibers that extend
outward from the osseous spiral lamina. The fibers are shortest and stiffest at the base of the
cochlea and they are longest at the apex. (Conversely, the osseous spiral lamina, a spiral ledge that projects
outward from the modiolus, is longest at the base and shortest at the apex of the cochlea.)

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2. Spiral organ
Within the cochlear duct, a spiral organ (organ of Corti) sits atop the basilar membrane
along its entire length from the base to the apex of the cochlea. The spiral organ features
receptor cells (hair cells) arranged along one inner row and three outer rows. Each hair cell has
dozens of stereo-cilia on its free surface. Hair cells are held in place by a reticular membrane
(plate) anchored to the basilar membrane. Stereo-cilia project above the reticular plate, making
contact with a tectorial membrane. The tectorial membrane arises from the limbus, a tissue
mass set solidly on the osseous spiral lamina.

3. Cochlear nerve
Afferent neurons of the cochlear nerve have bipolar cell bodies located in a spiral
ganglion, within the modiolus. From the spiral ganglion, axons traverse the osseous spiral
lamina. More than 90% of the axons synapse on inner hair cells. Less than 10% of the axons synapse
on outer cells, which have mostly a mechanical function adjusting the position of the tectorial membrane via cellular
elongation.
Centrally, axons leave the spiral ganglion and pass through the center of the modiolus to
form the cochlear division of the vestibular-cochlear nerve. In the brain, axons synapse in dorsal
and ventral cochlear nuclei.
The cochlear nerve also contains inhibitory efferent axons (from dorsal nucleus of the
trapezoid body) that synapse on dendritic endings of afferent neurons and on outer hair cells. Via
efferent axons, the brain selectively “tunes” ear sensitivity (attention) to different ranges of
sound pitch.
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 II.
Mechanics of Hearing
A. Transduction of sound (pressure) waves to neural activity
1. Pressure waves are transmitted to the cochlea and displace the basilar membrane.
Hearing begins with pressure waves impacting the tympanic membrane, causing it to vibrate.
The vibration is transmitted from malleus to incus to stapes. The stapes rocks in & out, causing
the membrane of the oval window to produce pressure waves within perilymph of the scala
vestibuli. Pressure is transmitted without lost to endolymph in the cochlear duct (the vestibular
membrane offers no resistance to fluid pressure). The pressure wave displaces the basilar
membrane, transmitting pressure to the scala tympani and displacing the membrane of the round
window. Note: A common cause of deafness with advanced age is localized bone deposition that impedes the
rocking action of the stapes. This is called conduction deafness and it can be treated by a hearing aid that amplifies
sound or imparts vibration to perilymph through temporal bone contact.
2. Movement of the basilar membrane leads to signal transduction in hair cells.
Movement of the basilar membrane imparts a rocking action, proportional to degree of
displacement, to the spiral organ, which rests upon the membrane. Cilia, in contact with the
stationary tectorial membrane, are displaced relative to the moving hair cells. The tectorial
membrane doesn’t rock because it is attached to the limbus, which sits on bone (osseous spiral
lamina).
Cilia displacement (in one direction) opens K+ channels leading to depolarization of hair cells,
release of glutamate neurotransmitter, depolarization of dendrites that synapse on the hair cells,
and increased frequency of action potentials in the cochlear nerve. Cilia displacement in the
other direction results in hyperpolarization and decreased frequency of action potentials.
Thus, cilia displacement modulates an on-going K++ current from the endolymph through the
hair cell to the perilymph. Hair cell excitability modulates actions potentials in the cochlear
nerve. The high K+ concentration of the endolymph is maintained by dedicated ion pumping
cells in the stria vascularis.

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 B. Properties of sound
Pressure waves of air (20 to 20,000 Hz in man; up to 40,000 Hz in the dog &100,000 Hz in the bat)
can be interpreted as sound. Sound has subjective properties – pitch, volume and direction
- that correspond to parameters of physics. Sound also has “color”— higher frequencies impart
overtones which enable one to distinguish different instruments playing the same note at the same volume.
1. Wave frequency or pitch (measued in cycles/sec, Hertz=Hz)
As a pressure wave travels from the base to the apex of the cochlea, displacement to the
basilar membrane is greatest where the membrane is resonant to the frequency of the traveling
wave. High frequency traveling waves cause displacement at the base of the cochlear and low
frequency waves travel to the apex of the cochlea. As the pitch or frequency (Hz) of a sound
increases, the peak amplitude of basilar membrane displacement regresses, from the apex
(longest fibers) toward the base (shortest fibers) of the cochlea. The location of peak amplitude of
basilar membrane displacement corresponds to maximal activity of the corresponding hair cells
and cochlear nerve fibers (relative to other hair cells in the spiral organ). The brain deciphers
pitch by determining which fibers of the cochlear nerve (which hair cells of the spiral organ;
what place along the basilar membrane) are maximally active (for > 200 Hz). The basilar
membrane contains a tonotopic map, which is maintained in the CNS. Place principle: pitch is
determined by the place of maximal amplitude displacement along the basilar membrane.

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2. Volume (amplitude from the low point to the high point in a pressure wave)
For a given pitch, the brain interprets volume as a function of the number of axons firing
and the frequency of their action potentials. Increased volume (amplitude) will result in greater
excursion of the basilar membrane, greater displacement of cilia, greater depolarization of
receptor cells, and higher frequencies of action potentials in more cochlear nerve axons
(whatever the pitch pattern of basilar membrane displacement).
3. Direction (location of the source of the sound waves).
For sounds of low frequency (pitch), the brain uses the phase difference (time-lag)
between inputs to right and left ears to determine which ear is closer to the source of the sound;
at high frequencies, the head acts as a barrier resulting in an intensity difference between the near
and far ear. (Also, the pinna may modify sound coming from different directions, and the animal
can move its ears and head to assist in sound localization.)

III. Auditory Pathway

A. Overview
1. Basic organizational principles
Bilateral projections
Tonotopic mapping
Parallel processing of different sound attributes
2. Summary of auditory pathways

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 Cochlear nerve fibers synapse in dorsal and ventral cochlear nuclei, typically each fiber
synapses in both nuclei. The cochlear nuclei contain second-order neurons. Thereafter, the
auditory pathway is bilateral and complex because of many synaptic possibilities.
Fibers from the cochlear nuclei project to
dorsal nucleus (and ventral nuclei) of the trapezoid body (the trapezoid body contains
decussating fibers from the cochlear nuclei)
caudal colliculus
nuclei of the lateral lemniscus
The lateral lemniscus is a tract that carries fibers from the cochlear nuclei and the dorsal
nucleus of the trapezoid body (and nuclei of the lateral lemniscus) to the caudal colliculus. Fibers
from the caudal colliculus project to the medial geniculate nucleus via the brachium of the
caudal colliculus. Neurons in the medial geniculate nucleus send their axons through the
internal capsule to cerebral cortex surrounding the sylvian sulcus (primary auditory cortex).

B. Main CNS nuclei in the auditory pathway

1. Cochlear nuclei (dorsal and ventral) — receive input from the ipsilateral cochlear nerve.
Second-order neurons, tonotopically organized within the nucleus, are the source of all central
auditory pathways. Like the cochlear nerve and the rest of the auditory pathways, second order
neurons exhibit continuous background firing that is increased/decreased by sound driven
excursions of the basilar membrane and spiral organ. Lesions of cochlear nuclei (or cochlear
nerve or a cochlea) produce unilateral deafness; lesions central to the cochlear nuclei affect
both ears (because central pathways are bilateral).

2. Dorsal nucleus of trapezoid body — each nucleus receives input from right and left ears (via
cochlear nuclei). The nucleus functions in sound localization, i.e., detecting phase and intensity
differences between the two ears. (Different neurons respond to the different time lags between
the two ears. Other neurons respond to different intensity differences between the two ears.)
The nucleus sends output to cranial nerves V and VII for reflex contraction of tensor tympani
and stapedius muscles to dampen loud sound.
The nucleus is the source of efferent axons which selectively “tune” the spiral organ for
frequency discrimination (e.g., listening to the play of one instrument within an orchestra).
(Efferent innervation affects the length of outer hair cells which changes the position of the
tectorial membrane which adjusts the sensitivity of inner hair cells.)

3. Caudal colliculus — receives input via the lateral lemniscus. The colliculus contains neurons that
are sensitive to phase and intensity differences between the ears. Also, caudal colliculus neurons that project to the
medial geniculate are part of a conscious auditory pathway.
Via tectospinal/tectobulbar tracts, output from the caudal colliculus produces reflex turning
of the head, ears and eyes toward a sudden sound stimulus. (Collateral branches of auditory pathway
axons go to the reticular formation to alert the whole brain to a loud sound stimulation.)

4. Medial geniculate — receives input via the brachium of the caudal colliculus. Imprecise
sound consciousness takes place at the medial geniculate level. Geniculate neurons project their
axons through the internal capsule to the primary auditory cortex. (Note: The geniculate body
functions for sound like the thalamus functions for tactile sense.)

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5. Primary Auditory Cortex — located
around the sylvian sulcus, this cortex is
necessary for recognizing temporal patterns
of sound and direction of pitch change, i.e.,
elements of melody, speech, etc. The cortex
has separate tonotopic maps for detecting
pitch and direction (pitch and direction
information is relayed to the cortex by
separate pathways).

6. Auditory association cortex surrounds

the primary auditory cortex from which it receives input. The association cortex is required to
extract meanings of sound patterns and associate learned significance with a particular sound
pattern.

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Lecture 11
Visual System
Objectives:
Become familiar with the anatomy of conscious and reflex visual pathways.
Become familiar with the histological organization of the retina.
Understand how visual stimuli are processed in the retina and the CNS.

I. Retina
A. Eyeball —
composed of three concentric
layers:
1. Outer, fibrous layer:
Sclera - white
Cornea - transparent
2. Middle, vascular layer (uvea):
Iris
Ciliary body
Choroid; contains a tapetum lucidum in
most domestic animals (absent in pig).
3. Retina = inner layer of the eyeball.
The pigmented epithelium of the retina lines the iris, ciliary body & choroid.
The functional optic part of retina lines the fundus to the level of the ora serrata.
Consists of 10 histological layers (see below), including retinal ganglion cells, which give
rise to the optic nerve.
4. Clinical relevance:
Blood occular barrier: formed by the retinal pirmented epithelium and the endothelium of
retinal capillaries, which lie within the nerve fiber layer of the retina (see below). Breakdown of
the barriers leads to uveitis.
Fundus: interior part of the eye consisting of retina, choroid and optic disk; can be
observed with an ophthalmoscope
- appearance of optic disk
- appearance of vasculature
- reflectivity of tapetum lucidum
- retina attachment

B. Histology of the retina

1. Embryonic development
The retina develops from the optic cup of the
diencephalon, and the optic nerve is histologically a
CNS tract. The optical part of the retina develops
from the inner wall of the optic cup. The outer wall becomes the pigmented epithelial layer.

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2. Histological organization
Ten histological layers are
recognized in the optic part of
the retina:
1 - pigmented epithelium
2 - rods and cones
3 - external limiting
membrane
4 - outer nuclear layer
5 - outer plexiform layer
6 - inner nuclear layer
7 - inner plexiform layer
8 - ganglion cell layer
9 - optic nerve fibers
10 - internal limiting
membrane
Light must penetrate eight of
the layers to reach outer
segments of rods and cones
where photons are absorbed.
Processes of pigmented
epithelial cells surround the
outer segments of rods and
cones.
Pigmented epithelial cells are a
source of Vitamin A that rods and
cones convert to retinal, the photon absorbing molecule.

Nonmyelinated axons of ganglion cells run to the optic disk and then exit the eyeball as
myelinated axons that comprise the optic nerve. Photoreceptor cells are absent at the optic disc
(blind spot). Retinal vessels enter at the disc and course along the retinal surface.
The area centralis (visual streak) of the retina has highest visual acuity.
3. Cell types in the retina
Photoreceptors transduce light energy to neural electrical activity. They are excited
(depolarized) in the dark and inhibited (hyperpolarized) by light.
Bipolar cells receive input from photoreceptors and synapse on ganglion cells (as well as some
amacrine cells). Bipolar cells are depolarized (ON) or hyperpolarized (OFF) in response to light.
Glutamate released from photoreceptors in the dark depolarizes OFF-bipolars by activation of
excitatory channels and hyperpolarizes ON-bipolars by activation of inhibitory G-protein coupled
receptors. In the light, glutamate release from photoreceptors is reduced, which has the dual effect of
decreasing the inhibition of ON-bipolars and the excitation of OFF-bipolars.

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Ganglion cells: Their axons leave the retina
and form the optic nerve. Unlike all other
retinal cells, ganglion cells generate action
potentials. Their rate of firing is increased or
decreased by visual stimuli.
Horizontal cells are always inhibitory. They
have complex interactions with photoreceptors
and modulate the activity of bipolar cells
indirectly. They are primarily responsible for
lateral inhibition (inhibition of cells as a result
of activity in a neighboring cell).
Amacrine cells are often inhibitory neurons
that make synaptic contact with bipolar &
ganglion cells. Some respond to the onset/offset
of light, others are responsive to direction of light
movement. The optic nerve contains efferent axons,
which synapse on amacrine cells to provide brain
control of retinal activity. There are 30 different
populations of amacrine cells with respect to
morphology and neurotransmitters released.
Radial glial cells (Mueller cells): modified
astrocytes which provide structural and
metabolic support. Like astrocytes they take up
excess ions and neurotransmitter molecules to
maintain homeostasis. Processes of these cells
form the internal and external limiting
membranes.

C. Transduction of visual signals by photoreceptors

There are two populations of photoreceptors: rods & cones. The outer segments of rods & cones
contain stacked membranous discs that are continually produced, sloughed, and phagocytized by
pigmented epithelium. The discs contain the photosensitive molecule rhodopsin (retinal +
protein) that intercepts photons.
Photoreceptor cells are excited (depolarized) in the dark and inhibited (hyperpolarized) by
light (photons). They do not generate action potentials. They respond to visual stimuli with
graded depolarization (excitation) and hyperpolarization (inhibition), which results in
proportional release of glutamate neurotransmitter. Rods form convergent circuits with bipolar
cells, which improves vision in dim light but at the expense of image resolution. Cones form
form relay circuits with bipolar cells, which provides good visual detail but requires bright light.

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 RODS
• 95% of photoreceptor cells (human retina)
• widely disributed throughtout the retina
• single population all containing rhodopsin
(protein + retinal); no color sensitivity
• functional in dim light, response saturates
in daylight
• participate in highly convergent circuits
(>1,000 rods converge on one ganglion
cell); low spatial resolution
• high senstivity — can respond to a single
photon
CONES
• 5% of photoreceptor cells (human retina)
• concentrated in Area Centralis
• multiple populations, based on different
wavelength (color) sensitivities, due to
protein differences (protein + retinal)
• operate under bright light conditions
• participate in relay circuits (few cones per
ganglion cell); high spatial resolution
• lower senstivity — need hundreds of
photons for a response

Rods Cones

Numbers

Location

Color
sensitivity
Functional in

Circuits

Sensitivity

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D. Processing of visual stimuli
Processing of visual stimuli in the retina (and in the visual system in general) is organized
in a way that optimizes the detection of contrast. The pattern of contrast in the visual scene is
the type of visual information most useful to the animal. For example, contrast at the edges of an
object defines its shape and motion involves both spatial and temporal contrast.
1. Vertical and lateral pathways in the retina
Cells in the vertical pathways (photoreceptors  bipolar cells  ganglion cells) are
specialized to detect changes in contrast. Bipolar and ganglion cells that specialize in detecting
increases in brightness/illumination (e.g. a bright object on a dark background) are termed “ON”
cells. Bipolar and ganglion cells that specialize in detecting decreases in brightness/illumination
(e.g. a dark object on a bright background) are termed “OFF” cells.

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Cells in the lateral pathways (horizontal and amacrine cells) contribute to contrast enhancement.
2. The detection of contrast is based on the organization of receptive fields.
The receptive field is the region of the retina that must be illuminated in order to obtain a
response in a visual neuron.
Receptive fields of retinal ganglion cells are round and have a center and a surround with
antagonistic properties. Responses in the
center are mediated by vertical pathways.
Responses in the surround are based on
lateral inhibition mediated by lateral
pathways. The receptive fields of ganglion
cells are overlapping so that every point of
the retinal surface is analyzed by several on-
center and off-center ganglion cells. Center-
surround receptive fields are first established
at the level of bipolar cells and persist at the
CNS levels of visual processing (i.e., lateral
geniculate nucleus and visual cortex).

3. Responses of ON-center and OFF-center ganglion cells

- On-center ganglion cells increase their rate of firing when the center is illuminated and decrease it when the
surround is illuminated.
- Off-center cells decrease their fire when the center is illuminated and increase it when the surround is
illuminated.
- The firing rate of a ganglion cell is a measure of the contrast between the illumination of the center and the
surround.

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4. Principles of visual processing
- Parallel processing
The visual system uses parallel pathways to process information about different features of the
visual scene (e.g. form, motion, color). These parallel pathways originate in the retina from
functionally distinct classes of ganglion cells. Ninety percent of the primate ganglion cells fall
into two functional classes designated as M (magni, large) and P (parvi, small): M cells have
larger receptive fields and signal motion, position, and depth; P cells have small receptive fields
and provide information about fine detail and color. The parallel pathways remain separate from
retina to cortex. The lateral geniculate nucleus is stratified, with input from each eye and P/M ganglion cell input
entering different layers.
- Retinotopic mapping in lateral geniculate nucleus and primary visual cortex (lost at
level of association cortex). In the primary visual cortex representation of the area centralis is
greatly enlarged compared to cortical surface area devoted to the rest of the retina.
- Hierarchial processing: receptive fields become larger and more complex at each
level.

5. Color Vision
- Humans have three populations of color sensitive cones. We are trichomatic and can
distinguish the range of colors with which you are familiar.
- Color vision in dogs is said to be comparable to people who are red-green color blind.
Dogs are dichromatic and seem to see blue and yellow but not green or orange-red.
- All of several horses tested could distinguish red and blue from gray. Some but not all of
the horses could also distinguish yellow and green from gray.
- Two populations of color sensitive cones are found in other species, e.g., cat and pig.
- Nocturnal animals are completely color blind (rat, hampster, etc.).
6. Non-image forming vision
- mediated by intrinsically photosensitive retinal ganglion cells, which contain melanopsin
(peak sensitivity in the blue/green range of the spectrum)
- detect ambient light
- involved in circadian clock

II. Visual pathways

A. Overview
1. Conscious pathway: retina lateral geniculate  cortex
2. Reflex pathways
retina rostral colliculus (eye, ear and head turning to orient to a visual stimulus)
retina pretectal region (pupil size regulation to compensate for light intensity)

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 B. Optic nerve, optic chiasm and optic tract
1. Optic nerve: axons from retinal ganglion cells (human - 1.5 million; dog - 0.2 million)
2. Optic chiasm: decussation of optic nerve axons; depending on species, percentage of axons
from the lateral side of each retina do not cross
— in submammalian vertebrates, e.g., fish, 100% of optic fibers cross in the chiasm
— in domestic animals: horse 90%; sheep 88%; pig 72%; dog 75%; cat 63% cross
— in human: 50% of optic nerve fibers cross in the optic chiasma.
(NOTE: % crossing is related to eye position in the head and visual field overlap)
3. Optic tract: axons from both eyes. The optic tract conveys contralateral visual field
information (i.e., axons from the lateral part of the retina of the ipsilateral eye & the medial &
central parts of the retina of the contralateral eye).

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4. Binocular vision: important for depth perception
- requires visual field overlap so that individual objects can be viewed simultaneously by
both eyes
- “corresponding” ganglion cells in each eye send their axons through the same optic tract
- the visual cortex in one cerebral hemisphere receives information about an object from
both eyes. In visual cortex, some columns monitor stimulation in corresponding loci of the two
eyes. The cerebral cortex controls extraocular eye muscles so that corresponding points in each retina
view the same object (otherwise double vision ensues).

C. Conscious visual pathway

Optic tract fibers synapse in the lateral geniculate nucleus. Neurons of the lateral geniculate
nucleus send their axons into the optic radiation of the internal capsule and then to the primary
visual cortex.
The primary visual cortex exhibits the typical columnar organization of neocortex.
Columns respond to the geometric & dynamic elements of an image. A cell column within visual
cortex becomes excited in response to light–dark boundaries oriented at a certain angle, moving
in a certain direction, affecting either or both eyes, etc. Some cell columns are activated by
particular colors.
The association cortex, surrounding the primary visual cortex, is required to associate
meaning and significance to the elements of the primary image. There are two separate visual
integrations:
• A phylogenetically older "where" system that analyzes motion and depth. Damage
produces:
- failed ocular pursuit of a moving target, i.e., inaccurate eye saccades (tiny movements);
- poor depth perception (astereopsis);
- deficient visually guided movements, e.g., reaching (optic ataxia); and
- deficits in visual attention.
• A phylogenetically newer "what" system that analyzes form and color. Damage produces:
- loss of color vision;
- impaired pattern recognition, including face/object recognition (visual agnosia).

D. Reflex visual pathways

Axons participating in subconscious visual reflexes leave the optic tract and travel in the
brachium of the rostral colliculus to reach two visual reflex centers, the rostral colliculus and
the pretectal region. (Axons also leave the optic tract to reach the hypothalamus.)
1. Eye, ear and head turning to orient to a sudden, prominent visual stimulus involves the
rostral colliculus. Neurons of the rostral colliculus send their axons to appropriate motor nuclei
via tectobulbar and tectospinal tracts. (The rostral colliculus is used by visual cortex for subconsious
eye movements.)
In higher mammals, the rostral colliculus depends on input from the cerebral cortex to function and
cortical damage produces apparent total blindness. In birds, the rostral colliculus equivalent (optic lobe)
provides all visual function.

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 2. Pupil size regulation to compensate for light intensity involves the pretectal region, with
fiber decussation in the caudal commissure. Axons go to the parasympathetic nucleus of the
oculomotor nerve for pupillary constriction (dilation is achieved by less constriction).
Pupil dilation in response to emotional situations (fight/flight) involves sympathetic preganglionic
neurons in the cranial thoracic spinal cord. Pupil constriction in response to accommodation for near
vision is controlled by the cerebral cortex.
3. Clinical relevance: the pupillary light reflex is important for diagnosing lesions in the
visual pathways.

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Lecture 13

Posture & Movement

Objectives:
• identify brain structures concerned with posture/movement and their regional locations within the brain
• describe the anatomy and function(s) of, particularly, the reticular formation, red nucleus, and basal nuclei
• explain voluntary movement initiation, including involved forebrain circuits and descending tracts
• imagine the clinical signs produced by lesions at different regions in the brain

I. Introduction:
In veterinary neurology, abnormalities of posture & movement are more important than sensory
disorders because animals readily express motor behavior but hardly at all report their feelings.

Preview: Posture/Movement Hierarchy

Spinal Cord and Cranial Nerve Motor Nuclei
Local reflex—useful response to a stimulus (determined by local interneuron circuits).

Hindbrain
Standing posture—excitation of alpha & gamma motor units of extensor muscles
(driven by spontaneous activity of reticular formation & vestibular neurons).
Equilibrium—maintaining normal position of eyes, head, & body (vestibular system).
Midbrain
Orientation—orienting head/eyes/ears toward abrupt visual/auditory stimuli (tectum).
Specific movements—moving individual joints (via red nucleus and rubrospinal tract).

Forebrain
Inherent movement sequences—species-specific patterns of reaction/posture/movement/gait
(circuits involving basal nuclei, thalamus, & motor areas of cerebral cortex).
Learned movements—including learned movement sequences performed too rapidly
for sensory feedback (involves pattern generator neurons in premotor cortex).

II. Brain Structures Concerned with Posture & Movement:

Hindbrain
A. Reticular Formation
1. Anatomy: network (mixture) of gray & white matter, found throughout the midbrain & hindbrain
— gets synaptic input from collateral branches of ascending tracts (e.g., spinothalamic tract)
2. Physiology: spontaneously active neuronal circuits; perform several major functions, including:
— ascending system to alert cerebral cortex (via non-specific thalamic nuclei) vs. coma
— vegetative centers: regulate heart rate, respiration, digestive tract, micturition, etc.
— standing posture and muscle tone via two pathways to alpha & gamma neurons:
• pontine reticulospinal tract — arises from neurons located laterally in pons & medulla
- dominant and spontaneously active (runs ipsilaterally in the ventral funiculus)
- activates alpha & gamma neurons to extensor muscles of proximal joints
• medullary reticulospinal tract — arises from neurons located medially in medulla
- inhibits neurons to extensor muscles & excites neurons to flexor muscles;
- not spontaneously active, it is driven by cerebral cortex to preset movement posture
- (descends bilaterally in the lateral funiculus)

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B. Vestibular nuclei discussed previously
Two descending tracts:
lateral vestibulospinal tract— which also drives standing posture, &
medial vestibulospinal tract (m.l.f.)— which controls neck muscles.
Note: vestibular nuclei also utilize the two reticulospinal tracts to adjust muscle tone.

Midbrain
C. Red Nucleus
Large neurons of the red nucleus gives rise to the
rubrospinal tract—the principal descending tract for voluntary
movement in domestic animals. Small neurons send axons to cranial
nerve and neck motor nuclei. Other small neurons relay cerebellar traffic to
the thalamus.
The red nucleus is merely a collection of projection neurons.
Axons from the motor area of cerebral cortex synapse on large
projection neurons in the red nucleus and control their activity.
The rubrospinal tract decussates in the midbrain and
descends in the dorsal half of the lateral funiculus. Rubrospinal
fibers synapse on spinal interneurons and produce independent
movements of shoulder/hip and elbow/stifle; carpus/hock (not
digits).

D. Tectum (tectum = roof of the midbrain)

Rostral & caudal colliculi are reflex centers which orient head eyes and ears toward sudden
visual and auditory stimuli, respectively. Sandwiched between visual & somatic sensory layers,
neurons in an intermediate layer of the rostral colliculus gives rise to two tracts:
1. tectospinal fibers — descend to the cervical spinal cord ( for head turning);
2. tectobulbar fibers — to cranial nerve nuclei that control ear & eye movement.
Using horizontal (pons) and vertical (midbrain) gaze centers in the reticular formation, the
tectum rapidly shifts the eyes to focus on novel stimuli (saccadic movement).
Note: saccade = quick eye movement used to shift focus to new visual feature;
visual perception occurs during the stops following saccades.
E. Substantia nigra
The dorsal region (pars compacta) contains dopaminergic neurons that project dopamine neuromodulation
widely in the brain, including basal nuclei to facilitate movement. In primates, the neurons are pigmented and their
degeneration results in Parkinson’s disease, which features decreased movement activity.
The ventral region (pars reticulata) has GABAergic neurons. It functions like the endopeduncular nucleus (see
below) and tonically inhibits brainstem motor nuclei such as those in the tectum.

Note: Dopamine is a neuromodulator produced by midbrain neurons. It is widely distributed in the brain and has
prolonged excitatory or inhibitory effects (via D1 or D2 metabotrophic receptors).

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 Forebrain
F. Subthalamus
Under direction of the cerebral cortex, the subthalamic nucleus participates in basal nuclei circuits that regulate
voluntary movements. The nucleus contains glutamatergic output neurons that excite the endopeduncular nucleus
which tonically suppresses movement activity. Damage to the subthalamus results in hyperkinetic movements such
as hemiballismus. (Physiologically the nucleus generates bursts of neuronal spikes, implying a pacemaker role in
rhythmic movements.)

G. Basal nuclei (Basal Ganglia)

Anatomically, the term "Basal Nuclei" refers to
non-cortical gray matter of the telencephalon. Seven
of the basal nuclei are listed to the right. The nuclei
may be grouped in different ways:
1] Striatum = accumbens, caudate, & putamen;
named for internal capsule gray matter striations.
2] Lentiform nucleus = putamen & globus
pallidus; together they have the shape of a lens.
Physiologically, acccumbens, caudate, putamen,
globus pallidus, and endopeduncular nuclei play a
motor role, participating in circuits that involve the
thalamus and cerebral cortex.

1. Basal nuclei suppress unwanted movements. They regulate the selection, onset and cessation
of “voluntary” movement by participating in thalamocortical circuits involving motor-related
areas of cerebral cortex. The motor cortex executes actual movements via pyramidal or
extrapyramidal descending tracts. (Basal nuclei themselves do not give rise to descending tracts.)
Note: Voluntary movement is initiated by regions of cerebral cortex responsible for emotionally
driven behavior (limbic cortex) or goal driven decisions (association cortex). Initiating areas of
cerebral cortex do not communicate their movement needs directly to the motor-related cortex.
Instead, the initiating cortices communicate via circuits involving basal nuclei and thalamus.
These forebrain circuits are the mechanisms for selection/execution of desired movements and
suppression of unwanted movements.

2. Functionally, there seems to be two categories of voluntary movement circuits: One, involving
the caudate nucleus is active in selecting & assembling movements, particularly during learning.
The other, involving the putamen controls amplitudes & durations of movements, particularly in
the case of habitually performed movements that can be performed with minimal thinking.

3. All projections from basal nuclei are inhibitory. The output basal nuclei (globus pallidus and
endopeduncular nucleus) are tonically active in suppressing movement. The input basal nuclei,
the striate body (accumbens, caudate and putamen), require excitatory input from the cerebral
cortex. To activate desired movements the input nuclei disinhibit the output nuclei!
Particularly in primates, damage to basal nuclei impairs either movement onset (hypokinetic
syndromes) or movement cessation (hyperkinetic syndromes). In domestic mammals, lesions of
the basal nuclei produce circling toward the damaged side, pacing, and muscle hypertonia.

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Notes:
• Basal nuclei (shown above within dark boxes) contain GABAergic neurons that produce
inhibitory output (dark arrows). Output basal nuclei (shown in dashed boxes) contain
spontaneous active inhibitory neurons.
• The role of basal nuclei is to facilitate desired voluntary movements (initiated by the
cerebral cortex) and dampen unwanted movements via participation in thalamocortical circuits
(excitated by cerebellar nuclei).

• Diverse regions of cerebral cortex project to three basal nuclei (accumbens, caudate &
putamen) that collectively constitute input nuclei, the anatomical striatum.
• Via two pathways, the striatum controls spontaneously active output nuclei:
— a direct pathway facilitates desired movements by inhibiting the endopeduncular
nucleus (and substantia nigra reticulata).
— an indirect pathway suppresses unwanted movement, by inhibiting the globus
pallidus which tonically inhibited endopeduncular and subthalamic nuclei.
• The substantia nigra compacta modulates the two striatal pathways, favoring movement
via dopamine release. Dopamine deficiency results in hypokinesia (Parkinson’s disease).
• The cerebral cortex suppresses movements directly via the subthalamic nucleus, which
enhances endopeduncular inhibition. Subthalamic lesions are expressed by hyperkinesia.

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 H. Cerebral cortex (motor-related areas)
The motor area of the cerebral cortex executes practiced voluntary movements. The other motor-
related areas of cortex are involved in planning/learning/selecting voluntary movements:
1. motor area — located around the cruciate sulcus. It is the main source of two descending
pathway systems: a direct pyramidal & an indirect extrapyramidal (see below).
Each output neuron from the motor cortex innervates multiple motor nuclei.
The cerebral cortex is organized to control movements not muscles.
2. premotor area — collection of cortical regions that project to the motor area. Involved in
assembling complex movements and generating learned, rapid-sequence
movements (pattern generator circuits).
3. supplementary motor area — the entire body is represented in this specialized premotor cortex
located medially. It is active when thinking about proposed movements.

III. Voluntary Movement:

Voluntary movements originate in the forebrain from circuits involving basal nuclei, thalamus,
and motor areas of the cerebral cortex. The forebrain circuits select and execute movements
decided by association cortex in response to stimuli and emotional drive.

Voluntary Movement Process

External Cue / Internal Urge —> Decision —> Selection (what) —> Execution (how)
[sensory cortex / limbic system] [association neocortex] [premotor & caudate] [motor area & putamen]
[limbic & accumbens]

A. Descending pathways for voluntary movement

Descending pathways for voluntary movement fall into two categories:
1] Pyramidal tract = a direct connection from motor & premotor areas of cerebral cortex to
motor unit efferent neurons, generally via local interneurons (a minority of pyramidal tract axons
synapse directly on motor neurons in primates and raccoons). Axons travel in the pyramids of the medulla
oblongata.

106
 The pyramidal tract controls particularly musculature of the manus and pes; it is especially
concerned with precise movements of individual digits (also lips and tongue).
Most pyramidal tract axons (85% in human) decussate at the medullary-spinal junction and
form the lateral corticospinal tract which terminates in lateral motor nuclei of ventral horn
enlargements (limb muscles). Remaining axons form the ventral corticospinal tract which crosses
at the level of termination in the spinal cord and innervates medial motor nuclei (postural muscles).
Note: Some corticospinal axons come from sensory areas of the cortex and affect projection neurons of
ascending pathways. This enables the cerebral cortex to modify sensory traffic on its way to the thalamus and
cortex.

2] Extrapyramidal tracts = the term applied non-pyramidal voluntary movement tracts.

Under the direction of cerebral cortex (motor areas), these tracts control trunk and proximal limb
musculature (vs. manus/pes), generating coarse components of posture/movement/locomotion.
Naturally, this system is most important in domestic animals. The principal extrapyramidal tracts
are:
rubrospinal tract, pontine reticulospinal tract, and medullary reticulospinal tract.

Note: Voluntary movements engage multiple descending tracts. A specific voluntary movement
(e.g., a feline paw swipe) would involve rubrospinal and pyramidal tracts and require associated
postural adjustments involving reticulospinal tracts.

IV Veterinary Clinical Considerations:

A. Upper Motor Neuron Damage: (in order of mild to severe deficits)
Loss of only pyramidal tract: paresis (partial paralysis or weakness) of manus & pes; inability to move
digits and lips independently & rapidly; deficient tactile placing (also evident by not clearing curbs & steps); clinical
hopping deficits.
Loss of motor cortex: disappearance of learned movement skills; spastic paralysis (absence of voluntary
movement capability, plus hypertonic limb extension due to release of pontine reticular formation suppression).
Loss of whole forebrain (= midbrain animal): persistent standing posture but may exhibit phasic actions
(sitting, stepping, etc.) if prodded to do so; capable of righting reactions to restore standing posture.
Loss of forebrain & midbrain (= hindbrain animal): limbs rigidly extended constantly in a "saw-horse"
attitude (decerebrate rigidity); no locomotion or righting capability; tonic neck reflexes present (postural adjustments
initiated by neck proprioceptors).
Loss of whole brain (= spinal animal): temporary areflexia may be evident with abrupt injury (spinal
shock); paralysis without spasticity; local spinal reflexes intact; crossed extension accompanies the withdrawal
reflex.

B. Lower Motor Neuron Damage:

Spinal cord or peripheral nerve damage: paralysis and areflexia (flaccid paralysis); severe
atrophy (denervation atrophy) of skeletal muscles over weeks.

107
108
Comments:
• Posture and movement are produced by excited alpha and gamma motor neurons. A motor unit is
one alpha motor neuron plus all of the muscle fibers that it innervates.
• Interneurons "hardwire" motor neurons so that logical movement patterns are produced (e.g.,
exciting synergists & inhibiting antagonists). Nearly all descending pathway axons synapse on
interneurons. Only a small minority of descending axons synapse directly on motor neurons (e.g., some
vestibulospinal axons; also, in primates and raccoons, a minority of pyramidal tract axons synapse
directly on motor neurons that innervate digits.
• Thus both voluntary and reflex pathways compete for control of the same interneurons and motor
units. To gain control of motor units, voluntary neurons must suppress reflex activity, and vice versa.
• While movement is underway, feedback from proprioceptors influences ongoing neuronal activity
in motor centers to effect desired movement goals. The cerebellum continuously modulates neuronal
activity in motor centers, based on information it receives from the motor centers and proprioceptive
feedback about body position & acceleration.

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Lecture 14

Cerebral Hemisphere and Cortex

Objectives:
• list the white and gray matter components of the cerebral hemispheres
• describe the histology of the cerebral neocortex, including horizontal layers and vertical cell columns
• locate functional areas of neocortex (motor, sensory & association) and explain their roles
• understand the several methods of elucidating cortical function

I. Cerebral Hemisphere:
Right & left cerebral hemispheres are derived from the embryonic telencephalon. Each
hemisphere is composed of gray and white matter.
A. Gray Matter:
1. Cerebral Cortex — coating of gray matter on the surface of the cerebral hemisphere.
Three phylogenetic categories of cerebral cortex are:
• archicortex — (hippocampus) oldest, composed of three layers
• paleocortex — (piriform lobe) old, three layers, olfaction related
• neocortex — new, six layers, detailed perception, learning, intelligence
2. Basal Nuclei — gray matter nuclei located deep within the white matter of the cerebral
hemisphere. Basal nuclei (basal ganglia) include: accumbens nucleus, caudate nucleus, putamen,
globus pallidus (pallidum), & amygdala.

B. White Matter:
Consists of myelinated axons that connect cerebral cortex with other brain regions. Three
categories of white matter fibers are recognized:
1. Projection Fibers — join the internal capsule. There are two categories of projection
fibers, relative to cerebral cortex:
• corticofugal: exit to terminate in basal nuclei, brainstem, or spinal cord;
• corticopedal: typically originate in thalamus & terminate in cerebral cortex.
2. Commissural Fibers—fibers that connect cortices of right and left cerebral
hemispheres. The largest bundle, the corpus callosum, connects neocortex
3. Association Fibers—fibers that connect regions of the cerebral cortex within one
hemisphere. Two categories are recognized:
• short association fibers connect adjacent gyri;
• long association fibers connect distant gyri (different lobes);

Note: The ventromedial portion of each cerebral hemisphere is designated rhinencephalon

(nose brain) because of its association with olfaction, the most primitive sensory
modality. Rhinencephalon is also involved in emotionally driven behavior, the most
primitive type of behavior. The rhinencephalon contains archicortex and paleocortex.

II. Cerebral Cortical (Neocortex):

Neocortex, the phylogenetically most recent cortex, is only found in mammals. Neocortex
specializes in: detailed sensory perception; higher cognitive interpretation; rapid fine
movements; learning; and goal oriented intelligence. It forms about 85% of the dog cerebral
cortex (the remaining 15% being archicortex and paleocortex).

110
A. Neocortical Cells and Afferent Fibers
Two neuron types predominate in the neocortex:
pyramidal cell — conical cell body with apical and basal dendrites and an axon that
leaves the base of the cell to enter white matter. Pyramidal cells vary in size. They are the output
cells of the cerebral cortex.
granule cell — small, round cell body. Serves as an interneuron, receiving input from
cortical afferent axons and synapsing on pyramidal output neurons.
Two types of afferent projection fibers from the thalamus enter the neocortex:
specific afferents — modality specific input; terminate in the inner granule cell layer
non-specific afferents — background excitation; terminate in the molecular layer.

Six layers of cerebral cortex as seen with three stains used to show different histologic features
(axons; cell bodies; whole neurons). The six layers are numbered at the left and named at the
right. P = pyramidal cell; S = granule (stellate) cell.

111
B. Horizontal Layers of Cerebral Cortical
The cerebral neocortex is organized into six horizontal layers (although layer boundaries are not
very obvious in routine sections). The individual layers have different roles and they vary in
relative thickness among cortical regions (e.g., sensory regions have a thick internal granule
layer; the motor area has a thick internal pyramidal cell layer).
From superficial to deep, the six layers are:
1] Molecular layer — predominantly fibers: apical dendrites & non-specific afferents;
2] Outer granule cell layer — interneurons for non-specific afferent input;
3] Outer pyramidal cell layer — small and medium cells; short association fiber output
4] Inner granule cell layer — interneurons for specific afferent input
5] Inner pyramidal layer — large cells; corticofugal projection & long association fiber output
6] Multiform layer — variably shaped cells that project to the thalamus

C. Cortical Column (Vertical) Organization of Cerebral Cortical

The entire cerebral cortex is organized into functional units consisting of cortical columns (about
0.4 mm diameter) that extend the entire thickness of the cortex (including all six layers). Each vertical
column constitutes a functional unit because all cells within an individual column are activated
by the same particular feature of a stimulus.
The vertical organization is the result of neuronal connections within a cortical column:
1. non-specific thalamic input to the column terminates superficially in the column, on distal
dendrites of pyramidal cells; it provides background excitation to the column;
2. specific thalamic input terminates in the internal granule cell layer, exciting interneurons
that spread excitation to other neurons of the column;
3. small pyramidal cells send their axons into the white matter to excite nearby cell columns;
4. large pyramidal cells (and multiform cells) send their axons into the white matter to excite
distant sites via long association fibers, commissural fibers, and corticofugal projection fibers.

Vertical cells
columns constitute
the functional units of
cerebral cortex.
Usually the
functional columns
are not anatomically
distinct, but in the
case of the massive
sensory input from
rat vibrissae, the cell
columns per
vibrissae are
morphologically
evident and give the
impression of a
“barrel” (reinforced
by this artistic
rendition).

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III. Functional areas (regions) of cerebral neocortex:
A. Motor area:
Located within the cruciate sulcus, the motor cortex is somatotopically organized by movement
(its neurons drive joints vs individual muscles). Motor cortex is the main driver of the red
nucleus and reticular formation (extrapyramidal tracts) and it is the primary source of pyramidal
tract fibers to cranial nerve nuclei (corticobulbar tracts) and spinal cord (corticospinal tracts).
Somatotopic organization = organization corresponds to regions of the body (e.g.,
neck is near the head; hindlimb is near the tail; etc.). The organization can be
represented by an animunculus, which appears distorted because area of cortex is
proportional to density of innervation not amount of body surface.

B. Primary sensory areas:

Receive specific afferents of a given modality first, from the thalamus or geniculate bodies:
• somatosensory (somesthetic) area — receives specific tactile input as well as information
related to pain, temperature and pressure sensation. The area is somatotopically
organized around the coronal sulcus.
• visual area — receives elements of an image (contrast-edges, shape, color, size). The area is
retinotopically organized in the occipital lobe (around the marginal sulcus).
• auditory area — receives auditory input (temporal & pitch changes). The area is
cochleotopically organized (around the apex of the pseudosylvian fissure).
• vestibular area — receives vestibular (acceleration) input. It is rostral to the auditory area.
Note: Taste is represented in the somesthetic area near the tongue region.
Olfaction is consciously detected at the piriform lobe (paleocortex).

C. Association areas:
Association cortex is concerned with sensory integration, cognitive interpretation, abstracting
complex significance, thinking, goal planning, creativity, and intelligent behavior. Association
cortex receive input from other cortical areas and from thalamic nuclei & limbic structures.
Sensory association areas immediately surround primary sensory areas, from which they receive
input. They extract cognitive significance from the primitive elements of sensory perception.
There are hierarchies of association cortex: the lowest areas, closest to primary sensory areas,
extract initial meaning; surrounding association areas extract higher levels of significance: e.g.,
(size, shape, texture, surface features) —> (coin, denomination, save, get more, exchange) —> (rare, exotic,
valuable, artwork, appreciation/devaluation over time, etc.)
Prefrontal association cortex occupies the frontal pole. It directs goal-oriented behavior, sending
projections to premotor cortex for movement selection. The prefrontal cortex processes
emotional status and cognitive perception as a prelude to deciding, planning, and temporally
organizing behavior directed toward achieving goals. Attention to goal-oriented behavior
involves short-term working memory and suppression of distracting influences, including
inappropriate emotional behavior. The medial portion of the prefrontal cortex has abundant
limbic connections; the lateral portion has strong somatic (premotor) connections.
Premotor cortex (motor association cortex) is located between the prefrontal cortex and the
motor cortex, it receives projections from the former and projects to the latter. Premotor cortex is
active particularly during complex movement selection and while learning new movements.
Also, patterns of sequential rapid movements are encoded in premotor regions. Premotor cortex
drives the motor cortex via circuits involving basal and thalamic nuclei. Premotor projection axons join the
pyramidal tract and synapse on pontine nuclei that project to the cerebellum.

113
(The premotor cortex is actually a collection of related cortical regions including a frontal eye field and
supplemental motor area. The frontal eye field is involved in visual attention and visually tracking objects of
interest. The supplementary motor area extends onto the medial surface of the hemisphere and is active when
movements are being contemplated or observed, prior to movement execution. The supplemental cortex receives
projections from prefrontal cortex and projects to motor cortex.)
Primate brains have relatively more association cortex than common domestic mammals.
Association areas comprise 85% of the human brain but only 20% of the canine brain. In primates . . .
• parietal association cortex is involved in body awareness; damage results in neglect syndromes
(denial of body parts)
• temporal association cortex is responsible for recognizing/identifying categories of objects; damage
produces agnosia, e.g., lost ability to recognized faces or familiar objects
• frontal association cortex (prefrontal cortex) is concerned with appreciation of self, goal-directed planning,
and appropriate behaviors. Damage impairs goal oriented behavior and personality. Animals are constantly
distracted by every incidental stimuli and are unable to pursue purposeful execution for a delayed reward.

Note: In humans, language processing (written, vocal, signing, reading) and math
calculation capability resides in one cerebral hemisphere (left hemisphere in 95% of
right handed and 70% of left handed persons). Visual-spatial processing (shapes, symbols,
pattern recognition, configuration analysis, directions in space) is dominant in the other
hemisphere. Handedness is also a representation of hemispheric dominance.

Top:
Diagram of a right cerebral
hemisphere of a dog,
illustrating locations of the
primary motor area and
various primary sensory
areas.

Bottom:
Superimposed on a cat
cerebral hemisphere,
representations of motor and
somesthetic areas are shown
by an animunculus in each
case.
An animunculus displays the
amount of cortical surface
devoted to each region of the
body. Notice that the hind
limbs and tail extends onto
the medial surface of the
hemisphere.

114
IV. Methods of Determining Cortical Function:
A. Destructive Lesions — information obtained by producing experimental lesions or by
observing patients whose lesions can be confirmed at necropsy. Findings include:
Somesthetic area — loss of the fine aspects of discrimination (e.g., cats lose the ability to
discriminate various degrees of texture roughness).
Auditory Area — bilateral lesions cause difficulty in localizing sounds and the
meaning (temporal & pitch pattern) of sound is lost.

B. Electrical Stimulation — stimulate with electrodes and observe the resulting response:
Motor area — stimulation of the area surrounding the cruciate sulcus causes contralateral
joint movement in a somatotopic pattern. Premotor cortical stimulation requires a
higher threshold to evoke movement.
C. Electrical Recording — following a stimulus the corresponding primary sensory areas
become excited first. This is employed clinically to evaluate pathway integrity.
Primary auditory area — (tonotopic organization)
high frequency tones activate neurons in the caudal sylvian gyrus;
low frequency tones activate neurons rostrally.
Primary Visual Area—different cell columns respond to edges, flashes, colors, and intensities
(the elements that comprise an image).

D. Metabolic Mapping —
Mapping studies utilize a radiolabeled glucose analogue, 2-deoxyglucose, which competes with glucose for
neuronal uptake. During a particular brain function, neurons which are active utilize more glucose and thus
take up more 2-deoxyglucose. These active neurons become radioactive and can be localized with
autoradiographic techniques (Positive Emission Tomography gamma rays).
More recently, Functional Magnetic Resonance is now the method of choice for detecting localized
increased blood flow to brain regions during mental tasks. Increased blood flow results in hyperoxygenated
hemoglobin and increase MRI signal.

115
Lecture 15
 

Cerebellum
 
Objectives: Given the information presented in this lecture you will be able to:
1) Diagram/describe the basic anatomical organization of the cerebellum and discuss the major
functional roles of the cerebellum.
2) Relate the organization of the cerebellar cortex and axonal inputs and outputs to cerebellar function
3) Describe the clinical abnormalities that occur following cerebellar damage and recognize the
symptoms that an animal with cerebellar damage would present with.

Location:
The term cerebellum literally means little brain. The cerebellum is located dorsal to the brain-
stem. It is connected to the brainstem by three pairs of cerebellar peduncles.
 
 
 
Functions: — three major functional roles:
 
1. Coordination of Movement—the cerebellum controls the timing and pattern of
muscle activation during movement.
 
2. Maintenance of Equilibrium (in conjunction with the vestibular system).
 
 
3. Regulation of Muscle Tone—modulates spinal cord and brain stem mechanisms
involved in postural control.
 
Dysfunction:
Damage (lesions) to the cerebellum result in the following:
 
1. Ataxia —a disturbance that alters the direction and extent of voluntary movements,
characterized by abnormal gait & uncoordinated muscle movements.
 
2. Dysmetria —altered range of motion (misjudge distance)—limbs are lifted too high
or not high enough.
 
3. Intention Tremor —oscillating motion, especially of the head, during movement.
 
4. Vestibular Signs —nystagmus, head tilt
 
 
Gross Anatomical Organization:
 
1. Internal Organization (similar to cerebral hemisphere):
 
Cerebellar Cortex — surface gray matter; divided by sulci into folia (small folds)
 
White Matter — internal
 
Cerebellar Nuclei — three pairs located deep in the white matter;
named from medial to lateral: Fastigial, Interpositus & Dentate

  116  
 2. Cerebellar Lobes:
A. Rostral Lobe = Spinocerebellum (paleocerebellum) — related to spinal cord, as-
sociated with postural tone. Damage results in forelimb hyperextension and hindlimb hip flexion.
 
B. Caudal Lobe = cerebrocerebellum (neocerebellum) — Damage results in hypoto-
nia (reduced muscle tone), hypermetria (ataxia where movements overreach), and intention tremor.
 
C. Flocculonodular Lobe = vestibulocerebellum — associated with the vestibular
system; involved in control of eye movements and balance. Damage results in dysequilibrium,
wide-based gait, nystagmus.
 
3. Longitudinal Zones:
A. Vermis — the most medial portion of the cerebellum, associated with the fastigial
nucleus — concerned with regulation of muscle tone for posture and locomotion.
 
B. Paravermis — intermediate part of the cerebellum, associated with the underlying
interpositus nucleus — participates in the control of an evolving movement by utilizing propriocep-
tive sensory information generated by the movement itself to correct errors in the movement.
 
C. Hemispheres — the largest and most lateral part of the cerebellum, associated
with the dentate nucleus — influences the output of the motor cortex and thus permits fine, delicate
adjustments in muscle tone that are important for skilled movements.
 

 
Cerebellar Peduncles (named by position):
1. Caudal Cerebellar Peduncle — connects the cerebellum with the medulla, contains both
afferent and efferent fibers.
 
 
2. Middle Cerebellar Peduncle — connects cerebellum with the pons, contains entirely
afferent fibers (axons) arising in from the pontine nuclei and terminating in the cerebellum.

  117  
 3. Rostral Cerebellar Peduncle—connects the cerebellum with the midbrain; it is
predominantly an efferent fiber bundle (carrying axons out of the cerebellum to other brain regions).
 
Cerebellar Cortex: the surface gray matter of the cerebellum, consisting of three layers:
1. Molecular Layer — the most superficial layer, consisting of axons of granule cells (termed
parallel fibers) and dendritic processes of Purkinje cells.
 
2. Purkinje Cell Layer — the middle layer of the cortex consisting of a single layer of large
neuronal cell bodies, termed Purkinje cells.
 
3. Granule Cell Layer — the deepest layer of cerebellar cortex found adjacent to the white
matter; consists predominantly of small neurons called granule cells.
 
Cell types & Afferent Fibers of the Cerebellar cortex:
1.Purkinje Cells — the only output neurons from the cortex; utilize GABA as an inhibitory
neurotransmitter; inhibit neurons in the deep cerebellar nuclei
2. Granule Cells — intrinsic cells of the cerebellar cortex, utilize glutamate as an excitatory
transmitter; excite Purkinje cells via parallel fibers
3. Basket Cells — inhibitory interneurons; utilize GABA to inhibit Purkinje cells
4. Climbing Fibers — arise from the olivary nucleus and terminate on Purkinje cells;
thought to utilize glutamate and aspartate as excitatory transmitters
5. Mossy Fibers — fibers that enter the cerebellum from all other sources except the olivary
nucleus (i.e., spinal cord, pontine nuclei, etc.); synapse on granule cells & excite them.
 
 

  118  
 Major Cerebellar Inputs (axons entering the cerebellum):
 
1. Climbing Fiber Inputs = Olivocerebellar Fibers
— arise exclusively from the olivary nucleus of the caudal medulla; have a
powerful excitatory effect on the Purkinje cells upon which they synapse.
 
2. Mossy Fiber Inputs:
A. Vestibulocerebellar Fibers — arise directly from the vestibular nerve and vestibular
nuclei; project primarily to the flocculonodular lobe and fastigial nucleus
[Helps coordinate head and eye movement].
 
 
B. Spinocerebellar Fibers — arise from the spinal cord (travel to cerebellum via
dorsal spinocerebellar and ventral spinocerebellar tracts); terminate predominately in the rostral
lobe.
[Makes cerebellum aware of ongoing movements via proprioceptive input
from muscle spindles and joint receptors].
 
 
C. Cerebropontocerebellar Fibers — arise from pyramidal cells in the cerebral cortex,
synapse in the pontine nuclei which then send their axons to the contralateral cerebellar cortex via
pon- tocerebellar fibers (which form the middle cerebellar peduncle).
[Alerts the cerebellum about anticipated movements].

 
Key concept: The cerebellum must monitor ongoing movements in order to correct errors in
movement, thus it receives input from proprioceptors that relay information via the spinal cord
(spinocerebellar tracts) as well as input from the semicircular canals and utricle and saccule of
the inner ear (vestibulospinal fibers) which provide information related to body or head
movement, respectively. It also receives input from the cerebral cortex (cerebropontocerebellar
fibers) and red nucleus to determine what the trajectory related to what the ongoing movement
should be. It can adjust for errors in movement via it output pathways described below.
 
Major Cerebellar Outputs (arise from neurons in deep cerebellar nuclei):
 
1. Fastigial Nucleus Projections: (via caudal peduncle)
— go to vestibular nuclei and reticular formation; via vestibulospinal and
reticulo- spinal tracts, the projections ultimately influence primarily extensor muscles related to
maintaining posture and balance.
 
2. Interpositus Nucleus Projections: (via rostral peduncle)
— go to red nucleus to influence rubrospinal tract activity; the projections make
corrections related to gross movements of the animal.
 
3. Dentate Nucleus Projections: (via rostral peduncle)
— go to thalamus to influence output from the motor cortex; the projections make
delicate adjustments related to fine, skilled movements.
 
 
 
  119  
 Clinical Abnormalities:
 
The most salient symptoms of cerebellar dysfunction are motor-related — the specific
symptoms depend on which part of the cerebellum is involved and how it is disrupted. Lesions of
the cerebellum (i.e., damage to cerebellar input, cerebellar output, or cerebellar cortex) result in
symptoms that occur because the cerebellum’s normal function is interrupted. Thus ataxia,
dysmetria, and intention tremor are the result of interference with the cerebellums normal role in the
coordination of movement and in the maintenance of equilibrium and appropriate muscle tone.
In general damage to the midline portion may disrupt whole-body movements, whereas damage
localized more laterally is more likely to disrupt fine movements of the paws or limbs (more skilled
movements).

Cerebellar disorders usually result from:

1. Tumors
2. Viral Infections (encephalitis; canine distemper) -- which may occur in utero
3. Heavy metal poisoning
4. Genetic disorders
5. Trauma
 
 
Lesions or Damage:
1. Small lesions may produce no signs or only transient symptoms. The cerebellum seems to
have a relatively large margin of physiologic safety built into the system. Small deficits can often
be compensated for by other parts of the brain.
 
2. Lesions of the cerebellar hemispheres result in loss of muscular coordination and jerky
puppet-like movements of the limbs (dysmetria) on the ipsilateral side (same side as the
lesion).
 
3. Lesions of the cerebellar vermis result in truncal tremor and gait ataxia (a splayed stance
and swaying of the body while walking).
 
4. Lesions of the flocculonodular lobe (vestibule cerebellum) result in nystagmus, head tilt,
tight circling & falling. As you might expect these symptoms are similar to what you would observe
with damage to the vestibular system.

Key concept:
When you see animals in the clinic that exhibit ataxia, dysmetria, intention tremor and/or
vestibular signs, you should consider cerebellar damage as a major contributor to the symptoms
that you observe.

  120  
 Lecture 16
 

Diencephalon and Hypothalamus

 
Objectives – Given the information presented in this lecture you will be able to:
1) Describe and identify the 4 regions of the diencephalon
2) Describe and discuss the major anatomical divisions and functions of the hypothalamus.
3) Discuss the anatomical and functional relationship between the hypothalamus to the
pituitary gland and contrast how damage to the posterior pituitary differs from damage to
the anterior pituitary gland.
 

Four Subdivisions of the Diencephalon:

1. Epithalamus — (“epi” means upon) the most dorsal part of the diencephalon; it forms a
caplike covering over the thalamus.
a. The smallest and oldest part of the diencephalon
b. Composed of: pineal body, habenular nuclei and the caudal commissure (see Fig 1)
c. Function: It is functionally and anatomically linked to the limbic system. It is
involved in regulating reproductive functions (mating behavior ; responsible for
postpartum maternal behavior). Melatonin, secreted by the pineal
gland at night, is concerned with biological timing including sleep induction.
 

2. Subthalamus — (“sub” = below), located ventral to the thalamus and lateral to the
hypothalamus (only present in mammals).
a. Plays a movement-focusing function selecting wanted and suppressing unwanted
movements. Involved in the generation of rhythmic movements
b. Stimulation of the subthalamus provides the most effective treatment for late-stage
Parkinson’s disease in humans.
 

3. Thalamus — largest component of the diencephalon

a. comprised of a large number of nuclei; the only two we ask you to know are the
lateral geniculate (vision) and the medial geniculate (hearing).
b. serves as the great sensory receiving area (receives sensory input from all sensory
pathways except olfaction) and relays sensory information to the cerebral cortex.
4. Hypothalamus — (“hypo” = below), the most ventral part of the diencephalon.

Epithalamus  

  121  
 
 Key concept: While there are 4 parts to the diencephalon, from a clinical
perspective, the most significant component is the hypothalamus, since lesions of
this area can cause abnormalities in endocrine, limbic or autonomic function.

Hypothalamus:
1. Functions — its most important job is to maintain homeostasis (or maintaining the body’s
status quo); it does so by regulating three interrelated functions:
a. Endocrine Secretion — controls hormone release by the pituitary gland.
b. Autonomic Function — integrates autonomic functions via direct projections
to preganglionic autonomic neurons located in the brain-stem and spinal cord.
c. Emotions and Drives — it has numerous interconnections with the limbic system
by which it generates behaviors involved in rage, aggression, escape, etc.

2. Subdivisions and Nuclei — the hypothalamus is small in size and presents no large
scale anatomical variations in different vertebrate species. It has three basic subdivisions
[supraoptic, tuberal and mammillary – see fig. 2] each of which contains various nuclei.

a. Supraoptic region — the most important division in veterinary medicine, it

lies above the optic chiasm and contains 3 important nuclei (see fig. 3):

1) Supraoptic Nucleus — contains neurons that produce antidiuretic hormone

(ADH or vasopressin); their axons project to the posterior pituitary
gland (neurohypophysis) where ADH is released and enters the blood.
2) Paraventricular Nucleus — contains neurons that produce predominately
oxytocin
3) Suprachiasmatic Nucleus — circadian rhythm role

.
Figure 2: Regions of the
hypothalamus and pituitary
gland in midsagittal view. Note
the tuber cinereum forms the
floor of the hypo- thalamus
between the optic chiasm &
mammillary bod- ies. The
hypothalamus is divided in a
rostrocaudal direction into 3
subdivisions: Supraoptic,
Tuberal and Mammillary,
respectively  
  122  
  

Figure 3: Schematic diagram illustrating the structures observed on histological sections

through the 3 regions of the hypothalamus
 
 
b. Tuberal Region — lies directly above the pituitary gland and contains cells that
produce orexins (hypocretins), which control various aspects of sleep. Dogs
with narcolepsy have a mutation in the orexin receptor gene.
c. Mamillary Region — most caudal portion of the hypothalamus comprised
primarily of the mamillary bodies – plays a role in memory.
 

Key concept: While there are a number of regions that comprise the hypothalamus the
supraoptic region is by far the most important and damage to this area can result in problems
with urination (damage to ADH cells or fibers), with circadian rhythms (sleep wake cycle) and
temperature regulation.

3. Afferent Inputs to the Hypothalamus (fibers coming from other brain regions)
In order to maintain homeostasis the hypothalamus must receive inputs about the state of the
body. The major inputs that convey this information include:
 
a. Nucleus of Solitary Tract — this nucleus collects all of the visceral sensory information from
the vagus nerve.
 
b. Limbic System via the fornix — structures such as the amygdala and olfactory cortex
(piriform lobe) project to the hypothalamus and help regulate behaviors such as eating and
repro- duction.
 
c. Retina via direct branches of the optic nerve that go to the suprachiasmatic nucleus.
 
  123  
 d. Blood — hypothalamus has intrinsic receptors including thermoreceptors and osmo-
receptors that monitor temperature and ionic balance; in addition hypothalamic cells are
sensitive to hormone concentrations and glucose levels, etc.)
 
4. Major Efferent Projections From the Hypothalamus
Once the hypothalamus is aware of a problem, it fixes the problem via the following routes of
communication::
 
a. Neural signals to the autonomic nervous system via projections to the brain stem vagal nuclei
and to preganglionic nuclei in the spinal cord.
 
b. Neural signals to the limbic system
 
c. Endocrine signals to/through the pituitary gland (see below)
 
Ultimately through these connections the hypothalamus can control every endocrine gland
and the hypothalamus can alter blood pressure, body temperature, and metabolism to
maintain body homeostasis.

5. The Hypothalamo-Pituitary Connection:

 
 
a. Pituitary gland: lies beneath the brain and is formed by 2 distinct parts: a neural part, the
neurohypophysis, and a glandular component derived from oral epithelium, called the
adenohypophysis.
 
b. The hypothalamus controls the endocrine system via two different routes:
1) Directly by secretion of neuroendocrine products into the general circulation via the vasculature of
the posterior pituitary gland (ADH and oxytocin).
2) Indirectly by secretion of releasing factors into the
local hypophyseal portal venous plexus
(a vascular plexus that carries these releasing factors
from the base of the hypothalamus [an area know as the
eminence] to the anterior pituitary). The hypothalamus
thus controls anterior pituitary hormone synthesis and
release via the transport of these releasing factors to the
adenohypophysis.

Fig. 4. Projections from the hypothalamus

to the pituitary gland. The hypothalamus is
connected directly via the axons of the
supraoptic and paraventricular nuclei and
indirectly via the hypophyseal portal
system.
 

  124  
 
  
 
6. Hypothalamic Function:
 
The hypothalamus: (1) controls the release of at least 8 major hormones by the hypophysis, and is
involved in (2) temperature regulation, (3) control of food and water intake, (4) sexual behavior and
reproduction, (5) control of daily cycles in physiological state and behavior, and (6) mediation of
emotional responses. Below we examine the direct and indirect effects of this small brain region:

1. Direct effects on the Endocrine system;

Secretion of oxytocin and vasopressin into the circulation.
 

A. Oxytocin—(Greek for “rapid birth”)- Produced by: neurons in the paraventricular nuclei of
the hypothalamus. Functions: acts on uterine smooth muscle to stimulate myometrial contrac-
tions and accelerates parturition (thus oxytocin or synthetic derivatives of oxytocin can be
used to induce parturition, eg. in the mare). Activates milk letdown reflex in response to suck-
ling (induces contraction of myoepithelial cells in mammary gland). It also acts on the amyg-
dala (and nucleus accumbens) to enhance bonding between a male and female once they have
mated and between a mother and her newborn.
B. Vasopressin (ADH): Produced by: neurons in the supraoptic nucleus. Function: to increase
reabsorption of water in the kidneys (via collecting ducts and convoluted tubules). Thus it de-
creases urine production and conserves body water. Capillary density of the supraoptic nucleus
is higher than any other part of the brain and increases in blood osmolarity stimulate release of
ADH.
Disease State: Diabetes Insipidus — a disorder of water balance in which there is a loss of
control of water excretion due to a failure of production, transport or release of ADH into the
blood stream from the neurohypophysis.
1) Cause: trauma or disease of pituitary or hypothalamus; Commonly associated with tumors
of the adenohypophysis which compress the neurohypophysis.
2) Diagnosis: imagery of the pituitary with a positive finding of a tumor; water deprivation
test- if animal is unable to produce more concentrated urine as water intake is restricted.
 

3) Treatment: Surgery or intranasal, oral or subcutaneous injection of desmopressin

 
2. Indirect effects on the endocrine system:
Production and release of hypothalamic releasing factors which either stimulate or inhibit the
release of hormones from the anterior pituitary gland.
Disease State: Hyperadrenocorticoidism (Cushing’s disease) often accompanies tumors of
the adenohypophysis, which produce excess adrenocorticotropic hormone. One of the most
common diseases of middle-aged and older dogs.
Symptoms: 1) Extremely hungry (polyphagia- 80-95% of dogs show this sign); 2) poor hair
coat - thinning hair or hair loss from the body (usually on the sides); 3) obesity- bloated
abdomen and “potbelly” due to increase of fat in the abdomen and increased liver size and
stretching of abdominal wall (90-95% have this symptom); 4) Muscle weakness, lethargy and
sometimes lameness (excess cortisol causes protein breakdown leading to muscle weakness).
Treatment: Surgery to remove pituitary tumor; Radiation to control tumor growth; Medica-
tion- Lysodren or mitotane—destroys the cortisol producing cells in the adrenal cortex.

  125  
 3. Control of the Autonomic Nervous System:
The hypothalamus projects to the parasympathetic vagal nuclei and the preganglionic sympathetic
nuclei and thus can control autonomic function including heart rate, vasoconstriction, digestion,
sweating, etc. There appears to be a segregation of function as follows:
Stimulate rostral hypothalamus — parasympathetic responses (e.g., slowed heart rate).
 

Stimulate caudal hypothalamus — sympathetic responses (e.g., increased heart rate,

vasoconstriction, etc.)
Disease State: alterations in cardiovascular function have been observed in cattle with
abscesses of the hypothalamus (slowing of heart rate).
 
4. Temperature regulation:
 

a. Rostral hypothalamus — heat loss center: warm blood, antipyretic substances or impulses
from heat receptors cause panting, vasodilation and sweating which serve to reduce body
temperature. Lesions cause hyperthermia in dogs and other species
b. Caudal hypothalamus — heat conservation center: cool blood, pyrogenic substances or in-
put from cold receptors causes shivering and vasoconstriction, which serve to increase body
temperature. Lesions result in hypothermia and disturbances in sweating mechanisms.
Disease State: damage to the rostral hypothalamus can cause hyperthermia (fever) while lesions
to the caudal hypothalamus can cause hypothermia (decreased body temperature); e.g., cattle
with abscesses of the pituitary gland that effect the hypothalamus are often hypothermic.
5. Regulation of Food and Water intake: The hypothalamus controls body weight and appetite as
well as water intake.
Disease State: Lesions of the hypothalamus often cause abnormal eating and drinking
behavior (see Fig. 5, below).
 
 
 
 
 
 
 
 
 
Fig. 4. The effect of
discrete bilateral
lesions in specific
hypothalamic areas
on appetite in the
cat. Lesions of the
ventromedial nuclei
produce hyperpha-
gia, while lesions
of the extreme lat-
eral hypothalamus
produce loss of ap-
petite (Anorexia).

  126  
Lecture 18

Olfaction and The Limbic System

Objectives – Given the information presented in this lecture you should be able to:
1. Explain the anatomical organization of the olfactory system
2. Explain the concept of the “limbic” system and discuss its role in behavior
3. Identify the major components of the limbic system and associate these components with
limbic system functions and behavior

I. The Olfactory System (The sense of smell):

A. Modality — Olfaction (SVA)

B. Receptors — bipolar cells located in the olfactory epithelium within the upper nasal cavity.

C. First Order Neurons = receptor cells = the bipolar olfactory neurons located in the olfactory
epithelium. The nonmyelinated axons of these neurons gather into bundles that collectively form the
olfactory nerve. Olfactory nerve bundles penetrate the cribriform plate of the ethmoid bone to enter the
olfactory bulb.

D. Second Order Neurons = mitral cells in the olfactory bulb. The axons of these cells form the
olfactory tracts (striae).
[Histologically, the olfactory bulb features several layers, including from superficial to deep, a
glomerular layer, where olfactory nerve fibers synapse on the dendrites of mitral cells; a mitral cell layer
and a granule cell layer.]

E. The olfactory tract terminates by bifurcating into a medial and lateral olfactory stria, which project,
respectively, to the septal area (olfactovisceral reflexes) and piriform cortex (conscious awareness of
olfaction).

Figure. 1.
Cellular
components
of the
olfactory
mucosa and
olfactory
bulb.

127
 Olfactory*
Receptor* Olfactory*
Neurons* Bulb*

Hippocampus*
Piriform*
Lobe* (Odor*Memory)*
Hypothalamus*
And*Amygdala*
(Conscious*
PercepAon*
(MoAvaAonal*and*
Of*smell)*
EmoAonal*aspects*
Of*Smell)*

Figure*2:*Summary*of*olfactory*pathways.!
!
Note: Olfactory bulbectomy leads to severe impairment of memory in rats

FIGURE 3. Schematic representation of the chemo–electrical transduction pathway in olfactory sensory

neurons. Upon binding of appropriate odorous ligands, odorant receptors in the ciliary membrane
act through specific G-proteins (Golf) to stimulate adenylyl cyclase (type III) generating cAMP. The
resulting elevated second-messenger levels elicit the activation of cation channels, allowing the influx of
sodium and especially calcium ions.

Key Concept: Odor molecules activate membrane receptors. The basic units of odor information appear
to be the epitopes of odorant molecules interacting with specific sites of distinct receptors. Activation of
receptors is linked via second-messenger cascades, amplifying the olfactory signal into the electrical
response of the sensory neuron. Thus, the various epitopic sites of an odor molecule are mapped into
activation of distinct subpopulations of olfactory neurons and, subsequently, into activation of
characteristic combinations of glomeruli in the olfactory bulb and ultimately to the olfactory cortex
allowing perception of distinct scents.
128
 II. The Limbic System
A. Historical Perspective:
The term limbic is derived from the Latin word “limbus” which means “border”. Limbic refers to fact
that the cortical structures which comprise the system form a border around the brainstem. James Papez
suggested in 1937 that the limbic structures, which surrounded the brainstem, were involved in emotions.
This hypothesis was subsequently found to be correct and these structures together with certain
components of the hypothalamus, thalamus and epithalamus were collectively called the Limbic System.

B. Functions:
In domestic animals the limbic system is concerned with
1) emotions of importance to survival (emotions associated with self preservation, such as escape,
defense, feeding, etc.; and emotions associated with species preservation such as territorial
defense, courtship, mating, etc.) and
2) processes involved in learning and memory.

C. Criteria for being included in the limbic system:

A. Rich innervation by axons containing indoleamine (i.e., serotonin) and/or
catecholamine (i.e., dopamine or epinephrine) neurotransmitters
B. Low threshold for seizure activity
C. Direct or indirect connections to the hypothalamus

D. Components:
Hippocampus; Cingulate Gyrus; Amygdala; Septal Area; portions of the Thalamus; Piriform lobe; and
Mammillary Bodies of the Hypothalamus

Fig. 3. A. Photograph of dissected dog brain illustrating limbic structures on medial view of the brain.
Cortical structures including the cingulate gyrus and septum (septal area) are shown and the
hippocampus has been dissected out to display its anatomical location. B. Schematic diagram of the
limbic system showing the hippocampus, amygdala and cingulated gyrus.

129
E. Individual Limbic Structures and Possible Functions:

Some areas of the brain are neither purely sensory nor purely motor but instead are modulatory. The
limbic system components represent one of these modulatory systems, but are nevertheless essential
components of the neural circuitry underlying complex behaviors. Complex behaviors are often directed
toward filling a primary need such as hunger, thirst, or sleep, but different types of emotions and
emotional responses are also within the limbic realm. To use hunger as an example, once blood sugar
drops below a certain critical level, an animal feels hunger. To satisfy hunger, perceptual and modulatory
processes must first be brought into play. Thus, when a predator surveys the environment for clues of
prey, including sights, sounds, or odors, modulatory systems in the brain focus the sensory apparatus on
stimuli that are relevant to feeding.

In general the neocortex has a dampening effect on emotional behavior. This is illustrated by sham rage a
type of rage reaction that occurs following removal of the cerebral cortex from a cat or dog. It is
characterized by: lashing of the tail, vigorous arching of the back, clawing and attempts to bite, and auto-
nomic responses. It is called sham rage because unlike genuine rage, the anger occurs spontaneously or
can be triggered by mild tactile or other non-noxious stimuli.

Hippocampus — a simple, three-layered cortical structure (archicortex), which has long been thought to
be an important cortical region for associative learning and memory (particularly memory acquisition or
short term memory). Both amnesia patients and animals with hippocampal damage exhibit ʻtime-de-
pendent impairmentsʼ in behavioral tasks generally described as associative or relational in nature. It is
also important to note that this area of the brain has a very low seizure threshold.

Figure 5: Three-
dimensional reconstructed
images of the
hippocampal
formation. (A)
Craniocaudal view. (B)
Right lateral view.
(C) Dorsoventral view.
The right and left halves
of the hippocampal
formations face each
other. The cranial and
Figure 4: Three-dimensional caudal hippocampal
hippocampal formation superimposed ends run medially,
on MR images prominently showing showing a “C” shape. D,
the hippocampal body. The dorsal; V, ventral.
hippocampal body has a dorsoventral
orientation and is vertical to the
transverse sectional image.

Septum — a small but conspicuous cortical area that is involved in a variety of physiological and
behavioral processes including emotions, relief of fear, docile behavior and stress, as well as, a role in
autonomic regulation (e.g., water/food intake, hibernation, etc.). Stimulation induces docile behavior and
can suppress many autonomic responses. Lesions result in rage and aggressive behavior and can trigger
many autonomic responses.
130
Amygdala — a highly differentiated region near the temporal pole of the mammalian cerebral hemis-
phere. It is a basal nucleus that is implicated in a bewildering variety of behavioral and regulatory
functions. These include emotion and memory, social behaviors such as reproduction, fear and ag-
gression, and modulation of the autonomic and neuroendocrine systems. Many amgdala effects appear
opposite to those of the septum. For instance, lesions result in docile behavior, while stimulation
produces rage and aggressive behavior.

Hypothalamus — the functions of this area were discussed previously. It should be noted that because
of its interconnections with other limbic structures, simulation of the hypothalamus produces many of the
behaviors seen with stimulation of other limbic sites. Thus stimulation reveals rage and aggression sites
as well as sites that produce cowering or docile behavior. Pigs exposed to acute immobilization stress
show dramatic increases in noradrenaline and adrenaline in the hypothalamus.

Thalamus — links the limbic system to the neocortex and provides a means by which sensory infor-
mation can gain access to the limbic system.

Key Concept: Each of the above limbic structure has been assigned certain functions, however, it
is important to appreciate that these structures work together to ultimately give rise to behaviors
that the animal exhibits.

F. Clinical Signs Associated with Damage to Limbic Structures Include:

1. Dullness
2. Lethargy
3. Sleepiness
4. Stupor or semicoma
5. Dementia
6. Failure to recognize owners or familiar environment
7. Inability to learn
8. Destructive behavior
9. Irritability or aggressiveness
10. Propulsive pacing or circling

131
 Initial Neuroanatomy Vocabulary Guide
Alar Plate = the dorsal bulge of the embryonic neural tube, which forms the cerebral
hemispheres among other structures in the adult brain.

Arachnoid = the middle layer of the 3 membranes (meninges) that cover and protect the
brain and spinal cord

Axon = part of the neuron that transfers an electrical impulse from the cell body to the
axon terminal

Basal Plate = the ventral portion of the developing neural tube, it gives rise to the motor
portions of the brainstem and spinal cord

Bifurcate = having two branches, axons can split into two branches

Brain = the major portion of the vertebrate central nervous system consisting of 3 main
parts: the cerebrum, the cerebellum and the brain stem.

Bulbar = term used as an adjective to refer to the brainstem

Caudal = toward or near the tail

Cell Body (Soma) = the part of a neuron containing the nucleus but not including the
dendrites or axon.

Cerebellum = a cauliflower-shaped brain structure located above the brainstem that

coordinates movement

Cerebrum = the largest part of the vertebrate brain consisting of two hemispheres

Commissure = a connecting band of nerve fibers in the brain or spinal cord

Corpus Callosum = the largest commissure of the brain connecting the 2 cerebral
hemispheres

Cortex = the outer layer of an organ (i.e., the cerebral cortex)

Decussate = to cross, nerve fibers or axons that cross from one side of the brain or spinal
cord to the other

Dendrites =short branching cell processes that extend away from the neuronal cell body
of neurons and increase surface area for receiving synapses from other neurons

Diencephalon = The rostral portion of the brain stem that connects the midbrain with the
cerebral hemispheres and serves as an important relay station for sensory information
Dura Mater = The outermost, toughest, and most fibrous of the three protective
membranes (meninges) covering the brain and spinal cord

i
Fasciculus = a little bundle of fibers, a nerve tract that runs in the spinal cord or brain

Ganglion = a group of neuronal cell bodies located outside the central nervous system

Glia = non-neuronal cells that help support neurons

Gray Matter = gray appearing tissue in the vertebrate brain and spinal cord comprised of
neuronal cell bodies and glia

Leminiscus = a bundle of nerve fibers ascending from sensory nuclei in the brain stem
and spinal cord and terminating in the thalamus

Limbic System = a group of interconnected deep brain structures involved in emotions

and behavior

Medulla (oblongata) = The caudal-most portion of the vertebrate brain stem, which is
responsible for controlling heartbeat and blood pressure.

Mesencephalon = the middle portion of the developing brain giving rise to the midbrain
in the adult animal

Neuron= specialized cells that process and transmit information in the form of electrical
signals from one part of the body to another

Nucleus = a functional grouping of neuronal cell bodies in the central nervous system

Pons = The part of the brain stem that plays an important role in regulating respiration,
sleep and arousal

Prosencephalon = The forebrain consisting of the diencephalon and the telencephalon

(cerebral hemispheres).

Reticular Formation = poorly differentiated network of gray and white matter found in
the central core of the brainstem which regulates consciousness and sleep

Rhombencephalon = The portion of the embryonic brain that gives rise to the adult
pons, cerebellum, and the medulla. Also called hindbrain.

Sulcus = a surface groove on the brain and spinal cord, sulci separate the convolutions on
the surface of the cerebral hemispheres

Tract = a bundle of nerve fibers in the CNS having a common origin, termination and
function

White Matter = is composed of bundles of myelinated axons which connect gray matter
areas of the brain and spinal cord

ii
 University of Minnesota
College of Veterinary Medicine

Syllabus
CVM 6120 Veterinary Neurobiology
Spring/2013

Course credits: Two Credits

Course Coordinator: Alvin J. Beitz, Ph.D

Office: 205D Veterinary Sciences Bldg.
Phone: 612-625-2595
E-Mail: beitz001@umn.edu

Instructors:
A. Beitz, Ph.D — 612-625-2595; beitz001@umn.edu
T. Fletcher, DVM, Ph.D. — 612-624-9765; fletc003@umn.edu
L. Vulchanova-Hart, Ph.D — 612-626-4073; vulch001@umn.edu

Course Description: CVM 6120 Veterinary Neurobiology provides an overview of the

neurohistology, neuroembryology, and the anatomy and physiology of the central nervous
system (brain & spinal cord) and the special senses (vision, hearing taste, & olfaction) of
domestic mammals.

Books and Supplies:

In addition to CVM 6120 Class Lecture Notes and the CVM 6120 Laboratory Manual, one
book is required: "Guide to Dissection of the Dog", by Evans & de Lahunta, 6th edition
(previously required for CVM 6100). These may be purchased from the Veterinary Student
Supply (651-645-1702; vssvth@umn.edu). The class lectures notes and lab manual will also
be made available on line on the course moodle site.

Also, the following textbook resources are available on reserve in the Veterinary Library:

• DeLahunta A: Veterinary Neuroanatomy and Clinical Neurology (2009). Because this

book is organized somewhat differently than the course, it offers another perspective. A
strength of the book is its clinical content, which is useful later in the curriculum.

• Fletcher TF & Beitz AJ: Brain and Spinal Cord chapters in Miller’s Anatomy of the
Dog (2013) edited by H. Evans and A. de Lahunta. This text contains more information than
you need to know for the course, but it has some nice illustrations.

• Beitz AJ & Fletcher TF: Nervous Tissue in Textbook of Veterinary Histology (2006)
edited by JA Eurell and BL Frappier; pp 91-116. This textbook chapter offers a comprehensive
presentation of neurohistology.

• Jenkins TW: Functional Mammalian Anatomy (1978) This text is a nicely organized
and offers a comprehensive presentation of neuroanatomy. (this book is currently out of print)

1
 • Note: Any anatomy or physiology text will present nervous system function and
structure.

Goals and Objectives -- Knowledge: When the student successfully completes the course,
he/she will have developed an understanding of how the nervous system of domestic mammals is
organized, in terms of relationships among the major components (brain, brainstem, spinal cord,
peripheral and cranial nerves) comprising the nervous system and how these components
contribute to nervous system function. The student will also develop an appreciation for the
clinical signs and altered behavior that occurs following damage to or disorders of nervous
system components. This course provides the a knowledge base for learning more detailed
information regarding the physiology, pharmacology and pathology of the nervous system
and for understanding clinical diagnosis and treatment, which will be taught in courses
that you will encounter later in the curriculum.

Goals and Objectives – Skills and Abilities: Upon successful completion of the course,
students will be able to identify, pronounce the names and understand the function of important
central nervous system components, which will facilitate their future understanding of
neurological disease and the medical literature and help facilitate their communication with
medical colleagues. They will be able to explain how neural components are structurally and
functionally related to one another and how specific neural damage leads to particular
neurological disorders. They will understand the rationale for procedures comprising a
neurological exam of a veterinary patient.

Participation Policy: Students are expected to attend class, to read the lecture notes prior to
attending lecture and to query instructors about course content that they do not understand.
Instructors are available for individual consultation during laboratory periods and at other times
by appointment.

Grading and Grading Standards:

Your CVM 6120 letter grade will be based on the following scale (percent total score rounded to
the nearest whole number):

A = 90-100%
B = 80-89%
C = 70-79%
D = 65-69%
F = below 65%

Examinations and Assignments:

There will be one major quiz and two examinations in the course. The quiz is worth 10% of the
grade, the midterm exam will account for 32% of the grade and the final exam will account for
40% of the grade. In addition students will be expected to learn basic vocabulary words (tested
via an on line 2 point quiz) and read 2 articles during the course that are related to the lecture
material. A short online quiz will be given for each article that is assigned (each quiz will be
worth 3 points). Thus, 8% of the grade will come from these 3 short quizzes (2 pts/vocabulary
quiz + 3 points per article quiz X 2 articles = 8 pts). An additional 5% of the grade will come
from a written report based on a clinical case study. The final 5% of the grade will come from an
on line, open book essay assignment that will test your understanding of basic concepts taught in
the course. The midterm and final exams will consist of a written test and a lab test (on gross
2
brain and glass slide material). The midterm exam will be worth 32% of your grade with the
lecture exam worth 17% of your grade and the lab exam worth 15% of the grade. The final exam
is worth 40% of your grade with the written and lab exams each accounting for 20% of the
grade. The range of subject matter per exam will be announced in class. Thus, the breakdown is
as follows:

Exam/Assignment Points Date or Due Date

Quiz 1 10 1/17/13
Midquarter Exam 32 1/29/13
(Written =17 + Lab Exam = 15)
Final Exam 40 2/21/13
(Written =20 + Lab Exam = 20)
3 Online Quizzes 8 (2-3 pts each) First 3 Weeks of Class
(1 vocabulary + 2 article quizzes)
Clinical Case Study 5 2/13/13
On Line Concept Essay 5 Anytime before 2/15/13
Total 100 points

Specifically, on written examinations you will be tested on the information presented in lecture
and in the CVM 6120 Class Lecture Notes. You will not be tested on the Clinical Correlation
session presented by Dr. Patterson. For each lab exam, you will be tested on underlined/bold
terms in the CVM 6120 Laboratory Manual, as presented in the accompanying Neuroanatomy
Lab Terms List. If the structure is not on the Lab terms list, you do not responsible for identify it
on the lab exams.

Questions on written exams may be any of the following types: essay, short answer, multiple
choice, T/F, matching. The practical/laboratory part will include identification of brain, spinal
cord or special sense organ structures, brain or spinal cord nuclei and fiber tracts and histological
structures associated with the brain, spinal cord or special sense organs or questions related to
these structures. Laboratory exam questions will be presented using a combination of whole
brains, special sense organs and spinal cord specimens as well as histological sections through
these structures. Lab exam questions will often ask you to identify a structure that is tagged, but
in some cases these questions may be may be second order questions that ask you to identify the
function of the structure tagged or the neurological deficit that occurs if the structure is damaged.

Clinical Case Study (5 pts): Students will be divided into groups of 6 students and each group
will be assigned a clinical case. Your Group is expected to discuss the assigned Case, arrive at
consensus conclusions, and prepare a report. Your grade (5 points) will be based on your Group
Report, to be submitted in a prescribed template that will be provided on the Moodle
Neurobiology course site. All members of a group will receive the same grade on the report.
More details will be provided in class.

On Line Concept Essay (5 pts): Students will be in the same group as indicated in the Clinical
Case study assignment above. Each group will be asked to pick one of the subjects covered in
the lectures given during the course and to address questions related to what they believe to be
the three most important significant concepts associated with this subject. All members of a
group will receive the same grade on the report. More details will be provided in class. The on
line Concept Essay will comprise 5% of your grade.
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Criteria for Evaluation:
Grades will be awarded based on examination scores, performance on quizzes, performance on
class assignments and performance on the clinical case study, as described above.

Academic Dishonesty: Students are expected to do their own assigned work. All examinations
will be conducted under honor code regulations of the College of Veterinary Medicine and
according to CVM academic policies on testing. Students are expected to complete exams in the
time allotted.

Make-up Examination Policy: We will follow the examination policy that was approved by the
College of Veterinary Medicine on 11/3/05. Students will be automatically excused from an
examination in only 2 situations:
a. Preapproved absence for medical reasons (personal or family). Preapproval requires
that the student contact the instructor prior to the test/deadline and provide an
explanation of the reason for the absence.
b. Emergency medical absence (post-test notification) if pre-approval was not possible
and proof of medical care is provided.
With the exception of emergency medical problems students must notify the course instructor
that they will miss a test or deadline before the test or deadline. Missed examinations must be
taken within 3 days of the originally scheduled test, except for adverse circumstances as
determined by the Office of Academic and Student Affairs.

Student Expectations
As a student you will be expected to:
· Attend each class and lab period and develop an understanding of how the nervous system
is organized, how it functions and what symptoms animals exhibit following damage to
central nervous system components.
· Complete the 2 examinations and the quiz, and show a competent understanding of the
material presented.
· Complete all class assignments
· Read the two articles assigned for class reading and take the quiz related to each article.
· Work with your group to complete the clinical case study.
· Complete a course evaluation form at the end of the course.

What You Can Expect from Your Instructors:

You can expect us to:
• plan and facilitate learning opportunities that will help you meet the course goals and
objectives
• provide constructive feedback on your performance
• be open to constructive feedback on our performance
• be open-minded in responding to your ideas and suggestions.
• allow you to wrestle with ideas in order to shape your own conclusions
• relate the information to clinical practice as much as possible.

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Clickers: We will be using clickers in the Veterinary Neurobiology class. You received clickers
during Fall semester and we will continue to use them during the Spring semester in several of
your courses including Neurobiology. You are responsible for bringing your clicker to each
Neurobiology lecture and to the neurobiology lab introduction in room 125. As you know each
i>clicker has a specific registration number and a clicker with a specific registration number is
assigned to each student. We assume you have already registered your clickers on line at
“iclicker.com”. Since the clickers may be used for short quizzes related to the two reading
assignments as well as for the quiz given on January 20th, do not give your clicker to another
student. You are responsible for returning the clicker to VSS at the end of the semester.

Moodle Site: There is a class Moodle site that you will have access to. This site will contain an
electronic copy of the class syllabus and schedule as well as PDF copies of the class notes and
lab manual. Reading assignments and exam scores will also be posted on the Moodle site.

Methods of Instruction:
Lectures will be based on the Lecture Notes that students purchase or download from the
Moodle site. Lectures will include additional images, video clips, and limited live animal
presentations.
Labs will involve identification of structures observed in gross brains and on tissue glass
slides, as described in the Laboratory Guide that students purchase or download from the Moodle
site. Lab content will be introduced in a lecture room context at the beginning of each lab. Lab
demonstration material will be displayed during each Lab period for purposes of subject matter
clarification and enrichment.
Independent Study. To access web-based courseware, visit the Neuroanatomy
Courseware section of the Veterinary Anatomy web site (http://vanat.cvm.umn.edu/). In
particular, we call your attention to the following CVM 6120 pertinent web sites:
Courseware Recommendations for CVM 6120 Students — presents courseware available on
the Veterinary Anatomy web site in the context of veterinary students studying neurobiology (CVM
6120).
Neurobiology Concepts Checker — this site provides students an opportunity to clarify their
understanding of neurobiology concepts via self-assessment. Per subject category, a series of query
screens is presented randomly. A Show Answer button reveals answers and offers a conceptual
explanation.
NOTE: A web app designed for smartphone & tablet devices is also available (Mobile
Neurobiology Concepts Checker).
Canine Brain Transections — this web site presents sixteen transverse sections through a
canine brain depicting structures students are expected to identify per brain section. Two modes of
identification are available: select a name & see the structure and a glossary comment or select a structure
& see its name.
Canine Brain Atlas — a web site presenting twelve labeled transverse sections through a canine
brain accompanied by a Glossary-Index. The images are enlarged and intended for computer screen
viewing. Labels may be toggled and images navigated via key strokes or mouse clicks.
Brain Gross Anatomy — a web site presenting a variety of gross dissection images of brains of
domestic animals. Images are organized by anatomical region and by viewing perspective. Each image
has an accompanying caption. Labels can be toggled on/off.

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 Neurohistology ATLAS — this web site presents a variety of neurohistology images with
captions. Via two-way links, a catalog of small images is available to locate large images with full
captions.
Embryology Highlights: Nervous System —narrated synopses (screencasts) of nervous system
embryonic development. Topics include: Early neural development, CNS development, and PNS &
Meninges development. The screencasts are presented as QuickTime video clips.
Neurobiology Labs: Preview/Review Images — a web site presenting neuroanatomy
information related to each of eight Neurobiology Labs. Content in the form of images with captions,
including links to other images, is organized per Lab.
Lab I: Neurohistology — this web site duplicates Lab I of the CVM 6120 Laboratory Guide,
presenting color images that correspond to the black & white images included in the Lab Guide. Each
section of the Lab Guide is a page in the web site.
Lab 2: Spinal Cord — a web site corresponding to Lab 2 of the CVM 6120 Laboratory Guide,
dealing with the spinal cord.
Lab 3: Brain — a web site corresponding to Lab 3 of the CVM 6120 Laboratory Guide,
including color images of dissected brains.
Lab 4: Cranial Nerves — a web site that relates to Lab 4 of the CVM 6120 Laboratory Guide. It
is also a stand-alone graphic tutorial for canine cranial nerves and cranial nerve nuclei.
Lab 6: Cerebellum — a web site corresponding to Lab 6 of the CVM 6120 Laboratory Guide,
dealing with the cerebellum.
Cranial Nerve Nuclei - Animated Quizzes — animated quizzes are provided for students to
reinforce their knowledge of cranial nerve nuclei with respect to nuclear names, innervation targets,
associated cranial nerves, and fiber-type per nucleus.
Diagnose Neurological Lesion Location Exercises — via clinical case presentations, this web
site allows students to exercise their neuroanatomy knowledge to locate destructive neurological lesions.
A Lesion Location Guide presenting neuroanatomy and clinical syndromes per neural region is included.
NOTE: A Lesion Location Guide designed for smartphones is also available.
Classroom Policies:
Cell phones and electronic devices. Turn phones, PDAs, and other electronic devices off or switch them
to a silent mode during lecture unless directed otherwise. iPads and laptops are permitted in class to
follow along with class notes or power point presentations; Note: Electronic devices are not allowed
during exams, turn all electronic devices off except in truly extraordinary situations (such as an imminent
birth or death).

Academic Problems Related to Veterinary Neurobiology:

This course will present new material (vocabulary and concepts) that many of you are unfamiliar with and
thus it may present a challenge to some of you. The course is only 7 weeks long and thus you will be
asked to learn a considerable amount of new material in a short period of time. However, one of our goals
in this course is to help you succeed. If you encounter academic issues or problems during the
Neurobiology course please schedule a meeting with Drs. Beitz, Fletcher or Hart to address these issues.
You can also receive academic assistance and counseling from the Office of Academic Affairs.

Student Mental Health:

As a student you may experience a range of issues that can cause barriers to learning, such as strained
relationships, increased anxiety, alcohol/drug problems, feeling down, difficulty concentrating and/or lack
of motivation. These mental health concerns or stressful events may lead to diminished academic

6
performance or reduce a student's ability to participate in daily activities. University of Minnesota
services are available to assist you with addressing these and other concerns you may be experiencing.
You can learn more about the broad range of confidential mental health services available on campus via
the following website: http://www.mentalhealth.umn.edu/.

Accommodations for Students With Disabilities: Participants with special needs are strongly
encouraged to talk to the instructors as soon as possible to gain maximum access to course information.
All discussions will remain confidential.

University policy is to provide, on a flexible and individualized basis, reasonable accommodations to

students who have documented disability conditions (e.g., physical, learning, psychiatric, vision, hearing,
or systemic) that may affect their ability to participate in course activities or to meet course requirements.
Students with disabilities are encouraged to contact Disability Services and their instructors to discuss
their individual needs for accommodations. Disability Services is located in Suite180 McNamara Alumni
Center, 200 Oak Street. Staff can be reached at http://ds.umn.edu or by calling 612/626-1333 (voice or
TTY).

Diversity and Collegiality: Because a key to optimal learning and successful teaching is to hear, analyze,
and draw from a diversity of views, the instructors expect collegial and respectful dialogue across
disciplinary, cultural, and personal boundaries.

Student Conduct: Instructors are responsible for maintaining order and a positive learning environment
in the classroom. Students whose behavior is disruptive either to the instructor or to other students will be
asked to leave. Students whose behavior suggests the need for counseling or other assistance may be
referred to their college office or University Counseling and Consulting Services. Students whose
behavior may violate the University Student Conduct Code may be referred to the Office of Student
Judicial Affairs.

Sexual Harassment: University policy prohibits sexual harassment as defined in the University Policy
Statement (http://www1.umn.edu/regents/policies/humanresources/SexHarassment.html) adopted on
December 11, 1998. Complaints about sexual harassment should be reported to the University Office of
Equal Opportunity, 419 Morrill.

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 CVM 6120 Veterinary Neurobiology
Class Schedule — Spring 2013

Week Lecture Topic Lab Subject Matter

1. Introductory Lecture (Mon [1/7] 1 pm)- Beitz
1 2. Neurohistology - Vulchanova-Hart 1] Neurohistology-I
(Tu [1/8] 1 pm) (Tu [1/8] 2 pm)
3. Cellular Neurobiology - Vulchanova-Hart
(W [1/9] 1 pm)
4. Neuroembryology - Fletcher 2A&B] Spinal Cord
(Th [1/10] 1 pm) (Th [1/10] 2 pm)
5. Spinal cord organization -Fletcher
(Fri [1/11] 1 pm)

2 6. Spinal cord reflexes - Fletcher 2C] Spinal cord Pathways

(Mon [1/14] 1 pm) 3A&B] Brain (Cerebrum)
7. Nociception I - Beitz (Tu [1/15] 2 pm)
(Tu [1/15] 1 pm)
8. Nociception II - Beitz QUIZ: Histology & Spinal Cord
(Wed [1/16] 1 pm) (Th [1/17] 1 pm)
Quiz – Thur 1/17 – 1:00 3C&D] Brain (Diencephalon, Midbrain)
(Th [1/17] 2:00 pm)

3 9. Cranial Nerves - Beitz

(Tu [1/22] 1 pm)
10. Vestibular system - Fletcher 3E&F] Brain (hindbrain)
(Tu [1/22] 2 pm) (Wed [1/23] 2 pm)
11. Auditory system – Vulchanova-Hart Cranial Nerves – Case study (Th 1:00)
(Wed [1/23] 1 pm) 4] Cranial Nerves, Vestibular System
Review Session (F [1/25] 1-3:00 pm) (Th [1/24] 2 pm)

4 FIRST EXAM (2 hours) FIRST EXAM (2 hours)

(Tu [1/29] 1-3 pm) (Tu [1/29] 1-3 pm)
12. Visual system – Vulchanova-Hart 5] Visual / Auditory System
(W [1/30] 1 pm) (W [1/30] 2 pm)
13. Posture & Movement - Fletcher
(Th [1/31] 1 pm)
14. Cerebral Cortex - Fletcher
(Tu [2/5] 1 pm)

5 15. Cerebellum - Beitz 6] Cerebral cortex/Motor centers

(Wed [2/6] 1 pm) (Wed [2/6] 2 pm)
16. Diencephalon & Hypothalamus - Beitz
(Wed [2/13] 1 pm) 7] Cerebellum Lab
17. Neurological Examination -Dr. Patterson (Wed [2/13] 3 pm)
(Wed [2/13] 2 pm)
6 18. Olfaction/Limbic system - Beitz 8] Rhinencephalon / Limbic system
(Th [2/14] 1 pm) (Th [2/14] 2-3:30 pm)
19. Discussion of Case Reports
Fr [2/15] 1 to 3:00 pm)
7 20. Neurobiology Review Session
(Tues [2/19] 1-3 pm)
FINAL EXAM (2 hours) FINAL EXAM (2 hours)
(Th [2/21] 1-3 pm) (Th [2/21] 1 pm)

Note: All classes will meet in Rm 125 AS/VM. Following a lab introduction in Rm 125, labs will continue
in Rm 104 AS/VM. Exams will be given in Rm 104 AS/VM.