2004

Veterinary Neurobiology
(CVM 6120)

Class Notes
by Alvin J. Beitz, PhD and Thomas F. Fletcher, DVM, PhD

CONTENTS
1: Neurohistology I: Cellular Features .......................3 2: Neurohistology II: Meninges/Receptors...............11 3: Nervous System Development (Embryology) ......18 4: Spinal Cord Organization .....................................31 5: Spinal Reflexes & Neuronal Integration ..............36 6: Cranial Nerves ........................................................44 7: Vestibular System ...................................................50 8: Posture and Movement ..........................................55 9: Cerebral Hemisphere and Cortex.........................60 10: Nociception I ...........................................................65 11: Nociception II .........................................................71 12: Cerebellum ..............................................................76 13: Diencephalon and Hypothalamus .........................81 14: Olfaction and Limbic System ................................86 15: Auditory System .....................................................90 16: Visual System ..........................................................96

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Lecture 1

Neurohistology I: Cells and General Features
Overall Objectives: to understand the histological components of nervous tissue; to recognize the morphological features of neurons; and to differentiate myelinated from non-myelinated axons

I. Basic Organization:
A. Central Nervous System (CNS)—brain and spinal cord B. Peripheral Nervous System (PNS)—all cranial and spinal nerves and their associated roots and ganglia Functional PNS Divisions: A. Somatic Nervous System—a one neuron system that innervates (voluntary) skeletal muscle or somatosensory receptors of the skin, muscle & joints. B. Autonomic Nervous System—a two neuron visceral efferent system that innervates cardiac and smooth muscle and glands. It is involuntary and has two major subdivisions: 1) Sympathetic (thoracolumbar) 2) Parasympathetic (craniosacral)

II. Histological Components: A. Supporting (non-neuronal) Cells— Glial cells provide support and protection for
neurons and outnumber neurons 10:1. The CNS has three types and the PNS has one: 1. Astrocytes—star-shaped cells that play an active role in brain function by influencing the activity of neurons. They are critical for 1) recycling neurotransmitters; 2) secreting neurotrophic factors (e.g., neural growth factor) that stimulate the growth and maintenance of neurons; 3) dictating the number of synapses formed on neuronal surfaces and modulating synapses in adult brain; and 4) maintaining the appropriate ionic composition of extracellular fluid surrounding neurons, by absorbing excess potassium and other larger molecules. 2. Oligodendrocytes— The oligodendrocyte is the analog of the Schwann cell in the central nervous system and is responsible for forming myelin sheaths around brain and spinal cord axons. Myelin is an electrical insulator. 3. Microglia—are 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. 4. Lemmocytes (Schwann Cells)— Schwann cells are glia cells of the PNS. They wrap individually around the shaft of peripheral axons, forming a layer or myelin sheath along segments of the axon. The Schwann cell membrane, which forms the myelin sheath, is composed primarily of lipids; the lipid serves as an insulator thereby speeding the transmission rate of action potentials along the axon.
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5. Ependyma — in addition to the above glial cells, the CNS has epithelial-like cells that line the ventricles of the brain and the central canal of the spinal cord. Note: Glial cells are capable of reproduction, and when control over this capacity is lost primary brain tumors result. Astrocytomas and glioblastomas are amongst the most deadly or malignant forms of cancer.

B. Neurons (nerve cells)—neurons are the structural and functional units of the nervous system;
they are specialized to conduct electrical signals. Note: The plasma membrane of the neuron contains both voltage gated ion channels (involved in generation and conduction of electrical signals) and receptors (which bind neurotransmitters and hormones and use distinct molecular mechanisms for transmembrane signaling; examples include ligand-gated ion channels and G protein coupled receptors). 1. Morphological Features of neurons (3 component parts; see Fig.1 below): A. Cell body — the expanded portion of the neuron that contains the nucleus; — stains basophilically due to the abundance of RER and polyribosomes; — the clumps of RER & polyribosomes are referred to as Nissl Bodies. B. Dendrites — one to many extensions of the cell body; — specialized to receive input from other neurons or from receptors; — contain Nissl bodies in their proximal parts and thus the initial portions of dendrites stain basophilically; — often have small protrusions, called dendritic spines, that expand the dendritic surface area and serve as sites of synaptic contact.

Multipolar Neuron
terminal) input (axon (telodendrite)
dendrite

cell body (soma)
initial segment (of axon)

next neuron (dendrite)

telodendritic branches (with terminal bulbs) myelin node

myelin internode

axon

axon hillock (of cell body)

axon (conducts excitation)
axon terminal branches telodendritic (transmit neuronal output) zone 4

dendritic zone (receives input)

Figure 1: Diagram of a neuron illustrating its component parts

C. Axon

— typically one per neuron; — an extension of the cell body that is specialized for conducting electrical impulses (action potentials). — lacks Nissl bodies and does not stain with routine histological stains.

Note: Axons are either myelinated (surrounded by a fatty insulating sheath that speeds conduction of the electrical impulse) or non-myelinated (lacking a myelin sheath and thus conduct impulses slowly).

2. Definitions: A. Ganglion — a collection of neuron cell bodies situated in the PNS B. 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) C. 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) D. Tract — a bundle of axons (nerve fibers) within the CNS (connective tissue is absent)

Types of Neurons
dendrite
telodendria (synapse in CNS) coiled proximal axon

axon

axon hillock (of cell body)

cell body

cell body

3. Neuronal Classification: A. Anatomically, by number of processes: 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 — has 2 processes (relatively rare; retina of eye and certain cranial ganglia). 3) Multipolar Neuron — many processes; typically 1 axon and 2 or more dendrites (most common type of neuron).

Bipolar Neuro

Unipolar Neuron

Multipolar Neuron

axon

cell body

receptor (free nerve endings)

dendritic zone (synapses on hair cells of cochlea)

telodendria

B. Functionally: 1) Motor (Efferent) — related to innervation of muscle, glands etc.; 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).
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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.

4. Axons: Axons are neuron processes that project to and synapse with dendrites or cell bodies of other neurons or with non-neuronal targets (e.g. muscle). Swellings, termed axonal varicosities/boutons, are found along the axon or at its terminal branches and are typically the sites where synapses occur (see Neurohistology, Lecture II). Morphologically axons are divided into two types: myelinated and non-myelinated.

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

1) Light microscopic appearance:
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 nonlipid components. This remaining protein configuration is called neurokeratin.

2) Nodes of Ranvier:
The nodes are breaks in the continuity of the myelin sheath which 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.
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3) PNS:
In the PNS, a typical myelinated axon has the following structure: axon, surrounded by myelin sheath, surrounded by lemmocyte, surrounded by basal lamina, surrounded by endoneurium. The PNS myelin sheath is richer in phospholipid & has less glycolipid then CNS myelin. The myelin is produced by the membrane of lemmocytes (Schwann Cells). Lemmocytes, derived from neural crest, are the supporting cells of the PNS. You will find them associated with all peripheral nerve fibers. A Fig. 4: Myelin Paranode—Myelin Node (of Ranvier)—Myelin Paranode chain of lemmocytes is required to provide myelin for one axon in the PNS. Myelin Formation—Myelination occurs when the axon attains a diameter > 1 µm. 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.

Figure 5: Schematic diagram illustrating the different phases of myelin formation in peripheral nerves.
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Myelin Development (PNS)
N a a neurolemmocyte

N

A
nonmyelinated axon a mesaxon

B

a

C
a myelin sheath

N

E

D

Figure 6: Diagrams showing features of myelinated and non-myelinated nerve fiber development.

4) CNS:
The myelin sheath is produced by oligodendrocytes (one of the CNS glial cells). A single oligodendrocytes will provide myelin for multiple axons. CNS myelin has more glycolipid and less phospholipid than PNS myelin. In the CNS, myelinated axons lack a basal lamina and endoneurium.

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Clinical Correlation
Demyelination - Demyelination is the destructive removal of myelin, an insulating and protective fatty protein that sheaths nerve cell axons. When axons become demyelinated, they transmit the nerve impulses 10 times slower than normal myelinated ones and in some cases they stop transmitting action potentials altogether. There are a number of clinical diseases associated with the breakdown and destruction of the myelin sheath surrounding brain, spinal cord or peripheral nerve axons. Degenerative myelopathy, for instance, is a progressive disease of the spinal cord in older dogs. The breeds most commonly affected include German Shepherds, Welsh Corgis, Irish Setters and Chesapeake Bay Retrievers. The disease begins in the thoracic area of the spinal cord and is associated with degeneration of the myelin sheaths of axons that comprise the spinal cord white matter. The affected dog will wobble when walking, knuckle over or drag their feet, and may cross their feet. As the disease progresses, the limbs become weak and the dog begins to buckle at the knees and have difficulty standing. The weakness gets progressively worse until the dog is unable to walk. Note: Unlike the PNS, axons in the CNS do not regenerate following injury. In part, this is due to the fact that CNS myelin contains several proteins that inhibit axonal regeneraltion.

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. 5, previous page). 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 — Nonmyelinated axons are not associated with oligodendrocytes but run free without any type of ensheathment. They are separated from one another by astrocytic processes.

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Size Range of Peripheral Nerve Fibers
Efferent Nerve Fibers Fiber Diameter
20 µ — — — 16 µ — — — 12 µ — — — — — 6 µ — — 3 µ — — 1 µ non-myelinated 0.2 µ

Afferent Nerve Fibers

annulospiral spindle endings

Extrafusal muscle fibers —large motor units ALPHA

Ia

tendon organs

Ib

A
BETA

Extrafusal muscle fibers —small motor units

secondary spindle endings encapsulated receptors in joints and skin

II

GAMMA

Intrafusal muscle fibers

DELTA

B C

hair follicle receptors free ending mechanoreceptors pricking pain receptors

III IV

GVE Preganglionic

GVE Postganglionic

slow pain nociceptors thermoreceptors

NOTE: Nerve fiber = axon + myelin for myelinated fibers and axon for nonmyelinated fbers. Conduction velocity (m/sec) = fiber diameter (µm) X 6 (approximately). Thus, a 20µm fiber conducts at approximately 120m/s = 270 mph.

Two classification schemes for peripheral nerve fibers:
1] Based solely on nerve fiber diameter (I—IV). . . commonly applied to afferent fibers. 2] Derived from the compound action potential:
!

Compound Action Potential (hypothetical)
" # $

A

B

C
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Lecture 2

Neurohistology II: Synapses, Meninges, & Receptors
Overall Objectives: To understand the concept of the synapse; to understand the concept of axonal transport; to learn to identify the three layers of the meninges; and to understand how receptors are classified.

I. The Synapse:
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. Synaptic Anatomy . . . The synpase 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. Synapses are comprised of three elements: a) Presynaptic nerve terminal — contains synaptic vesicles which house a chemical neurotransmitter that is released after vesicle fusion with the presynaptic terminal plasma membrane. b) Postsynaptic element— a dendrite, a cell body, or a target cell receiving the synaptic input. Receptor protein molecules, to which neurotransmitter molecules bind, are embedded in the postsynaptic plasma membane. c) Synaptic Cleft— a gap between pre- and post-synaptic elements into which neurotransmitter molecules are released.
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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.
En passant varicosities Neuromuscular end plates

Terminal bulbs

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).

Synaptic ultrastructure: • The presynaptic enlargement Microtubule (bouton, varicosity, or end Neurofilament plate) contains synaptic vesicles (20 nm diameter), clustered around an electron dense active zone (protein-rich plasma membrane). Vesicles are Synaptic anchored in place by actin vesicle microfilaments.
Mitochondrion

Presynaptic terminal bulb

Astrocyte

• Pre- and postsynaptic plasma membranes are separated by a synaptic cleft (20 nm wide). The Synaptic cleft contains glycoprotein cleft linking material and is surrounded by glial cell processes. Postsynaptic dendrite • The postsynaptic plasma membrane may appear unremarkable or thickened (electron dense). Receptor proteins (typically ligand-gated channels) are embedded in the plasma membrane.

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Synaptic Physiology . . . Presynaptic events: Neurotransmitter molecules are released in proportion to the amount of Ca++ influx, in turn proportional to the amount of presynaptic membrane depolarization, i.e., — in the resting state, the presynaptic membrane is polarized — when an action potential arrives at the end of the axon, the adjacent presynaptic membrane is passively depolarized (toward zero transmembrane potential) — voltage-gated Ca++ channels allow Ca++ influx (driven by [Ca++] gradient). — elevated [Ca++] triggers vesicle mobilization and docking with the plasma membrane — a number of vesicles fuse with presynaptic plasma membrane and release neurotransmitter molecules (about 5,000 per vesicle) by exocytosis. — transmitter molecules diffuse across the cleft & bind with postsynaptic receptor proteins — neurotransmitter molecules are eliminated from synaptic clefts via pinocytotic uptake by presynaptic or glial processes and/or via enzymatic degradation at the postsynaptic membrane. The molecules are recycled. — subsequently, presynaptic plasma membrane repolarizes (due to K+ channel conductance). Postsynaptic events: 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
(voltage activated K+ channels dominate conductance)

— arriving neurotransmitter molecules bind briefly/repeatedly to ligand-gated receptors, which opens ion channels directly or by means of second messengers
activation of [Na+ & K+] channels —> leads to depolarization toward zero potential; activation of Cl- or K+ channels —> hyperpolarization of postsynaptic membrane.

— a postsynaptic potential (PSP) results from the altered membrane conductance EPSP = Excitatory PSP = depolarization toward zero potential, excites the postsynaptic cell IPSP = Inhibitory PSP = hyperpolarization (serves to cancel EPSPs), inhibits the postsynaptic cell Electrotonic Conduction — following the removal/degradation of neurotransmitter molecules, the -70 postsynaptic membrane is + re-polarized (K channel conductance
again dominates.) -70

Note: 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 time. The magnitude of a PSP depends on the number of open ion channels which, in turn, depends on the amount of neurotransmitter released.

-70 0

EPSP

T i m e

mV
-70

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

II. Connective Tissue Coverings of Axons in the PNS:
1. Endoneurium-- surrounds each myelinated axon, or a group of nonmyelinated axons. 2. 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 which 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.) 3. Epineurium— surrounds the entire nerve

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III. Axonal Transport:
1. The net movement of substances along the axon; 2 rates: A. Fast Axonal Transport—100-500 mm/day B. Slow Axonal Transport—1-10 mm/day 2. 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. 3. Retrograde Transport—transport from the axon terminal toward the cell body; important mechanism by which virus particles (rabies) and neurotoxins (tetanus toxin) gain access to the CNS. [Note: Tetanus and Botulinum toxins are proteases which cleave neuronal SNARE-proteins.]

IV. Meninges: protective connective tissue sheaths surrounding the brain and spinal cord.
There are three layers of meninges: 1. Dura Mater— the outermost layer consisting of coarse, irregular connective tissue; composed of collagen and elastic fibers. 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”), the innermost layer of the meninges, it forms a thin protective membrane which adheres to the surface of the brain and spinal cord. It consists of flattened fibrocytes superficial to elastic and collagen fine fibers that extends into the numerous depressions and fissures on the surface of the brain and cord. It is very vascular.

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Cranial Meninges
Subarachnoid space Arachnoid villus Dorsal sagittal venous sinus Dura mater Arachnoid

Arachnoid trabecula Pia mater Cerebral cortex Falx cerebri White matter
V. Receptors:
1. 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. 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.

2. Classification of receptor populations: 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). Receptor classification based on Location: 1) 2) 3)

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1) Exteroceptors—associated with skin and subcutaneous tissue (GSA) 2) Proprioceptors—associated with muscles, tendons and joints (GSA) 3) Interoceptors—located in viscera (GVA)

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 detect 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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Lecture 3

Development of the Nervous System and Special Senses
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 those 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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Central Nervous System
Formation of neurons and glial cells from neuroepithelium: Neuroepithelium gives rise to neurons, glial cells (astrocytes and oligodendrocytes), 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); — the nucleus moves toward the neural cavity and the cell becomes spherical and looses its connection to the outer surface of the neural tube for mitosis; this inward-outward nuclear movement is repeated at each cell division.

Some 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 glioblasts lose contact with surfaces of the neural tube and migrate toward the center of the neural tubewall. Note: Microglial are derived from mesoderm associated with invading blood vessels. Layers and plates of the neural tube: Accumulated neuroblasts and glioblasts form the mantle layer, a zone of high cell density in 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 cellsparse zone where axons of neurons 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 lateral wall of the neural tube is divided into two 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.

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Generally, neurons are incapable of cell division (however, a few neurons do divide, e.g., neurons in olfactory epithelium). The last division of a neuroblast results in two neurons that are able to migrate but unable to divide.
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.

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 by neurons to modify target cells). Selective degeneration of neurons and neuronal processes is the result of functional competition. More appropriate targets are associated with more excitation conduction and more neurotransmitter release. Thus developmental remodeling is a consequence of electrochemical activity related to experiences/behavior. Throughout life, experiences drive nervous system remodeling through selective growth and pruning of neuronal synapses.
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 initial muscle fibers and individual muscle fibers will retain only a single neuromuscular synapse. The survivors (winners) released more neurotransmitter per terminal branch. (Neurons having fewer branches are able to release more neurotransmitter per terminal branch, giving them a competitive advantage over neurons with many more processes.) 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). (Note: different studies show different timelines for degeneration of neurons and dendrites.)

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Formation 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).

Adult CNS Structures Derived From Embyonic Brain Divisions
Embryonic Brain Division Derived Brain Structures Definitive Brain Cavities Associated Cranial Nerves

FOREBRAIN Telencephalon Diencephalon

Cerebrum Thalamus; hypothalamus; etc.

Lateral ventricles Third Ventricle

Olfactory (I) Optic (II)

MIDBRAIN Mesencephalon HINDBRAIN Metencephalon Myelencephalon

Midbrain

Mesencephalic aqueduct

III & IV

Pons and Cerebellum Medulla Oblongata

Fourth ventricle

V VI—XII

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

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Spinal cord development

— the neural cavity becomes central canal 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 (bundle), a lateral funiculus, and a ventral funiculus ).

Enlargements of spinal cord segments that innervate limbs (cervical and lumbosacral enlargements) are the result of greater numbers of neurons in those segments, due to less neuronal degeneration compared to segments that do not innervate limbs. Hindbrain: Medulla oblongata and pons
— alar plates move 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); 22

— cellular migrations: • superficial and deep layers of neurons are evident within the mantle layer of the future cerebellum; the deep cells migrate (pass the 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. Midbrain
— the neural cavity of the midbrain becomes mesencephalic aqueduct (which is not a ventricle

because it is completely surrounded by brain tissue and thus it lacks a choroid plexus).

— alar plates form two pairs of dorsal bulges which become rostral and caudal colliculi (associated with visual and auditory
reflexes, respectively);

— 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 (derived entirely from alar plate)
Diencephalon: — the neural cavity expands dorsoventrally and becomes the narrow third ventricle, the roof plate
is stretched 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 the pituitary gland);
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amus enlarges to the point where right and left sides meet at the midline and obliterate the center of the third ventricle.

— the mantle layer of the diencephalon gives rise to thalamus, hypothalamus, etc.; the thal— the optic nerve develops from an outgrowth of the wall of the diencephalon.

Telencephalon (cerebrum): — bilateral hollow outgrowths become right and left cerebral hemispheres; the cavity of each outgrowth forms a lateral ventricle that communicates with the third ventricle via an interventricular foramen (in the wall of each lateral ventricle, a choroid plexus develops that 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 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.

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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; — afferent neurons originate from neural crest as bipolar cells that subsequently become unipolar; in the case of cranial nerves, afferent neurons also originate from placodes (placode = localized thickening of ectoderm in the head); — postganglionic visceral efferent neurons arise from neural crest, the cells migrate to form autonomic ganglia at positions within the head, or beside vertebrae (along sympathetic trunk), or near the aorta, or in the gut wall (the latter are

parasympathetic and come from sacral and hindbrain regions);

— 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 branchial arch and innervate derivatives of these embryonic structures.
Innervation continuity is retained even when the derivatives are considerably displaced or when other structures have obstructed the pathway. The early establishment of an innervation connection explains why some nerves travel extended distances and make 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, because the heart migrates from the neck to the thorax pulling the nerve with it.

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

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 becomes the subarachnoid space which contains cerebrospinal fluid.

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Special Senses
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.

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— 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.

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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.

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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 branchial 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 branchial arches; — the external ear canal (meatus) is formed by the groove between the first and second branchial 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.

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Lecture 4

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

BRAIN

tract

Afferent neuron reflex interneuron cell body muscle receptor

Efferent neuron

Spinal Cord Section

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

terminal filament

cervical enlargement

lumbar enlargement

conus medullaris

A spinal cord segment = a portion of spinal cord that spinal ganglion gives rise to a pair (right & left) of spinal nerves. Each spinal dorsal nerve is attached to the spinal cord by means of dorsal and root ventral roots composed of rootlets. Spinal segments, spinal (rootlets) 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 vertebral canal. Spinal nerves (which are formed in intervertebral foramina) are covered by connective tissue (epineurium, perineurium, & endoneurium) rather than meninges.

spinal nerve ventral root (rootlets)

Spinal cord histology (transverse section):
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.
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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.
dorsal intermediate sulcus dorsolateral sulcus dorsal funciculus dorsal median sulcus and septum

dorsal horn intermediate substance

lateral funiculus central canal

ventral horn ventral white commissure

ventral funiculus

Segment C 6
ventral median fissure

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.
substantia gelatinosa

L7 Gray Matter Laminae

Selected Spinal Nuclei (Cell Columns)
nuc. thoracicus motor nuc. XI medial motor nuc. intermediolateral nuc. nuc. proprius marginal nuc. sacral parasymp. nuc.

C3

T1 0

L6

S3
lateral motor nuc.

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Types of spinal neurons:
All neurons in spinal cord gray matter have multipolar cell bodies. Based on axon destination, they can be divided into three major types, each of which has several 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: alpha motor neurons— innervate ordinary skeletal muscle fibers (motor units); 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).

Spinal Pathways
Primary Afferent Neuron = the first neuron in a spinal reflex or ascending spinal pathway.
Primary afferent Spinal Nerve neurons have their unipolar cell bodies in Spinal spinal ganglia. Receptors Ganglion are found at the periphPrimary Afferent Neuron eral terminations of their Dorsal Root axons. Their axons Collateral branches to spinal gray mater traverse dorsal roots, Spinal Cord Cranial branch to brain 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 (discriminative touch), the cranial branches of incoming axons ascend directly to the brainstem where they synapse on projection neurons of the pathway.
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Note: Pathway = sequence (chain) of neurons synaptically linked to convey excitability changes from one site to another.

Ascending Pathways:
Chains of neurons carrying information from receptors to the brain (cerebral cortex). 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. Ultimately, the pathway leads to thalamic neurons that project to the cerebral cortex. The function of a particular pathway is determined by: 1] which primary afferent neurons synapse on the particular projection neurons of the pathway, and 2] where the projection neurons synapse in the brain. 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).

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 interneurons. By synapsing on interneurons, descending tracts regulate: 1] spinal reflexes; 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). 34

Ascending Pathway Examples
Discriminative Touch Spinal Pathway
Fasciculus gracilis

Spinal Cord
midline (dorsal view)

BRAIN Medial
Nucleus gracilis lemniscus to thalamus Medial Cuneate Nuc.

Fasciculus gracilis Pelvic limb neuron

Fasciculus cuneatus Thoracic limb neuron

Spinothalamic Pathway (pain & temperature)
Spinothalamic Tract Dorsomarginal Nuc.
midline

To thalamus

Spinal Cord

BRAIN

Pelvic limb neuron

Thoracic limb neuron

Spinocervicothalamic Pathway (touch and pain)
Spinal Cord
Dorsal horn
midline

Spinocervicothalamic Tract

BRAIN
Medial lemniscus to thalamus
C-1,2

Lateral Cervical Nuc. Pelvic limb neuron Thoracic limb neuron

Spinal Pathways for Proprioceptive Feedback to Cerebellum
Spinal Cord
Nucleus Thoracicus
midline L- 4

Dorsal Spinocerebellar Tract Fasciculus cuneatus
T-1

BRAIN
Lateral Cuneate Nuc. Caudal cerebellar peduncle

Thoracic limb neuron Pelvic limb neuron

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Lecture 5

Spinal Reflexes & Neuronal Integration

Reflex = an inherent, subconscious, relatively consistent responses to a particular stimulation. Reflexes may be categorized as: somatic (involving skeletal m.) or autonomic (impacting viscera); and as brainstem (involving cranial nn.) or spinal (involving spinal nn. and the spinal cord)
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:
— extensor thrust: paw proprioceptors trigger lib extension

— panniculus reflex: pricking skin triggers contraction of cutaneus trunci m. — myotatic reflex: muscle stretch is resisted by contraction of the muscle — withdrawal reflex: limb is withdrawn from a noxious stimulus 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. Since "voluntary movement" and "involuntary reflex/reaction" compete for control of the same interneurons circuits, they cannot be independent on one another. Thus, brain activity will influence spinal reflex responses, making reflex evaluation an interpretive art.

Withdrawal Reflex = Flexor (Crossed Extensor) Reflex
Features of the reflex (diagrammed on the next page) 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; — 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 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 as descending pathways mature; but later in life, the normally inhibited crossed extension reappears if “upstream” damage to descending fibers removes the inhibition.
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Withdrawal Reflex
1 3 2 DL F. DL Sulcus

A

C

B
D

D

flexor
extensor

flexor

extensor

BACKGROUND PROPRIOCEPTIVE INFORMATION 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 receptors: free nerve endings: endings pain (Golgi) tendon organs: organs located in series with muscle fibers (tension detector) muscle spindles: spindles located in muscle belly (length detector)
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Muscle Spindle and Myotatic Reflex
Muscle spindles are:
• elaborate proprioceptors positioned in parallel with muscle fibers; • designed to signal muscle length. Types of nerve fibers found in a muscle nerve

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.

Intrafusal muscle fibers:

vs. extrafusal (typical) muscle fibers • very small, anchored in endomysium • do not contribute anything 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 region contains chain of nuclei.

Muscle & Tendon Receptors

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) they are endings of large nerve fibers (type IA); initially AP frequency reflects rate of stretch; then steady AP frequency reflects degree of stretch

1] primary (annulospiral) endings — spiral around central (nuclear) regions;

2] secondary endings — "flower-spray" formations adjacent to nuclear chain regions;

they are endings of type II nerve fibers; AP frequency is proportional to degree of stretch.

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tendon

Myotatic Reflex

b a II
reticulospinal tract from brain

s ding n e e p l at d n e ings d n le tr ai

GAMMA neurons

ALPHA neurons extrafusal muscle fiber 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.
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same muscle antagonist muscle

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).

Functions of the myotatic reflex:
• Muscle tone = the resistance muscles offer when being stretched (lengthened)
= the resistance encountered when an appendage is manipulated — 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.

• 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. 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].

• Voluntary movement
For slow movements, posture can be sequentially adjusted to produce movement, e.g., hindlimb scratching the flank; learning any new movement sequence; etc. For abrupt voluntary movements, the brain co-activates alpha & gamma neurons to maintain spindle sensitivity while muscles shorten (spindles fire during movement). Gamma neurons (myotatic reflexes) must be inhibited in antagonistic muscles as agonists are excited. 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.
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Neuronal Integration
A typical multipolar neuron in the CNS receives many thousands of synaptic inputs (excitatory/ 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 integrtion.
inhibitory; axosomatic/axodendritic; from interneurons/projection neurons; etc.).

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 toward a lower resistance (asymmetrical diameter = asymmetrical resistance).

NOTE: Inhibitory synapses behave like excitatory ones, except that they produce IPSPs that hyperpolarize the soma and cancel EPSPs). 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.
The magnitude of soma depolarization (an analog signal ideal for integration) is converted to frequency of APs along the axon (a digital signal ideal for distance conduction).

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.
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• synaptic effect is increased by repetitive firing (temporal summation); • synaptic effect is increased by collaborative firing of different sources (spatial summation).

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

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

42

6 7 8 4 3 5 1

2
triceps brachii m.

Neuronal Integration Scenario
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 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.

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

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).
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Lecture 6

Cranial Nerves
Overall Objectives: To understand the organization of cranial nerves with respect to their nuclei within the brain, their course through and exit from the brain, and their functional roles.

I. Factors Responsible for Complex Internal Organization of Brain Stem:
1. Development of the Fourth Ventricle a) Medulla Oblongata and Pons are ventral to the fourth ventricle b) Alar Plate is displaced lateral to Basal Plate. 2. Cranial nerve nuclei form discontinuous cell columns rather than continuous cell columns as seen in the spinal cord. 3. Some cranial nerve nuclei migrate from their primitive embryonic positions (e.g., nuclei of nerves V & VII). 4. Special senses (hearing, balance, taste and vision) develop in association with the brain stem (SVA & SSA). 5. Development of the cerebellum and its connections adds additional components.

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

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 or 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 axctivity.
44

III. Motor Efferent Nuclei (Basal Plate Derivatives):
1. 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. A) 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: 1) Oculomotor, trochlear or abducent (cranial nerves III, IV, &VI): Abnormalities in eye movement, deviation of the eyes (strabismus). 2) Hypoglossal (XII): Paralysis and atrophy of tongue muscles; deviation of tongue toward the side of damage, problems chewing & swallowing.

Afferent and Efferent Nuclei
GVA IV
alar plate basal plate

GSA

GSA GVA VE SE

VE SE SE (SVE)
olivary nucl.

spinal cord

brain stem

Comparison of the four major cell columns in the spinal cord with the more complicated picture seen in the brainstem. Note that the adult location of the alar derivatives (sensory nuclei) is located laterally in the brainstem instead of dorsally as it is in the spinal cord.

B) 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 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. (Formerly this cell column was regarded as (SVE)). Damage or lesions involving these nuclei or their nerves result in the following clinical signs: 1) 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).
45

2) Facial nucleus: Innervates muscles of facial expression (ears, eyelids, nose & lips); damage to the nucleus or facial nerve results in facial paralysis. 3) 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. 2. 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 contriction 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.

IV. Sensory Afferent Nuclei (Alar Plate derivatives):
1. 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: a) 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. b) 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. c) Mesencephalic nucleus of the trigeminal nerve: located in the midbrain, receives proprioceptive information from the face.

46

2. 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.

3. SVA (Special Visceral Afferent) Nuclei: A. 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. B. 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.

4. 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). 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. 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 animal’s ability to see or hear, respectively.

Cranial Nerve Cell Columns

inner ear (SSA) skin (GSA)

v is la ce ff ra le som ff ati c eff

Diagram indicating the nuclear columns in the brain stem and illustrating the type of structures supplied by the different categories and the nerves containing fibers from the different nuclear columns.

so

t ic ma ra ce s i v

f af

.

taste (SVA) (GVA)

somatic efferent

visceral efferent

47

Sensory (left) and Motor (right) Cranial Nerve Nuclei
rostral colliculus

m tectu

III ventricle

genu VII V

po

ns

VI

VII facial nerve olivary nucl.

optic chiasma
al c ap su le

crus cerebri

inte rn

thalamus

p.III III pons genu VII mes.tr.V n.pon.sen.V dorsal nucl. trapezoid body vestibular nucl. n.sp.tr.V sp.tr.V VI p.VII p.IX p.X n.amb. XII n.sol.tr. XI olivary nucl. VII IV motorV n.mes.tr.V

48

Cranial Nerves and Their Functions: Name and Number
Olfactory - I

Brain Region Function Associated (Functional With Components)
Cerebrum Smell (SVA)

Clinical Examination
Owner’s Observations

Symptom Seen After Injury
Anosmia (Loss of Smell)

Optic - II

Diencephalon

Vision (SSA)

Menace Response Anopsia (Loss of Vision) Horizontal Eye Strabismus: eye Movement; Pupil- deviated down & lary Light Reflex out. Large Pupil Extend head and Cat: dorsal aspect look for dorsoof vertical pupil lateral strabismus deviated laterally Bilateral damage = Dropped jaw, Asymmetric chewing, atrophy Double vision; Strabismus: eye deviated medially

Oculomotor - III

Midbrain

Eye Movement (SE, VE) Eye Movement (Dorsal Oblique Muscle: SE)

Trochlear - IV

Midbrain

Trigeminal - V

Pons

Abducens - VI

Medulla

Masticatory Move- Jaw movement Ments, sensation Eye blink reflex From face (SE, GSA) Eye Movement Lateral Eye (Lateral Rectus Movement Muscle; SE)

Facial - VII

Medulla

Facial Movement; Facial Movement Facial paralysis, Taste, rost. tongue drooling (SE, SVA, VE) Hearing and Balance (SSA) Tongue and Pharynx (GVA, VE, SVA) Horizontal and Vertical Eye Movement Pharyngeal gag reflexes Deafness, Head tilt, nystagmus Choking, Swallowing Difficulty Hoarseness, Inspiratory dyspnea Weakened turning of neck Deviation of Tongue toward Side of lesion 49

Vestibulocochlear - VIII Glossopharyngeal - IX Vagus - X

Medulla

Medulla

Medulla

Pharynx, Larynx, Gag reflexes, Heart, Viscera Blood Pressure, (SE, VE, GVA ...) Heart Rate Trapezius, + three. Neck movement neck mm. (SE) Tongue Muscles (SE) Tongue movement

Spinal Accessory - XI Hypoglossal - XII

Medulla

Medulla

Lecture 7

Vestibular System
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.

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: Osseous Labyrinth — tubes and chambers in the petrous part of the 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

bone perilymph fluid memb. labyrinth endolymph fluid otolith memb. macula

cupula membrane BONE

crista ampularis

UTRICLE semicircular duct

Schematic diagram of the osseous labyrinth containing the membranous labyrinth. The vestibule relationship (left) and the semicircular canal relationship (right) are shown.

Membranous Labyrinth — consists of interconnected tubes and sacs that are 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.)

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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 — larger of two sacs located in the vestibule 3) Saccule — smaller of two sacs located in the vestibule 4) 3 Semicircular Ducts — each duct is located within one of the semicircular canals. Each duct has a terminal enlargement called an ampulla which contains a crista ampullaris, a small crest bearing sensory receptor cells.

Ducts

Vestibular Apparatus:
Vestibular apparatus is a collective term for sensory areas within the membranous labrinth responsible for detecting linear acceleration (e.g., gravity) and angular acceleration of the head. The vestibular apparatus 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 of the duct.

kinocilium

otolith membrane

vestibular ganglion
efferent bipolar

vestibular nerve

CNS

Schematic illustraion of a macula, including neurons of the vestibular nerve. Two types of receptor (hair) cells have stereocilia that extend into the overlying otolith membrane.
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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 (hair) cells. From the apical surface of each hair cell, stereocilia protrude into an overlaying membranes. Membrane movement 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. This depolarization (receptor potential) cause release of glutamate from the basolateral cell membrane 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 reduces glutamate release. Crista Ampullaris. Stereocilia are embedded in a gelatinous membrane called a cupula. The cupula is moved by fluid inertia when the head rotates in the plane of a semicircular duct. The direction of head rotation is indicated by the relative amount of activity from the three semicircular ducts.
kinocilia

stereocilia tip-link

+ + ++ +

hair cell

Rate of firing — vestibular

nerve axon

time resting state (tonically active)

one Action Potential

depolarized

on

stimulus

off

Macula. Stereocilia are embedded in a gelatinous membrane termed the otolith membrane because it contains calcium concretions (“ear stones”). Being denser than surrounding endolymph, the otolith membrane has more inertia than the fluid and it lags during linear acceleration or deceleration of the head. Notes: 1) Receptor cells are spontaneously active and vestibular nerve axons continually conduct action potentials to the brainstem. Thus, movement of sterocilia results in an ncrease 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, spontaeous activity, which is bilaterally balanced under normal postural conditions, is quickly imbalanced during head acceleration.
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hyperpolarized receptor (hair) cell

on

stimulus

off

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

lateral

caudal (descending)

medial

Four Vestibular Nuclei (lateral view)

thalamus

III IV VI
cerebellar peduncles

oculomotor trochlear

abducent rostral medial lateral

caudal

lateral vestibulospinal tract reticulospinal tracts medial longitudinal fasiculus (mlf) Spinal Cord

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Vestibular Reflexes:
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 the eyes to move to the 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. 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).

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. Vestibular syndrome: (you should be capable of diagnosing which side is lesioned) • head tilt — lesion is on the “down ear” side • stumbling, falling, rolling — direction is toward the lesion side • nystagmus (oscillatory eye movement — abnormal when the animal is not rotating) — slow phase of nystagmus is directed toward the side of the lesion Note: 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. (During balanced vestibular activity, bilateral reflex effects cancel).

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.

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Lecture 8

Posture & Movement
In veterinary neurology, abnormalities of posture & movement are more important than sensory disorders because animals readilty 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 interneuronal 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 posture/movement/gait (basal nuclei interacting with thalamus & motor areas of cerebral cortex). Learned movements—including learned movement sequences performed too rapidly for sensory feedback (involves premotor cerebral cortex).

Brain Structures Concerned with Posture & Movement
----------------------------------------------------------------------------------------------------------- Hindbrain

Reticular Formation
Anatomy: network (mixture) of gray & white matter, found throughout the brainstem — synaptic input from collateral branches of ascending tracts (e.g., spinothalamic tract) Physiology: spontaneously active neuronal circuits; perform three major functions: — ascending system to alert cerebral cortex (via non-specific thalamic nuclei) vs. coma — vegetative centers: regulate heart rate, respiration, digestion, micturition, etc. — standing posture and muscle tone via pathways to alpha & gamma neurons: two divisions — the lateral one is spontaneously active & dominant: 1} located laterally in pons & medulla: pontine reticulospinal tract — activates alpha & gamma motor units of extensor muscles 2} located medially in medulla: medullary reticulospinal tract — inhibits neurons to extensor mm. & excites neurons to flexor mm.; not spontaneously active — driven by cerebral cortex

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. Vestibular nuclei also utilize the two reticulospinal tracts to adjust muscle tone.
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-------------------------------------------------------------------------------------------------------------Midbrain

Red nucleus
The nucleus gives rise to the rubrospinal tract—the principal descending tract for voluntary movement in domestic animals. (Rubrobulbar fibers go to cranial nerve motor nuclei.) The red nucleus is merely a collection of projection neurons. Axons from the motor area of cerebral cortex synapse on neurons of 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; elbow/stifle; and carpus/hock (not digits).

Tectum

(tectum = roof of the midbrain) Rostral & caudal colliculi give rise to two tracts (which arise from rostral colliculus): 1} tectospinal fibers—descend to the cervical spinal cord (head turning); 2} tectobulbar fibers—to cranial nerve nuclei that control ear & eye movement.

Substantia nigra
Functions like a basal nucleus (see below). It has reciprocal connections with the striate body (caudate & putamen), where its telodendria release the neurotransmitter dopamine. Deficiency of dopamine in primates results in Parkinson's Disease (hypokinesia, rigidity, tremor).

------------------------------------------------------------------------------------------------------------Forebrain Subthalamus
Functions like a basal nucleus (see below). It play a role in producing rhythmic movements such as are employed in locomotion. In primates, lesions (damage) to subthalamus result in involuntary release of large flailing movements (hemiballismus).

Basal nuclei
Three basal nuclei (caudate, putamen, & pallidum or globus pallidus) are associated with movement. The nuclei do not give rise to descending tracts. Instead they participate in forebrain circuits in which they communicate with cerebral cortex via thalamic nuclei. Damage to basal nuclei impairs coordinated movement by affecting the magnitude, timing and sequencing of individual components of a movement. (In domestic animals, lesions of the basal nuclei usually result in circling to the affected side.)
Anatomically, the term "Basal Nuclei" refers to non-cortical gray matter of the telencephalon. There are five major nuclei (and several smaller ones). The major nuclei can be anatomically subgrouped in different ways: 1] Striate body (gray matter connecting caudate & putamen produce striations in the intervening internal capsule). 2] Lentiform nucleus (the putamen and globus pallidus together have the shape (form) of a lens. Physiologically, only caudate, putamen, and globus pallidus play a motor role.

Caudate
Lentiform Nucleus

Putamen Globus Pallidus Amygdaloid Claustrum

Striate Body

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Functionally, basal nuclei are involved in two separate circuits: one, involving the caudate nucleus, is active in selecting & assembling movements; the other, involving putamen, regulates amplitudes & durations of movement components.
Note: Caudate nucleus & putamen both inhibit globus pallidus which, in turn, inhibits thalamic neurons that project to motor related areas of cerebral cortex.

Cerebral cortex
Motor-related areas of cerebral cortex: • motor area—located around the cruciate sulcus; principal source of output for all voluntary movement; it's the main source of two descending pathway systems (below) • premotor area—located in frontal lobe rostral to the motor area; required for re-calling learned, rapid-sequence movements (particularly involving distal muscles). • supplementary motor area—located medial to premotor area; active when thinking about a proposed movement; projects to motor area Descending pathways for voluntary movement fall into two categories: 1] Pyramidal tract = a direct connection from primary and other motor areas of cerebral cortex to efferent neurons, generally via local interneurons. Axons travel in the pyramid of the medulla oblongata. Most axons decussate at the medullary-spinal junction (lateral corticospinal tract); some cross at the level of termination in the cord (ventral corticospinal tract). The tract controls particularly musculature of the manus and pes. It is concerned with fine (vs. coarse), precise movements.
Some corticospinal axons affect projection neurons of ascending pathways to enable the cerebral cortex to modify sensory traffic on its way to the thalamus and cortex. The axons come from sensory areas of the cortex.

2] Extrapyramidal tracts = all other voluntary movement tracts directed by the cerebral cortex (motor area). The tracts control proximal musculature and thus direct relatively coarse components of posture/movement/locomotion. Naturally, this system is most important in domestic animals. The principal tracts are: rubrospinal tract, pontine reticulospinal tract, and medullary reticulospinal tract.
Voluntary movement: Urge —> Decision —> [limbic system] [association neocortex]

Selection (what) —> Execution (how) [premotor & caudate] [motor & putamem]

Veterinary Clinical Considerations:
Upper Motor Neuron Damage:
Loss of only pyramidal tract: paresis (partial paralysis or weakness) of manus & pes; inability to move digits and lips independently & rapidly; loss of tactile placing. Loss of motor cortex: disappearance of learned movement skills; spastic paralysis (absence of voluntary movement capability, plus release of the pontine reticular formation). Loss of whole forebrain (= midbrain animal): persistent standing posture but exhibits phasic actions (crouching, stepping, etc.) if prodded to do so; capable of maintaining standing posture (righting reactions are intact). 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 is possible with abrupt injury (spinal shock); paralysis without spasticity; local spinal reflexes intact; crossed extension accompanies the withdrawal reflex.

Lower Motor Neuron Damage: Spinal cord or peripheral nerve damage: paralysis and areflexia (flaccid paralysis); denervation atrophy of skeletal muscles with time.
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Movement Initiation Schema
Voluntary Movement
Globus pallidus Thalamus
Purpose
Limbic Drive & Association Neocortex

Descending Tracts:

Caudate and Putamen

Pyramidal tract: = lateral & ventral corticospinal tracts. Extra-pyramidal tracts: 1 = Rubrospinal tract 2 &`2 = Reticulospinal tracts Reflex tracts: 3 = lateral vestibulospinal tract 4 = medial vestibulospinal tract 5 = tectospinal fibers

Motor-related Neocortex

NOTE: Substantia nigra and subthalamus are also involved in basal nuclei loops.

Red Nucleus

Reticular Formation
Pons Medulla

Reflex Movement
Vestibular Nuclei

P.T.

Ex.-P.T. 1 2 `2 3 4 5

Tectum

local interneurons

Spinal & Brainstem Reflexes

P.T. = Pyramidal Tracts Ex-P.T. = Extra-pyramidal Tracts

alpha and gamma (final common pathway) neurons in motor nuclei
58

ADDENDUM

Movement and Posture Overview

Comments:
• Posture and movement result from excited alpha and gamma motor neurons (a motor unit is one neuron plus all of the muscle fibers it innervates). • Interneurons "hardwire" motor neurons so that logical movement patterns are produced (e.g., synergists are excited & antagonists are inhibited) Thus, most descending pathway axons synapse on interneurons. However, a minority of descending axons synapse directly on motor neurons (e.g., vestibulospinal axons; a minority of pyramidal tract axons synapse directly on motor neurons that innervate digits in primates and raccoons). • Both voluntary and reflex pathways compete for control of the same interneurons and motor neurons. Thus voluntary neurons must suppress reflex neurons, and vice versa, to gain control of motor units. • Neurons initiate a voluntary movement by exciting a particular pattern of motor units at a certain intensity — while the movement is underway, feedback from proprioceptors influences subsequent neuronal activity in motor centers to effect the desired movement; — the cerebellum influences neuronal activity in the initiating motor centers (the cerebellum continuously modulates neuronal activity, based on information about motor commands and proprioceptive feedback about position and acceleration).
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Lecture 9

Cerebral Hemisphere and Cortex
Cerebral Hemisphere
Right & left cerebral hemispheres are derived from the embryonic telencephalon. They are composed of gray and white matter. Gray Matter: Cerebral Cortex — layer of gray matter at the surface of the cerebral hemisphere. Three phylogenetic categories of cerebral cortex are: • archicortex — (hippocampus) oldest, composed of two layers • paleocortex — (piriform lobe) old, three layers, olfaction related • neocortex — new, six layers, detailed perception, learning, intelligence Basal Nuclei — gray matter nuclei located deep within the white matter of the cerebral hemisphere. Basal nuclei include: caudate nucleus, putamen, pallidum, claustrum. White Matter: Myelinated axons which connect cerebral cortex with other brain regions. Three categories of white matter fibers are recognized: Projection Fibers — fibers that leave the cerebral white matter. Projection fibers form the internal capsule. Two categories of projection fibers are: 1] corticofugal: terminate in the basal nuclei, brainstem, or spinal cord; 2] corticopedal: typically originate in thalamus & terminate in cerebral cortex. Commissural Fibers—fibers that connect cortices of right and left cerebral hemispheres. The largest bundle forms the corpus callosum. 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 because it is association with olfaction, the most primitive sensory modality.

Cerebral Cortical (Neocortex)
Neocortex, the phylogenetically most recent cortex, is only found in mammals. It is organized horizontally into six layers and varies in thickness among different regions of the hemisphere. Neocortex is involved in detailed sensory perception, in performing rapid sequences of finemovements, and in learning and intelligent behavior. It is most abundant in the human brain. It forms about 85% of the dog cerebral cortex (the remaining 15% being archicortex and paleocortex).
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Two neuron types predominate in the neocortex: pyramidal cell — conical cell body (>30 µm in diameter) 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 (<10 µm in diameter). Granule cells serve as interneurons, receiving input from cortical afferent fibers and synapsing on output neurons (pyramidal cells) of the cortex. Two types of afferent projection fibers from the thalamus enter the neocortex: specific afferents — modality specific input; terminate in inner granule cell layer non-specific afferents — background excitation; terminate in molecular layer.

Fig. 1. 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.
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Horizontal Layers of Cerebral Cortical
The cerebral cortex is organized into six horizontal layers (although layer boundaries are not very obvious in routine sections). The individual layers have different roles and vary in relative thickness among cortical regions (e.g., a sensory region has a thick internal granule layer; a motor area has a thick internal pyramidal cell layer). From superficial to deep, the six layers are: 1] Molecular layer — fiber layer; 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 output 4] Inner granule layer — interneurons for specific afferent input 5] Inner pyramidal layer — large cells; projection & long association output 6] Multiform layer — variably shaped cells; projection & long association output

Cell Column (Vertical) Organization of Cerebral Cortical
The entire cerebral cortex is organized into functional units, each unit being a column (about 0.4 mm diameter) extending the entire thickness of the cortex (including all six layers). Each vertical column is 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: — non-specific input to the column terminates in the molecular layer on distal dendrites of pyramidal cells, to provide background excitation to the column; — specific thalamic input terminates in the internal granule layer, exciting interneurons which excite other neurons of the column; — small pyramidal cells send their axons into the white matter to excite nearby cell columns; — 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.

Fig. 2. 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”.

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Functional areas (regions) of cerebral neocortex:
Motor area: somatotopically organized around the cruciate sulcus. The motor area drives voluntary movement and it is the primary source of pyramidal tract fibers to cranial nerve nuclei and spinal cord (corticospinal tracts). Somatotopic organization = organization based on regional organization 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 amount of cortex is proportional to density of innervation, not area of body surface. Primary sensory areas: receive specific afferents of a given modality from the thalamus or geniculate bodies: • somesthetic (somatosensory) 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 visual input. The area is retinotopically organized in the occipital lobe around the marginal sulcus. • auditory area — receives auditory input. The area is cochleotopically organized around the apex of the pseudosylvian fissure. • vestibular area — receives vestibular apparatus input. It is rostral to the auditory area. Note: Taste is represented in the somesthetic area near the tongue region. Olfaction is conscious detected at the piriform lobe (paleocortex).

Association areas: These are cortical areas that receive their specific input from other cortical areas, and so they are not involved directly with processing sensory and motor information. Rather these areas are involved integrating and interpreting information derived from primary sensory areas. There are different hierarchies of association areas: the lowest association areas (adjacent to primary sensory areas) extract significance from components of a stimulus, the highest areas are involved with thought, planning, memory, speech, creativity, etc. Association areas comprise 20% of the
canine brain and 85% of the human brain.

Note: In humans, language processing (written, vocal, signing) occurs in one cerebral hemisphere (left hemisphere in 95% of right handed and 70% of left handed persons) and visualspatial processing (shapes, symbols, patterns, configuration analysis) is dominant in the other hemisphere. Handedness is also a representation of hemispheric dominance.

Methods of Determining Cortical Function:
Destructive Lesions — information obtained by producing experimental lesions and by observing patients whose lesions can be confirmed at necropsy. Findings include: Somesthetic area — loss of the fine aspects of discrimination (e.g., cats loose the ability to discriminate various degrees of texture roughness)

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Auditory Area — bilateral lesions cause difficulty in localizing sounds and the meaning (temporal & pitch pattern) of sound is lost. Electrical Stimulation — stimulate with electrodes and observe the resulting response. Motor area — stimulation of the area surrounding the cruciate sulcus causes contraction of contralateral muscles in a somatotopic pattern. Electrical Recording — following a stimulus the corresponding primary sensory areas become excited first. Next sensory information is relayed to association areas of cortex. Primary auditory area — high frequency tones; activate neurons in the caudal sylvian gyrus; low frequency tones activate neurons in the rostral sylvian gyrus (tonotopic organization). Primary Visual Area—cell columns respond to edges, flashes, colors, and intensities the elements that comprise an image. 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 of the 2-deoxyglucose. These neurons become highly radioactive and can be localized with autoradiographic techniques.

Figure 3: Diagram of a right cerebral hemisphere illustrating locations of the primary motor area and various primary sensory areas.

Figure 4: A schematic diagram illustrating a left cerebral hemisphere of a cat. Representation of the motor area and somethetic are is shown by an animunculus in each case. The anumunculus displays the the amount of cortical surface devoted to each region of the body. Notice that the hindlimbs and tail extends onto the medial surface of the hemisphere.
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Lecture 11

Nociception II
1. 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). A. Receptors: Free nerve endings 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.

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
midline

Spinocervicothalamic Tract

BRAIN
Medial lemniscus to thalamus
C-1,2

Lateral Cervical Nuc. Pelvic limb neuron Thoracic limb neuron

Fig. 1: Diagrams of the spinothalamic and spinocervical pathways.
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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.

III. Types of Pain:
A. Transient Pain—elicited by activation of nociceptive transducers in skin or other tissues of the body in the absence of any tissue damage. It is evoked to protect animals or humans from physical damage by the environment or by excessive stress of the body tissues. B. Acute Pain (Prolonged, subchronic, e.g. surgical pain; inflammatory pain)—elicited by substantial injury of body tissue and activation of nociceptive transducers at the site of local tissue damage. The local injury alters the response characteristics of nociceptors, their central connections and the autonomic nervous system in the region. This type of pain is seen after trauma, surgical interventions and some diseases. Lasts a few days or weeks, but “healing” typically occurs. C. Persistent or Chronic Pain—(arthritis; neuropathies, back pain, etc.) are commonly triggered by an injury or disease, but may be perpetuated by factors other than the cause of the pain. Because chronic pain is unrelenting (lasting months or longer), it is likely that stress, environmental, and affective factors may be superimposed on the original damaged tissue and contribute to the intensity and persistence of the pain. Note: The central (CNS) and peripheral (PNS) nervous systems are dynamic, not static, and are modulated by tissue damage and injury. In the spinal cord, immune-like glial cells (astrocytes & microglia) are activated in response to subcutaneous inflammation, nerve trauma, and tumors. These glia are involved in the creation and maintenance of pathological pain states, in part by releasing proinflammatory cytokines (TNF, IL-1,etc.).

THE ENDOGENOUS ANALGESIA (Pain Suppression) SYSTEM:
Since the pioneering studies of Magoun and colleagues, it was known that the brain stem can exert a strong control over the spinal cord. 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. 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 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.

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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 on the following page. The system is organized such that various stimuli or natural events, including stress, fear, exercise and pain itself can activate the PAG which in turn activates the nucleus raphe magnus and locus coeruleus. These nuclei in turn send descending axonal projections via the dorsolateral funiculus and the ventrolateral funiculus, respectively, to inhibit spinal cord dorsal horn neurons. When this system is active it leads to suppression of nociception or pain. It is interesting to note that female animals have a separate descending system from the PAG that is sensitive to estrogen. This unique descending inhibitory system appears to be active when blood levels of estrogen are high, such as during birth. 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 seems to be centered in the brainstem. The periaqueductal gray and the raphe magnus have collections of two physiologically different types of neurons that appear to be related, on the one hand, to pain enhancement and, on the other hand, to pain suppression.

midbrain

periaqueductal gray

locus coeruleus

pons

medulla oblongata

nucleus raphe magnus

+
periaqueductal gray

locus coeruleus nucleus raphe magnus

-

spinal cord dorsal horn

+

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Pain Relief in Animals:
1. Drugs: Apirin, Rimadyl (carprofen, a non-steroidal anti-inflammatory drug), butorphanol 2. 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 nor-epinephrine, 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).
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Size Range of Peripheral Nerve Fibers
Efferent Fibers Fiber Diameter Afferent Fibers
20 µm — annulospiral spindle endings — Extrafusal muscle fibers — —large motor units 16 µm — ALPHA tendon organs — — Extrafusal muscle fibers 12 µm —small motor units — — secondary spindle endings BETA encapsulated receptors in — joints and skin — — Intrafusal muscle fibers GAMMA 6 µm — DELTA — hair follicle receptors 3 µm free ending mechanoreceptors pricking pain receptors — GVE Preganglionic — 1 µm non-myelinated slow pain nociceptors GVE Postganglionic thermoreceptors 0.2 µm
NOTE: Conduction velocity (m/sec) = fiber diameter (µm) X 6 (approximately). Thus, a 20µm fiber conducts at approximately 120m/s = 270 mph.

Ia Ib

A

II

III IV

B C

Schematic illustration of free nerve endings.
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Lecture 10

Nociception I
Overview of Pain
I. 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 pain stimulus. It is a complex sensory experience with many subjective components: 1) discriminative; 2) learning and memory—associate pain with certain events; 3) unpleasantness, displeasure and 4) suffering, escape. B. Noxious—a stimulus that damages or threatens damage to tissue, it can be mechanical, thermal or chemical. C. Nociceptor—a primary afferent neuron that is preferentially sensitive to a noxious stimulus. D. Nociception—the detection of tissue damage by specialized transducers (nociceptors) attached to “A delta” and “C” peripheral nerve fibers. The term “Nociception” is often used interchangably with the term “Pain”, but technically 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. E. Algesic—pain producing vs. Analgesic—pain preventing F. Hyperalgesia—increased pain sensation elicited by a noxious stimulus G. Allodynia—a pathological condition in which pain is produced by a stimulus that is normally innocuous (sunburn).

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II. How to Recognize Pain in Animals:
1) Altered Behavioral Responses—increased aggressiveness, avoidance behavior, reluctance to be touched, decreased appetite, lethargy. 2) Altered Autonomic Function—increased heart rate, increased respiratory rate (hyperventilation), increased sweating, salivation. 3) Lameness 4) Vocalization— crying/ yelping

III. Pain Transmission and Pain Pathways:
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 (unmyelinated terminals which contain synaptic vesicles). Damage to tissue causes the release of a number of mediators that activate nociceptor free nerve endings. These mediators include ATP from damaged cells and bradykinin from blood (Fig. 2 ). In response to activation these terminals may actually release their transmitters (substance P, CGRP and other peptides) into the extracellular fluid in the area that they are located, this amplifies the pain sensation (Substance P for example causes neurogenic inflammation by inducing mast cell degranulation).

Fig. 2: Influence of inflammatory mediators upon the activity of a “c-fiber” nociceptor following 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.). Pain terminals then conduct an electrical signal to the spinal cord.
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2. Peripheral nociceptors have their cell body or soma in a dorsal root or cranial nerve ganglia. The cell body gives rise to: 1) a peripheral process or primary afferent axon that innervates 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. 3: Diagram of a nociceptor showing the cell body and processes.

Pain Sensitivity: Pain receptors become sensitized after tissue damage. When tissue is damaged or a noxious stimulus is repeated nociceptors exhibit sensitization in that there can be a reduction in the threshold for activation, an increase in response to a given stimulus, or the appearance of spontaneous activity. This sensitization results from the actions of second messenger systems activated by the release of inflammatory mediators (bradykinin, histamine, prostaglandins, serotonin) at the site of injury. This causes some of the features of hyperalgesia produced by tissue damage or by pathological processes. 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—unmyelinated, conduct at velocities of less than 2 M/sec (2nd pain).
NOTE: A! and C fibers can be classified into various types based on their functional properties. For example C fibers can be divided into: C-mechanical/heat nociceptors; C Polymodal Nociceptors (sensitive to heat, mechanical & chemicals) and Cold Nociceptors.

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

Mechanical Stimulation:
action potentials:

innocuous brushing Thermal Stimulation:
action potentials:

innocuous pressure

light pinch

hard pinch

40° C 30° C

45° C

50° C

Figure 4: Response characteristics of C polymodal (mechanoheat) nociceptors.

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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

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. Although this pathway clearly plays an important role in carnivores, the spinocervicothalamic pathway (discussed in pain lecture 2) plays an equally important role in pain transmission in dogs and cats. 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. 5].
Note: The transmitters utilized by these first order neurons are glutamate and aspartate. In addition, several peptides (Somatostatin, Substance P) are present which may modulate the effects of excitatory amino acid transmitters.

Fig. 5: Diagram illustrating the termination sites of nociceptive fibers in the marginal nucleus and nucleus proprius. (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 which also carry pain sensation. These axons collectively form a tract in the ventral part of the lateral funiculus called the Spinothalamic Tract (Fig. 6 ). 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 (eg. relationship between emotion [mood] and pain; attention to and memory of pain).
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(D). These 3rd order neurons in the thalamus in turn send their axons to the cerebral cortex. Note: Neurons in the lateral thalamus (for discrimination) project to the somatosensory cortex; Neurons in the medial thalamus (for affective aspects of pain) project to other areas of cortex (prefrontal, insular and cingulate 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. It should also be noted that in addition to pain the spinothalamic pathway conveys temperature sensation.

Fig. 6: Simplified diagrams illustrating the main features of the spinocervicothalamic pathway and the spinothalamic pathway.

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Lecture 12

Cerebellum
Objectives: 1) To learn the basic anatomical organization and functional roles of the cerebellum. 2) To understand the anatomical and chemical organization of the cerebellar cortex (i.e., cell layers, cell types, and neurotransmitters). 3) To appreciate the clinical abnormalities that occur following cerebellar damage.

Location:
The term cerebellum literally means little brain. The cerebellum is located dorsal to the brainstem. 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; it is characterized by abnormal gait & uncoordinated muscle movements. 2. Dysmetria—altered range of motion (misjudge distance) 3. Intention Tremor—oscillating motion, especially of the head, during movement.

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
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2. Cerebellar Lobes: A. Rostral Lobe = Spinocerebellum (paleocerebellum) — related to spinal cord, associated with postural tone. Damage results in forelimb hyperextension and hindlimb hip flexion. B. Caudal Lobe = cerebrocerebellum (neocerebellum) — Damage results in hypotonia, hypermetria, 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 proprioceptive 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.
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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.

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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 pontocerebellar fibers (which form the middle cerebellar peduncle). [Alerts the cerebellum about anticipated movements].

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 reticulospinal 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.

Clinical Abnormalities:
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 maintanence of equilibrium and appropriate muscle tone.

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Cerebellar disorders usually result from: 1. Tumors 2. Viral Infections (encephalitis) -- which may occur in utero 3. Heavy metal poisoning 4. Genetic disorders 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 on the ipsilateral side (same side as the lesion). 3. Lesions of the vermis result in truncal tremor and gait ataxia (a splayed stance and swaying of the body while walking).

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Lecture 13

Diencephalon and Hypothalamus
Objectives: 1) To become familiar with the four major divisions of the diencephalon 2) To understand the major anatomical divisions and functions of the hypothalamus. 3) To appreciate the relationship of the hypothalamus to the 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 has been implicated in a number of autonomic (ie. respiratory, cardio-vascular), endocrine (thyroid function) and reproductive (mating behavior) functions 2. Subthalamus — (“sub” = below), located ventral to the thalamus and lateral to the hypothalamus (only present in mammals). a. Plays a role in the generation of rhythmic movements b. Lesions in primates lead to hemiballism (a violent form of hyperkinesia) 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. thalamus habenula pineal gland caudal commissure

fornix rostral commissure lamina terminalis

hypothalamus

midbrain

mamillary body

optic chiasm tuber cinereum neurohypophysis adenohypophysis

Fig. 1. Schematic diagram illustrating the components of the diencephalon.
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4. Hypothalamus — (“hypo” = below), the most ventral part of the diencephalon; it is the most significant component of the diencephalon from a clinical standpoint because lesions result in abnormalities in endocrine, limbic and/or autonomic function

Hypothalamus:
1. Functions — its most important job is to maintain homeostasis; 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 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 each of which contains various nuclei. a. Supraoptic region — lies above the optic chiasm and contains three important nuclei: 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 — appears to be the hypothalamic nucleus critically involved in controlling circadian rhythms (endogenous biological rhythms that have a period of about 24 hours). The nucleus synchronizes rhythms to light and dark. Other circadian rhythms: sleep-wakefulness; body temperature. b. Tuberal Region c. Mamillary Region 3. Afferent Inputs to the Hypothalamus: a. Brain Stem via the Medial Forebrain bundle b. Limbic System via the fornix c. Retina via direct branches of the optic nerve and tract d. Blood (hypothalamic cells are sensitive to hormone concentrations, glucose levels, etc.) 4. Major Efferent Projections From the Hypothalamus: a. To the brain stem and spinal cord (via the dorsal longitudinal fasciculus) b. To the thalamus (mammallothalamic tract) c. To the limbic system d. To the pituitary gland

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Figure 2: Regions of the hypothalamus and pituitary gland in midsagittal view. Note the tuber cinereum forms the floor of the hypothalamus between the optic chiasm & mammillary bodies. The hypothalamus is divided in a rostrocaudal direction into 3 subdivisions: supraoptic, tuberal and mammillary, respectively. 5. Relationship to Pituitary Gland: [The 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.] The hypothalamus controls the endocrine system via two different routes: a. Directly by secretion of neuroendocrine products into the general circulation via the vasculature of the posterior pituitary gland (ADH and oxytocin). b. Indirectly by secretion of releasing factors into the local hypophyseal portal venous plexus (which 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 via these releasing factors. Fig. 3. 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.
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Hypothalamic Function:
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 contractions 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 suckling (induces contraction of myoepithelial cells in mammary gland). 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 decreases 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 — loss of control of water excretion due to a failure of production, transport or release of ADH into the blood stream. Commonly associated with tumors of the adenohypophysis. 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: Hyperadrenocorticoidism often accompanies tumors of the adenohypophysis which produce excess adrenocorticotropic hormone. Symptoms: Extremely hungry; hair loss from the body; enlarged liver; lameness with skeletal muscle atrophy. 3. Control of the Autonomic Nervous System Stimulate rostral hypothalamus — parasympathetic responses (e.g., slowed heart rate). Stimulate caudal hypothalamus — sympathetic responses (e.g., increased heart rate, vasoconstriction, etc.) Disease: 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. b. Caudal hypothalamus — heat conservation center: cool blood, pyrogenic substances or input from cold receptors causes shivering and vasoconstriction which serve to increase body temperature.

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Disease: damage to the rostral hypothalamus can cause hyperthermia (fever) while damage or 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: Disease: Lesions of the hypothalamus often cause abnormal eating and drinking behavior (see Fig. 4, below).

6. Behavior: together with the limbic system the hypothalamus participates in behavioral circuits responsible for controlling an animals behavior. Diseases: A. Lesions of the hypothalamus in cats can cause rage reactions B. Cattle with pituitary abscesses that effect the hypothalamus are often depressed and hold head and neck extended as if “star gazing”.

Fig. 4. The effect of discrete bilateral lesions in specific hypothalamic areas on appetite in the cat. Lesions of the ventrolateral nuclei produce hyperphagia, while lesions of the extreme lateral hypothalamus produce loss of appetite (Anorexia).

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Lecture 14

Olfaction and The Limbic System
Objectives: 1. To understand the anatomical organization of the olfactory system 2. To understand the concept of the “limbic” system 3. To be able to identify the major components of the limbic system and associate these components with limbic system functions

The Olfactory System:
1. Modality — Olfaction (SVA) 2. Receptors — bipolar cells located in the olfactory epithelium within the upper nasal cavity. 3. 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 cribiform plate of the ethmoid bone to enter the olfactory bulb. 4. 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.] 5. 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).

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

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Fig. 2. The olfactory epithelium. A) Schematic illustration of the olfactory epithelium, showing the major cell types. The inset shows the location of putative 7 transmembrane odorant receptors (7TMr) on cilia of olfactory receptor neurons. B) Hypothesized olfactory receptor-transduction mechanisms. Odor molecules bind to specific 7TMr proteins located in the cilia. These 7TMrs are thought to be coupled to G proteins that activate either adenyl cyclase (AC) to generate cAMP or phospholipase C (PLC) to generate phosphitidal inositol (IP3). These second messengers open channels that admit calcium or sodium into the cilium. Entrance of these ions lead to membrane depolarization and the generation of action potentials that are conducted along olfactory nerve fibers to the olfactory bulb.
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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

The Limbic System:
1. 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. 2. 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 3. Components: Hippocampus; Cingulate Gyrus; Amygdala; Septal Area; portions of the Thalamus; Piriform lobe; and Mammillary Bodies of the Hypothalamus

Fig. 3. Illustrations of limbic structures on medial views of the brain. A. 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. Parts of the cortex and diencephalon have been removed to illustrate the fornix, mamillothalamic tract and other limbic structures.
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Individual Limbic Structures and Possible Function:
In general the neocortex has a dampening effect on emotional behavior. This is illustrated by sham rage— which 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 autonomic responses. It is called sham rage because unlike genuine rage, the anger occurs spontaneously or can be triggered by mild tactile or other nonnoxious stimuli. Hippocampus — a 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 ‘time-dependent impairments’ 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. 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. Amygdala — a highly differentiated region near the temporal pole of the mammalian cerebral hemispere. 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 aggression, 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. [Note: Recent evidence indicates that the amygdala is neither a structural nor a functional cohesive unit, but rather it consists of different parts performing different functions. For instance, the central nucleus of the amygdala projects to visceral areas of the brainstem and is a specialized autonomic projecting motor region. In contrast the cortical amydala together with the nucleus of the lateral olfactory tract form the caudal end of the piriform lobe and play a role in olfactory function.] 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. Thalamus — links the limbic system to the neocortex and provides a means by which sensory information can gain access to the limbic system.

Also: Rhinencephalon (nose-brain) — includes the piriform lobe and olfactory bulb. It is concerned with olfaction and is a major component of the limbic system where it functions together with other limbic structures in affective behavior (urges, behavioral drives).

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Lecture 15

Cochlea and Auditory Pathways
Anatomical Considerations

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

Middle ear: 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.

Function of Middle Ear To 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.) Note: 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 in the cat). Inner ear: 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).

Cochlea
bisected

Within the cochlea, the cochlea 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.

cochlear nerve spiral ganglion
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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.

BONE Scala vestibuli

Vestibular membrane

Cochlear duct
Stria vascularis Spiral ligament

Spiral ganglion

Osseous spiral lamina

Basilar membrane

Scala tympani

An osseous spiral lamina and basilar membrane separate cochlear duct from the scala tympani. Within the cochlear duct, a spiral organ sits atop the basilar membrane along its entire length from the base to the apex of the cochlea. 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.)

BASE of cochlea

APEX of cochlea

The spiral organ (organ of Corti) 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. 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.

Spiral Organ
Limbus axons

tectorial membrane reticular membrane inner outer sensory hair cells

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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BONE

Scala tympani
oval window

helicotrema vestibular membrane basilar membrane

Scala vestibuli External Auditory Meatus
incus stapes malleus tympanic membrane

Cochlear duct Scala tympani
round window

Middle Ear

View from Scala tympani

basilar membrane

osseous spiral lamina

Mechanics of Hearing
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. 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. 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.
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. 92

Perilymph & Extracellular

Endolymph K+
pump
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

K+

+ + + +

_ _ _ _

+ ++ ++ _+ _ +_+ _ _ +_+ _ _

+ + + + + + + + + + + + + +

K+

K+
_ _ _ _ _ _ _ _ ++++++++++

40mV

90mV

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 that correspond to parameters of physics: pitch = wave frequency = Hz = Hertz = cycles/sec., volume = amplitude from the low point to the high point in a pressure wave, and direction = location of the source of the sound waves. (Sound also has “color”— higher frequencies impart overtones which enable one to distinguish different instruments playing the same note at the same volume.)

Pitch — 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). As the pitch (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. (Place principle: pitch is determined by the place of maximal amplitude displacement along the basilar membrane.) Volume — 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). Direction — at low frequencies, 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.)
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Auditory Pathway
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. We can say that more fibers decussate (in the trapezoid body) than remain ipsilateral, that the pathway ascends in the lateral lemniscus and then in the brachium of the caudal colliculus, and that the conscious sound pathway synapses in the medial geniculate body, from which neurons send their axons through the internal capsule to cerebral cortex surrounding the sylvian sulcus (primary auditory cortex).
Additional synaptic possibilities include: ventral nuclei of trapezoid body (gray matter among fibers of the trapezoid body); dorsal nucleus of the trapezoid body; nuclei of the lateral lemniscus; and caudal colliculus.

Internal Capsule

Auditory Cortex
Sylvian Sulcus

Medial Geniculate

commissure of caudal colliculus

Gray Matter

Caudal Colliculus
Nuclei of Lateral Lemniscus Dorsal Nucleus of Trapezoid body Dorsal and Ventral Cochlear Nuclei
commissure of lateral lemniscus

Brachium of Caudal Colliculus

White Matter

Lateral Lemniscus Cochlear Nerve

Trapezoid Body

Ventral Nuclei of Trapezoid Body

Comments about gray matter in the auditory pathway:
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).
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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.) 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.)

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.) 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). 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.
auditory association cortex

primary auditory cortex

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Lecture 16

Visual System
EYEBALL — composed of three concentric layers:
1] SCLERA (white) and CORNEA (transparent) = outer, fibrous layer. 2] IRIS, CILIARY BODY and CHOROID = middle, vascular layer (uvea). The choroid contains a tapetum lucidum in most domestic animals (absent in the pig). 3] RETINA = inner layer of the eyeball (develops embryologically from an optic cup). 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.

Fundus of Right Eye
Ciliary body Iris Cornea Retina Lens area centralis

Tapetum lucidum RETINA vessel Area centralis (visual streak)

Optic disc ora serrata Sclera

Optic disc

Optic nerve

RETINA
Overview. The retina develops from the optic cup of the diencephalon, and the optic nerve is histologically a CNS tract. Ten histological layers are recognized in the optic part of the retina. 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.

Circuitry. Photoreceptor cells (rods and cones) synapse on bipolar cells which, in turn, synapse on ganglion cells. Photoreceptor cells also synapse on horizontal cells which provide lateral inhibition to sharpen the visual image, as do amacrine cells. 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.
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Photoreceptor cells:
There are two populations of photoreceptor cells: rods & Retinal cones. The outer segments of Layers: rods & cones contain stacked 1. pigmented membranous discs that are epithelium continually produced, sloughed, and phagocytized by 2. rods & cones 3. ext. limiting membrane pigmented epithelium. The 4. outer nuclear discs contain the photosensitive pigment (retinal) that 5. outer plexiform intercepts photons. bipolar Photoreceptor cells are cells 6. inner nuclear excited (depolarized) in the dark and inhibited (repolarized) by light (photons). 7. inner plexiform Excitation (depolarization) spreads electrotonically and 8. ganglion cell triggers proportional release of 9. optic n. fiber glutamate neurotransmitter 10. int. limiting membrane which either excites or inhibits the bipolar cells they synapse on.
Sclera Choroid Retina

horizontal c. amacrine c.

radial glial cell (astro cyte)

area centralis

Bipolar cells:
In general, bipolar cells are spontaneously active, and they are either hyperpolarized (inhibited) or depolarized (excited) by photoreceptor cells. Bipolar cells generate electrotonic potentials and they synapse on ganglion cells (as well as some amacrine cells). Bipolar cells associated with rods form convergent circuits (spatial summation), which improves vision in dim light but at the expense of image resolution. Bipolar cells associated with cones form relay circuits (temporal summation) which provides good visual detail but requires bright light. RODS • 95% of photoreceptor cells (in human retina) • widely disributed throughtout the retina • single population all containing rhodopsin (protein + retinal) and the same wavelength (color) sensitivity • functional in dim light • participate in highly convergent circuits (>1,000 rods converge on one ganglion cell) • exhibit spatial summation CONES • 5% of photoreceptor cells (in human retina) • concentrated in the Area Centralis of the retina • 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) • exhibit temporal summation

disks

Outer segment
outer limiting membrane
mitochondria

Inner segment
nucleus

Rod

Cone
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Transduction: Photon to Neural Signal
Transduction = converion of energy from one type to another = converting photon energy into neural signals.

Dark condition in rods . . .
• Rhodopsin builds up in the rod outer segment. Rhodopsin = protein (scotopsin) bound to retinal (11-cis Vitamin A aldehyde) • cGMP is abundant and acts to keep cation channels open. • Na+ and Ca++ influx depolarizes the rod cell in a graded electrotonic manner (-40 mV). • The depolarized rod cell releases glutamate at its synapse with bipolar and horizontal cells.

Photon effect in rods . . .
• Photon energy converts cis-retinal to all trans-retinal, destabilizing rhodopsin which becomes enzymatically active as it dissociates. • Activated rhodopsin triggers a G protein (transducin) to activated many phosphodiesterase molecules which enzymatically convert cGMP to GMP. • Cation channels close in the absence of cGMP and the rod cell becomes polarized (-70 mV). (One photon activates one rhodopsin molecule which triggers closure of hundreds of cation channels.) • The rod cell releases less glutamate at its synapse. Note: Transduction is the same in cones, except that the protein is different (not scotopsin).

Ganglion cells
Ganglion cell axons leave the retina and form the optic nerve. Unlike all other retinal cells, ganglion cells generate action potentials. They fire continuosly, and the presence/absence of light merely changes their firing rates. Ganglion cells respond to a spot of light with a center "ON/surround-OFF" pattern (or an "OFF/ON" pattern), i.e., the spot causes stimulated ganglion cells to increase their firing rates and lateral inhibition (by horizontal cells) causes surrounding ganglion cells to decrease their firing rates. Three functionally different populations of ganglion cells have been discovered: 1] Large cells that receive rod input from a broad area and signal motion, position, and depth; 2] Small cells with small receptive fields that are unaffected by color differences; and 3] Small cells that are color sensitive, i.e., excited by one color and inhibited by another.

Other retinal cells
Horizontal cells are always inhibitory. They are primarily responsible for lateral inhibition, i.e., the inhibition that surrounds the excitation generated by a spot of light. 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.
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VISUAL PATHWAY
Optic nerve — axons from ganglion cells of the retina (1.5 million axons in human; 0.2 million in dog) Optic chiasm (chiasma) — optic nerve axons decussate, except that a percentage of axons from the lateral side of each retina do not cross, depending on species:
— 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)

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).

Visual Fields
Binocular vision, which is important for depth perception, requires visual field overlap so that individual objects can be viewed simultaneously by both eyes. For binocular vision to occur, the visual cortex in one cerebral hemisphere must receive information about an object from both eyes. This requires that “corresponding” ganglion cells in each eye send their axons through the same optic tract. 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).

OVERLAP

Left field

Right field

Optic nerve Optic chiasma Visual cortex Lateral geniculate Optic tract

optic radiation (internal capsule)

Brachium of the rostral colliculus

Pretectal region Rostral colliculus
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Conscious Visual Pathway
Optic tract fibers synapse in the lateral geniculate nucleus, which exhibits a retinotopic organization and "ON/surround-OFF" receptor fields. Neurons of the lateral geniculate nucleus send their axons into the optic radiation of the internal capsule and then to the visual cortex. Actually, the lateral
geniculate nucleus is stratified, with input from each eye and large/small ganglion cell input entering different layers.

The visual cortex is retinotopically organized. Representation of the area centralis is greatly enlarged compared to cortical surface area devoted to the rest of the retina. The 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. 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: 1] 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. 2] 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). Three principles of conscious visual transmission are: • Retinotopic mapping — eventually lost at level of association cortex • Parallel processing — color/form/motion remain separate from retina to cortex • Hierarchial processing — receptive fields become larger and more complex at each level. Color Vision Humans have three populations of color senstive 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 senstive cones are found in other species, e.g., cat and pig. Nocturnal animals are completely color blind (rat, hampster, etc.).

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.)
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Two important visual reflexes are: 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.

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.

Pupil Size — Reflex Pathways
Retina Optic nerve Optic chiasma Optic tract Brachium of rhe rostral colliculus Pretectal region and Caudal commissure Lateral geniculate

Pupil (light sensitive) constriction
ciliary nerve ciliary ganglion oculomotor nerve

Pupil (emotion-related) dilation
plexus on internal carotid A.

Oculomotor nucleus

cranial cervical ganglion

Cervical spinal cord

cervical sympathetic trunk

Spinal cord segment T-1

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