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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; andto 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 associatedroots 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 thatinnervates cardiac and smooth muscle and glands. It is involuntaryand has two major subdivisions:
1) Sympathetic (thoracolumbar)2) Parasympathetic (craniosacral)
II. Histological Components:A. Supporting (non-neuronal) Cells— Glial cells provide support and protection forneurons 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 mainte-
nance 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 trans-
mission rate of action potentials along the axon.
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dendritic zone (receives input)
axon (conducts excitation)
telodendritic zone
myelin node
myelin internode
telodendritic branches(with terminal bulbs)
next neuron (dendrite)
axon hillock(of cell body)
input (telodendrite) dendritecell body (soma)
initial segment (of axon)
axon
Multipolar Neuron
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 (in-volved in generation and conduction of electrical signals) and receptors (which bind neu-rotransmitters and hormones and use distinct molecular mechanisms for transmembranesignaling; 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.
Figure 1: Diagram of a neuron illustrating its component parts
axon terminal branches(transmit neuronal output)
(axon terminal)
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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 speedsconduction of the electrical impulse) or non-myelinated (lacking a myelin sheath andthus conduct impulses slowly).
2. Definitions:A. Ganglion — a collection of neuron cell
bodies situated in the PNSB. Nucleus — this term is used in a special
sense in neurobiology to describe a collection ofneuronal cell bodies in the CNS (accumulation ofgray matter)
C. Nerves — bundles of axons that extendout from the brain as cranial nerves and from thespinal cord as spinal nerves (surrounded by connec-tive tissue sheaths)
D. Tract — a bundle of axons (nerve fibers)within the CNS (connective tissue is absent)
3. Neuronal Classification:
A. Anatomically, by number of processes:1) Unipolar (pseudounipolar)
Neuron — has one process that bifurcates; the cellbody of this neuronal type is found in spinal andcranial ganglia.
2) Bipolar Neuron — has 2 pro-cesses (relatively rare; retina of eye and certaincranial ganglia).
3) Multipolar Neuron — manyprocesses; typically 1 axon and 2 or more dendrites(most common type of neuron).
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 variousspinal reflexes).
MultipolarNeuron
Unipolar Neuron
Bipolar Neuro
telodendria(synapse in CNS)
coiled proximal axon
cell body
cell bodyaxon hillock(of cell body)
dendrite
axon
cell body
axon
dendritic zone(synapses on hair cells ofcochlea)
receptor(free nerveendings)
telodendria
Types of Neurons
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4. Axons:
Axons are neuron processes that project to and synapse with dendrites or cell bodies of otherneurons 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 andnon-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 structureformed 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 anaxon. Myelinated axons located in the PNS differ from those in the CNS both in chemical composi-tion 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 clearingin xylene) dissolves lipid components of the myelin leaving nonlipid components. This remainingprotein 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 adjacentsegments of myelin and occur at the junction of two lemmocytes in the PNS or two oligodendrocytesin the CNS. The nodes appear as constrictions along the nerve fiber.
Fig. 3. Peripheral nerve tissue (light microscopy).
Top. Longitudinal illustration of a myelinated
axon (myelin is gray; cytoplasm is black).
Lemmocytes form myelin sheaths around one
axon. Adjacent lemmocytes (myelin sheaths) are
separated by nodes. Cytoplasm filled clefts are
sometimes evident in myelin sheaths.
Right. Myelin sheaths appear as individual black
rings in a transverse section through a nerve
fascicle.
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3) PNS:In the PNS, a
typical myelinated axonhas the following structure:axon, surrounded by myelinsheath, surrounded bylemmocyte, surrounded bybasal lamina, surroundedby endoneurium.
The PNS myelinsheath is richer in phospho-lipid & has less glycolipidthen CNS myelin. Themyelin is produced by themembrane of lemmocytes(Schwann Cells).
Lemmocytes,derived from neural crest,are the supporting cells ofthe PNS. You will findthem associated with allperipheral nerve fibers. Achain 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. Thelemmocyte wraps around the nerve fiber (axon) several times producing a membranous sheath thatvaries in thickness depending on the number of times the lemmocyte wraps around the axon.
Figure 5: Schematic diagram illustrating the different phases ofmyelin formation in peripheral nerves.
Fig. 4: Myelin Paranode—Myelin Node (of Ranvier)—Myelin Paranode
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A B
C
DE
mesaxon
NN
N
a
a
a
a
a
myelin sheath
neurolemmocyte
nonmyelinated axon
Myelin Development (PNS)
Figure 6: Diagrams showing features of myelinated and non-myelinatednerve 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 moreglycolipid and less phospholipid than PNS myelin. In the CNS, myelinated axons lack abasal 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 im-
pulses 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 com-
prise 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 achain 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 associ-ated lemmocytes are surrounded by basal lamina and endoneurium.
2) CNS — Nonmyelinated axons are not associated with oligodendrocytes but run freewithout any type of ensheathment. They are separated from one another by astrocytic processes.
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Ib
Ia
II
III
IV
A
slow pain nociceptorsthermoreceptors
secondary spindle endingsencapsulated receptors in
joints and skin
tendon organs
annulospiral spindle endings
hair follicle receptorsfree ending mechanoreceptorspricking pain receptors
GVE Postganglionic
Extrafusal muscle fibers—large motor units
Intrafusal muscle fibers
Extrafusal muscle fibers—small motor units
ALPHA
BETA
GAMMA
DELTA
GVE Preganglionic
C
B
Size Range of Peripheral Nerve Fibers
Efferent Nerve Fibers Fiber Diameter Afferent Nerve Fibers
20 µ — — —
16 µ — — —
12 µ — — — — —
6 µ — —
3 µ — —
1 µ non-myelinated
0.2 µ
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
α
βγ
δ
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.
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Lecture 2
Neurohistology II:Synapses, Meninges, & Receptors
Overall Objectives: To understand the concept of the synapse; to understand the concept ofaxonal transport; to learn to identify the three layers of the meninges; and to understandhow 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 targetcells.
Synaptic Anatomy . . .The synpase is a site of apposi-
tion between a presynaptic element ofone neuron and a postsynaptic mem-brane of a target neuron (or an effector
organ); where, typically, a presynapticaxon enlargement releases transmittermolecules that diffuse across a synap-tic cleft and bind to receptor channelsin the postsynaptic membrane.
Synapses are comprised of threeelements:
a) Presynaptic nerve terminal —contains synaptic vesicleswhich house a chemicalneurotransmitter that is re-leased after vesicle fusion withthe presynaptic terminalplasma membrane.
b) Postsynaptic element— adendrite, a cell body, or atarget cell receiving the synap-tic input. Receptor proteinmolecules, to which neu-rotransmitter molecules bind,are embedded in the postsyn-aptic plasma membane.
c) Synaptic Cleft— a gap between pre- and post-synaptic elements into which neurotransmittermolecules 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 formmotor end plates on skeletal muscle fibers.
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(bouton, varicosity, or endplate) contains synapticvesicles (20 nm diameter), clus-tered around an electron denseactive zone (protein-richplasma membrane). Vesicles areanchored in place by actinmicrofilaments.
• Pre- and postsynaptic plasmamembranes are separated by asynaptic cleft (20 nm wide). Thecleft contains glycoproteinlinking material and is sur-rounded by glial cell processes.
• The postsynaptic plasma mem-brane may appear unremark-able or thickened (electron dense). Receptor proteins (typically ligand-gated channels) areembedded in the plasma membrane.
Terminalbulbs
En passantvaricosities
Neuromuscularend plates
Postsynaptic dendrite
Presynapticterminal bulb
Astrocyte
Synapticcleft
Synapticvesicle
Mitochondrion
NeurofilamentMicrotubule
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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 postsynapticmembrane. 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 natureof 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, whichopens 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 conductanceEPSP = Excitatory PSP = depolarization toward zero potential, excites the
postsynaptic cellIPSP = Inhibitory PSP = hyperpolarization (serves to cancel EPSPs), inhibits the
postsynaptic cell — following the removal/degradation of
neurotransmitter molecules, thepostsynaptic membrane isre-polarized (K+ channel conductance
again dominates.)
Note: PSPs constitute electrotonic conduc-tion, a passive voltage spread (in contrast tothe regenerative conduction of which axonsare capable). PSPs decay exponentially, overdistance and with time. The magnitude of aPSP depends on the number of open ionchannels which, in turn, depends on theamount of neurotransmitter released.
0
-70
mV
Distance
Time
Electrotonic Conduction
EPSP
-70
-70
-70
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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 perineuralepithelium and associated collagenous connective tissue. The perineurium participates in forming ablood-nerve barrier which limits the passage of water-soluble substances and proteins from bloodinto the endoneurial compartment. (The integrity of this barrier is altered in certain neuropathiesand 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/dayB. 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; importantmechanism 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 ofthe meninges; it consists of a distinctmembrane and numerous fibrous trabecu-lae on its inner surface. This trabecularnetwork forms the structural framework forthe subarachnoid space which lies betweenthe arachnoid proper and the underlyingpia mater.
The subarachnoid spacecontains cerebrospinal fluid (CSF). Atcertain points the subarachnoid space isdilated and forms “cisterns”. The cisternamagna and lumbar cisterns are importantclinically because that is where CSF tapsare performed.
[Note: CSF is a clear colorlessfluid that surrounds and permeates theentire central nervous system. It functionsto protect, support and nourish the CNS.]
3. Pia Mater—(from the latin term meaning”tender mother”), the innermost layer of themeninges, it forms a thin protective membrane which adheres to the surface of the brain and spinalcord. It consists of flattened fibrocytes superficial to elastic and collagen fine fibers that extends intothe numerous depressions and fissures on the surface of the brain and cord. It is very vascular.
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V. Receptors:
1. Receptor = a specialized region located on a peripheral terminal branch of an axon of aprimary afferent neuron, that can serve as a transducer—converting environmentalenergy (sensory stimuli) into depolarizing ionic current (nerve signals). The number ofreceptors per neuron ranges from several (small receptive field) to several dozen (largereceptive field).
vs.Sense organ = an organized collection of receptor cells, with which the dendritic zones of afferent neuronssynapse. The excitability of receptor cells is modified by environmental energy, i.e., the receptor cells actas transducers.
Sense organs are: retina, cochlea,vestibular apparatus, taste buds, andolfactory epithelium. Neurons that synapse onreceptor 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:
Falx cerebri
Arachnoid villus
Dura materArachnoid
Subarachnoid space
Arachnoid trabecula
White matter
Cerebral cortex
Pia mater
Dorsal sagittal venous sinus
Cranial Meninges
3)1) 2)
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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 itch4) electromagnetic—detect light on the retina of the eye5) chemoreceptors—detect chemical molecules, including: taste receptors, olfactory
receptors, arterial oxygen receptors in the aortic arch and carotid bodies, bloodosmolarity in the hypothalamus and blood glucose and fatty acid receptors in thehypothalamus.
Schematic diagram illustrat-ing various types of periph-eral receptors:
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Lecture 3
Development of the Nervous Systemand 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 de-tached 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 SystemFormation 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 mito-sis; 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 cell-sparse zone where axons of neurons and some glial cells are present is designated the marginal layer. The mantle layer becomes gray mat-ter 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 evi-dent 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 re-gions dorsal and ventral to the neural cavity constitute, respectively, the roof plate and the floor plate. The basal plate contains efferent neu-rons 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 di-vide, 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 CircuitsSculpting – 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 neurotransmit-ter 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 neuromus-cular 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 CortexIn 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 differ-ent 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 di-vide into the five primary divi-sions of the brain. Caudal to the brain the neural tube develops into spinal cord.
Flexures: During devel-opment, 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 do-mestic animals). The pontine flexure is con-cave dorsally (the other flexures are concave ventrally).
Adult CNS Structures Derived From Embyonic Brain Divisions
Note: The portion of brain remaining after the cerebrum and cerebellum are removed is referred to as the brain stem.
Embryonic Derived Definitive Associated Brain Division Brain Structures Brain Cavities Cranial Nerves FOREBRAIN Telencephalon Cerebrum Lateral ventricles Olfactory (I)
Diencephalon Thalamus; Third Ventricle Optic (II) hypothalamus; etc.
MIDBRAIN Mesencephalon Midbrain Mesencephalic aqueduct III & IV
HINDBRAIN Metencephalon Pons and Cerebellum V Fourth ventricle Myelencephalon Medulla Oblongata VI—XII
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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 dor-sal 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 lumbo-sacral 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); cer-ebellar 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 rela-tively 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 expan-sions 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);
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— cellular migrations: • superficial and deep layers of neu-rons are evident within the mantle layer of the future cerebellum; the deep cells migrate (pass the superfi-cial 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 estab-lished 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 troch-lear (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 neurohyp-ophysis (neural lobe of the pituitary gland);
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— the mantle layer of the diencephalon gives rise to thalamus, hypothalamus, etc.; the thal-amus enlarges to the point where right and left sides meet at the midline and obliterate the center of the third ventricle. — 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 ven-tricle (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 hemi-sphere, guided by glial cells that extend from the ventricular surface to the outer surface of the cere-bral 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 SystemNOTE: • 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 pregan-glionic 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 orig-inate from neural crest as bipolar cells that subsequently become uni-polar; 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 au-tonomic 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 SensesFormation 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 dien-cephalon 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 collage-nous 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 de-veloping lens; when the membrane degenerates following development of the lens, a pupil is formed; — the cornea develops from two sources: the layer of ectomesen-chyme that forms sclera is induced by the lens to become inner epithe-lium and stroma of the cornea, while surface ectoderm forms the outer epithelium of the cornea; the anteri-or 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 mesen-chyme 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 somito-meres (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 vitre-ous 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 in-vaginates 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 macu-lae 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 appo-sition of endoderm and ectoderm where the first pharyn-geal 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 bran-chial 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 chemore-ceptive; 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 OrganizationThe spinal cord . . .
• connects with spinal nerves, through afferent& efferent axons in spinal roots;
• communicates with the brain, by means ofascending and descending pathways thatform tracts in spinal white matter; and
• gives rise to spinal reflexes, pre-determinedby interneuronal circuits.
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. Theregion 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.
A spinal cord segment = a portion of spinal cord thatgives rise to a pair (right & left) of spinal nerves. Each spinalnerve is attached to the spinal cord by means of dorsal andventral roots composed of rootlets. Spinal segments, spinalroots, and spinal nerves are all identified numerically byregion, e.g., 6th cervical (C
6) spinal segment.
Sacral and caudal spinal roots (surrounding the conusmedullaris and terminal filament and streaming caudally toreach corresponding intervertebral foramina) collectivelyconstitute the cauda equina.
Both the spinal cord (CNS) and spinal roots (PNS) areenveloped by meninges within the vertebral canal. Spinalnerves (which are formed in intervertebral foramina) arecovered by connective tissue (epineurium, perineurium, &endoneurium) rather than meninges.
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 latterfeatures a lateral horn (sympathetic preganglionic neurons) in thoracolumbar spinal segments.
terminal filament
conus medullarislumbar enlargementcervical enlargement
BRAIN
Spinal Cord Section
tract Afferent neuron
receptor
muscle
cell body
reflexinterneuron
Efferent neuronwhite matter
gray matter
spinal ganglion
dorsalroot
(rootlets)
spinal nerve
ventralroot(rootlets)
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L 7GrayMatterLaminae
dorsal median sulcus and septum
dorsal funciculus
lateral funiculus
ventral funiculus
dorsalhorn
intermediatesubstance
ventralhorn
Segment C6
central canal
ventral median fissure
dorsal intermediate sulcus
dorsolateral sulcus
ventral white commissure
White matter (derived from embryonic marginal layer) is superficial to gray matter. It iscomposed of concentrated myelinated fibers, gliocytes, and low capillary density. White matterregions include: dorsal funiculus; ventral funiculus; lateral funiculus; and white commissure.
Gray matter organization:Two schemes have evolved for organizing neuron cell
bodies within gray matter. Either may be used according towhich works best for a particular circumstance.
1] Spinal Laminae—spinal gray matter is divided intoten laminae (originally based on observations of thick sections in a neona-
tal cat). The advantage is that all neurons are included. Thedisadvantage is that laminae are difficult to distinguish.
2] Spinal Nuclei—recognizable clusters of cells areidentified as nuclei [a nucleus is a profile of a cell column]. Theadvantage is that distinct nuclei are generally detectable; thedisadvantage is that the numerous neurons outside of distinctnuclei are not included.
sacralparasymp.nuc.
lateralmotor nuc.
medialmotor nuc.
nuc.thoracicus
intermedio-lateral nuc.
motornuc. XI
marginal nuc.
substantia gelatinosa
nuc.propriusC 3
T1 0 L6S 3
Selected Spinal Nuclei (Cell Columns)
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Types of spinal neurons:All neurons in spinal cord gray matter have multipolar cell bodies. Based on axon destina-
tion, 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 intermediatesubstance (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 adistant part of the spinal cord). The axons form tracts associated with ascending spinal pathways thathave different functions.
Projection neurons may be categorized according to the types of stimulation that ultimatelyexcites 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 maintainalertness). Some projection neuron respond only to somatic stimuli (exteroceptors or proprioceptors); others respond toboth 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 inter-posed 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 inher-ent reflex responses of the spinal cord (spinal reflexes).
Spinal PathwaysPrimary Afferent Neuron = the first neuron in a spinal reflex or ascending spinal pathway.
Primary afferentneurons have theirunipolar cell bodies inspinal ganglia. Receptorsare found at the periph-eral terminations of theiraxons. Their axonstraverse dorsal roots,penetrate the spinal cord(at the dorsolateralsulcus) and bifurcate intocranial and caudalbranches which extendover several segments within white matter of the dorsal funiculus.
Collateral branches from the cranial and caudal branches enter the gray matter to synapse oninterneurons and projection neurons (or directly on efferent neurons for the myotatic reflex).
In some cases (discriminative touch), the cranial branches of incoming axons ascend directlyto the brainstem where they synapse on projection neurons of the pathway.
Spinal Nerve
Spinal Ganglion
Dorsal Root
Spinal Cord Cranial branch to brain
Collateral branches to spinal gray mater
Primary Afferent Neuron
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Note: Pathway = sequence (chain) of neurons synaptically linked to conveyexcitability 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 inthe brain. Ultimately, the pathway leads to thalamic neurons that project to the cerebralcortex.
The function of a particular pathway is determined by: 1] which primary afferent neuronssynapse on the particular projection neurons of the pathway, and 2] where the projectionneurons 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, discriminativetouch, 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 theconscious 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 spinalpathways to the brainstem. Projection neurons are non-specific. They receive synaptic input ofdifferent modalities and signal an ongoing magnitude of sensory activity, but they cannot signalwhere or what activity.
3] Subconscious sensory feedback for posture/movement control involves ascending spinalpathways principally to the cerebellum or brainstem nuclei that project to the cerebellum. Generallythere are only two neurons in a subconscious pathway and the axon of the projection neuron joins anipsilateral 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. Theyarise 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); and3] 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 afferentneurons, blocking release of neurotransmitter (presynaptic inhibition).
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(dorsal view)
Pelvic limb neuron Thoracic limb neuron
Fasciculus gracilis
Medial Cuneate Nuc.
Nucleus gracilis
Fasciculus cuneatus
midline
Spinal CordBRAIN Medial
lemniscusto thalamus
Fasciculus gracilis
Discriminative Touch Spinal Pathway
Spinothalamic Tract
midline
BRAIN
Pelvic limb neuron Thoracic limb neuron
Dorsomarginal Nuc.To thalamus
Spinal Cord
Spinothalamic Pathway (pain & temperature)
Ascending Pathway Examples
midline
BRAIN
C-1,2
Pelvic limb neuron Thoracic limb neuron
Lateral Cervical Nuc.
Spinocervicothalamic TractDorsal hornMediallemniscusto thalamus
Spinal Cord
Spinocervicothalamic Pathway (touch and pain)
Lateral Cuneate Nuc.
midline Fasciculus cuneatusDorsal Spinocerebellar Tract
Nucleus Thoracicus
Spinal Cord
T-1L- 4
Pelvic limb neuronThoracic limb neuron
Caudal cerebellarpeduncle
BRAIN
Spinal Pathways for Proprioceptive Feedback to Cerebellum
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Lecture 5
Spinal Refl exes &Neuronal Integration
Refl ex = an inherent, subconscious, rel a tive ly consistent responses to a particular stimulation.
Refl exes may be categorized as:somatic (involving skeletal m.) or autonomic (impacting viscera); and asbrainstem (involving cranial nn.) or spinal (involving spinal nn. and the spinal cord)
In contrast . . .Reaction = an inherent, subconscious, rel a tive ly consistent responses to a particular stimula-
tion, involving the cerebellum and cerebral cortex; e.g., hopping reaction & tactile placing reaction.
Examples of brainstem refl exes include: — eyelids close when the cornea is touched (corneal refl ex)— lip moves in response to a noxious stimulation (pin prick)
Examples of spinal refl exes, involving spinal nerves and the spinal cord, include:— extensor thrust: paw proprioceptors trigger lib extension
— panniculus refl ex: pricking skin triggers contraction of cutaneus trunci m.— myotatic refl ex: muscle stretch is resisted by contraction of the muscle— withdrawal refl ex: limb is withdrawn from a noxious stimulus
NOTE: Refl ex responses are determined by interneurons which “hard-wire” afferent input to efferent
output. In ter neu rons 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 refl ex/reaction" compete for control of the same interneurons circuits, they cannot be independent on one another. Thus, brain activity will infl uence spinal refl ex responses, making refl ex evaluation an interpretive art.
Withdrawal Refl ex = Flexor (Crossed Extensor) Refl ex
Features of the refl ex (diagrammed on the next page) include . . .— primary afferent neuron (1) participates in both refl exes (2) and ascending pathways (3);— divergent interneuronal circuit propagates to several segments and right and left sides;— pos i tive feed back pro longs the re fl ex be yond the time of the stimulus (A);— individual interneurons are either excitatory or inhibitory (black cells) in their effect;— an tag o nists are in hib it ed while agonists are excited (reciprocalreciprocal innervation) (D); — descending pathways (C) modify refl ex cir cuit (refl ex is not independent of brain con trol).
NOTE: As the refl ex is tested clinically, the crossed extension component disappears after the fi rst 3 weeks of age as descending pathways ma ture; but later in life, the nor-mally inhibited crossed extension reappears if “upstream” damage to de scend ing fi bers removes the inhibition.
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BACKGROUND PROPRIOCEPTIVE INFORMATION
Proprioceptors are mechanoreceptors, located in muscles/tendons & joint capsules/lig a ments. Proprioceptors provide: • subconscious feedback about the status of muscles & joints, subconscious feedback about the status of muscles & joints, subconscious feedback • conscious kinesthesia (sense of position & move ment), and • pain
Joint receptors: • free nerve endings that respond to extreme movement or in fl am ma tion (pain) • encapsulated receptors: — tonic: signal joint position — phasic: respond to rate of change in joint position (largely sub con scious)
Muscle & tendon re cep tors: free nerve endingsfree nerve endings: pain (Golgi) tendon organstendon organs: lo cat ed in series with muscle fi bers (ten sion de tec tor) muscle spindlesmuscle spindles: located in muscle belly (length de tec tor)
Withdrawal Refl ex
flexor
extensor
flexor
extensor
DL F.DL Sulcus
1
2
3
A
B
C
D D
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Muscle Spindle and Myotatic Refl ex
Muscle spindles are: • elaborate prop ri o cep tors po si tioned in parallel with muscle fi bers; • designed to signal muscle length.
Morphologically, a muscle spindle consists of a connective tissue capsule enclosing: — two kinds of mechanoreceptors, — two kinds of intrafusal muscle fi bers, — two kinds of gam ma ef fer ent neurons.
Intrafusal muscle fi bers: vs. extrafusal (typi cal) muscle fi bers • very small, anchored in endomysium • do not con trib ute anything to whole muscle tension • center of each fi ber is packed with nuclei & lacks myofi laments • polar regions are striated and innervated by gamma neu rons • two kinds of intrafusal muscle fi bers: nuclear bag fi bers — central region is dilated; fi ber extends beyond the capsule; nuclear chain fi bers — smaller, central region contains chain of nu clei.
Mechanoreceptors within muscle spindle : They are activated by stretch of the central region, which is stretched either 1) by contraction of polar re gions of intrafusal muscle fi bers, or 2) by passive stretch of the whole muscle (including the intrafusal fi bers)
1] primary (annulospiral) endings — spiral around central (nuclear) re gions; they are endings of large nerve fi bers (type IA); initially AP fre quency refl ects rate of stretch; then steady AP fre quency refl ects degree of stretch
2] secondary endings — "fl ower-spray" formations adjacent to nuclear chain regions; they are endings of type II nerve fi bers; AP frequency is proportional to degree of stretch.
Types of nerve fi bers found in a mus cle nerve
Muscle & Tendon Receptors
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Myotatic Refl ex Clinically, a myotatic refl ex is elicited by abruptly tapping a tendon (e.g., the pa tel lar ten don). Suddenly deforming/displacing a tendon effectively stretches the associated muscle. When a whole muscle is suddenly stretched (as a result of tendon deformation), annulospiral re cep tors in muscle spindles are simultaneously excited, triggering a volley of action potentials in IA af fer ent axons. Within the CNS, the axons activate ex ci ta to ry syn apses on alpha motor neu rons that in ner vate the muscle that was stretched. Also, alpha motor neu rons to an tag o nis tic mus cles are in hib it ed via in ter neu rons. As a result, the stretched muscle im me di ate ly con tracts. Thus, the myotatic refl ex func tions to oppose muscle stretch. Since interneurons are by-passed in eliciting the contraction, the response is rapid, localized, and rela tively re sis tant to hy- poxia, fa tigue, drugs, etc.
endplate
endings
trailendi
ngs
Myotatic Reflextendon
extrafusalmuscle fiber
GAMMAneurons
ALPHA neurons
IIa
b
same muscleantagonist muscle
reticulo-spinal tractfrom brain
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Refl ex sensitivity: Sensitivity of the myotatic refl ex (the extent to which a muscle can be stretched be fore it re- fl ex ly contracts) is determined ultimately by the contractile state of the polar re gions of the in trafusal muscle fi bers—because the degree of contraction of the polar regions de ter mines 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, sen si tiv ity of the myotatic refl ex is set by the fre quen cy of AP's in axons of gam ma neurons, and gamma neuron excitability is con trolled by descending tracts from the hind brain (reticulospinal tracts & vestibulospinal tracts).
Functions of the myotatic refl ex:
• Muscle tone = the resistance muscles offer when being stretched (lengthened) = the resistance encountered when an appendage is ma nip u lat ed
— tone is set by: brain ——> descending pathways ——> gamma neuron fi ring rate— tone is set by: brain ——> descending pathways ——> gamma neuron fi ring rate— — normal tone is variable, but appropriate to the animal’s current behavioral state
vs. hypertoniahypertonia (spasticity) = fi xed excessive tone, i.e., excess resistance to ma nipu la tion — due to excessive gamma neuron excitation (rate of fi ring)
or or or hypotoniahypotonia ("weakness") = fi xed defi cient tone, e.g., “rag-doll” appendages — the result of insuffi cient gamma neuron ex ci ta tion.
• Posture maintenance under changing conditions of load & fatigue By using myotatic refl exes, the brain is able to set muscle lengths and fi x joint position (i.e., posture) without con cern for load and fatigue. The brain sets lengths of in trafusal muscle fi bers to correspond to desired whole-muscle lengths. Any muscle that is longer than the desired length will have its spindle re cep tors activated and the re sult ant myotatic refl ex 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 suffi ciently. By analogy, this is a servosystem, e.g., one sets a thermostat [the brain sets gamma neu ron excitation] to control a furnace [myotatic refl ex] to maintain a desired temperature [posture].
• Voluntary movement For slow movements, posture can be sequentially adjusted to produce move ment, e.g., hin dlimb scratch ing the fl ank; learning any new movement sequence; etc. For abrupt voluntary move ments, the brain co-activates alpha & gamma neurons to maintain spindle sensitivity while muscles shorten (spindles fi re during movement). Gamma neurons (myotatic refl exes) must be inhib-ited in an tag o nis tic 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 seg ments; and 2) evaluate brain control and the integrity of descending tracts — looking particularly for evidence of fi xed hyper tonia or hypotonia.
41
Neuronal IntegrationA typical multipolar neuron in the CNS receives many thousands of synaptic inputs (excitatory/
inhibitory; axosomatic/axodendritic; from interneurons/projection neu rons; etc.). How does a neuron integrate all of its diverse synaptic input? How does it make "sense" of the diversity and "fi re" appropriately to effectively infl uence other neurons in its circuit? The answer — neuronal integrtion.
Synaptic inputs — — — predominantly on dendrites & soma (receptive zone): axosomatic excitatory synapses — de po lar ize entire soma (cell body) surface. The cell body acts like a sphere (charges/ions distribute evenly over a spherical sur face). Although each EPSP affects the whole soma, a single EPSP has a very limited effect.
axodendritic excitatory synapses — de po lar ize preferentially toward the soma. The EPSP is
passively conducted toward a lower resistance (asymmetrical diameter = asymmetrical resistance).
NOTE:Inhibitory synapses behave like ex ci ta to ry ones,
except that they produce IPSPs that hy per po lar ize the soma and cancel EPSPs).
Neuronal output: • an action potential (AP) originates at the initial seg ment of the axon where high density of voltage-gated Na+ channels are present; • the initial segment is greatly infl uenced 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 mem brane of each neuron integrates total syn- ap tic input at each moment of time! In te gra tion is the result of al ge bra ic sum ma tion of syn ap tic activity (EPSPs and IPSPs). The fl oat ing soma mem brane po ten tial refl ects the net ex ci ta to ry and in hib i to ry syn ap tic input to a par tic u lar neuron at a par tic u lar time.
The mag ni tude of soma depolarization (an an a log signal ideal for integration) an a log signal ideal for integration) an a log signalis con vert ed to frequency of APs along the axon (a dig i tal signal ideal for dig i tal signal ideal for dig i tal signaldistance conduction).
Factors infl uencing 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 ef fec tive
• 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 fi rst, large neurons last.
42
• synaptic effect is increased by repetitive fi ring (temporal summation);
• synaptic effect is increased by collaborative fi ring 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.
43
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 fi nal common pathway (FCP) neuron innervates skeletal muscle. The neuron and the skeletal muscle fi bers 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 fi re)
1. reticulospinal axons = muscle activity for standing 2. vestibulospinal tract = balance and muscle activity for standing 3. propriospinal axons = intersegmental refl exes
Major excitatory inputs — (axosomatic synapses; excite neurons to fi re APs)4. commissural interneurons = crossed-extensor refl ex
5. rubrospinal tract = voluntary movement 6. primary muscle spindle afferent axon (IA) = stretch (myotatic) refl ex
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 fl accid paralysis of skeletal muscles (neither voluntary movement nor refl ex activity is present).
tricepsbrachii m.
43
1
2
5
8
6
7
44
Lecture 6
Cranial NervesOverall Objectives: To understand the organization of cranial nerves with respect to
their nuclei within the brain, their course through and exit from the brain, andtheir 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 ventricleb) Alar Plate is displaced lateral to Basal Plate.
2. Cranial nerve nuclei form discontinuous cell columns rather thancontinuous 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 developmentof 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 primaryafferent axons synapse in connection with ascending pathways or reflex axctivity.
45
III. Motor Efferent Nuclei (Basal Plate Derivatives):
1. SE (Somatic Efferent) Nuclei: SE neurons form two longitudinally oriented but discon-tinuous columns of cell bodies in the brain stem. The neurons that comprise these columns areresponsible for innervating all of the skeletal musculature of the head. Refer to the diagram on page46 for the location of brain stem nuclear columns.
A) Oculomotor, Trochlear, Abducent and Hypoglossal Nuclei — are formed by a columnof cells located near the dorsal midline of the brainstem. The nuclei innervate muscles of the tongueand 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): Abnormalitiesin eye movement, deviation of the eyes (strabismus).
2) Hypoglossal (XII): Paralysis and atrophy of tongue muscles; deviation oftongue toward the side of damage, problems chewing & swallowing.
Comparison of the four major cell columns in the spinal cord with the more complicatedpicture seen in the brainstem. Note that the adult location of the alar derivatives (sensorynuclei) 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 nerveVII) and Nucleus Ambiguus (cranial nerves IX & X)— are formed by a column of cells located inthe ventrolateral brainstem. This location results from the ventrolateral migration of the cell columnduring development. These neurons innervate muscles derived from somitomeres in pharyngealarches. (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 anddamage to it or the trigeminal nerve results in paralysis of these musclesand associated muscle atrophy (bilateral damage results in dropped jaw).
GSAGVA
SE
VESE (SVE)
olivarynucl.
GSAGVA
SEVE
IValar plate
basalplate
spinal cord brain stem
Afferent and Efferent Nuclei
46
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, andpharynx (involved with speech, coughing, swallowing & gagreflexes); damage results in swallowing and vocalization difficulties.
2. VE (Visceral Efferent) Nuclei: Represent the cranial portion of the parasympatheticdivision of the autonomic nervous system (preganglionic parasympathetic neurons). Four nuclei arerecognized, but only two are important to remember: the parasympathetic nucleus of the vagusnerve and the parasympathetic nucleus of the oculomotor nerve.
The parasympathetic nucleus of the vagus innervates cervical, thoracic and abdominalviscera while the parasympathetic nucleus of III innervates pupillary constrictor muscle and theciliary body muscle of the eye:
1) Parasympathetic nucleus of III — damage causes loss of pupillarycontriction 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 com-plex which is located quite laterally in the brain stem. The complex is composed of the followingthree major subdivisions:
a) Nucleus of the spinal trigeminal tract (spinal trigeminal nucleus)—located in themedulla; associated predominately with pain and temperature sensation from the face and oralcavity; 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 inthe pons; associated with touch and pressure sensation from the face and oral cavity; damage resultin loss of touch and pressure sensation from the face.
c) Mesencephalic nucleus of the trigeminal nerve: located in the midbrain, receivesproprioceptive information from the face.
47
2. GVA(General Visceral Afferent) Nucleus: Located lateral to the GVE column andcomprised of a single nucleus termed the nucleus of the solitary tract (nucleus solitarius). The GVAportion of this nucleus is associated with cranial nerves IX and X. It mediates visceral sensation fromthe 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 associ-ated with cranial nerves VII, IX and X which convey taste from the tongue and pharynx. Lesions ordamage to the nucleus solitarius will disrupt taste sensation.
B. The olfactory nerve is associated with olfactory SVA sensation. This nerve how-ever is not foundf in the brainstem; rather, olfaction is conducted directly to the piriform lobe of thetelencephalon. Lesions or damage to the olfactory nerve will interrupt olfaction.
4. SSA (Special Somatic Afferent) Nuclei: These brain stem nuclei relate to the sense ofvision (lateral geniculate nucleus), the sense of hearing (cochlear nuclei) and the ability to maintainbalance (vestibular nuclei).
The medullary SSA column related to hearing and balance is located dorsally and laterally inthe 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 opticnerve/tract input. Obviously damage to cranial nerves II or VIII or their associated nuclei will haveprofound effects on the animal’s ability to see or hear, respectively.
Diagram indicating the nuclear columns inthe brain stem and illustrating the type ofstructures supplied by the different catego-ries and the nerves containing fibers fromthe different nuclear columns.
somatic efferent
skin(GSA)
taste(SVA)
(GVA)
inner ear(SSA)
visceralefferent
som
atic
eff
visce
ral e
ff
visce
ra
l aff
somaticaff.
Cranial Nerve�Cell Columns
48
tectum
p.IX
p.X
III
IV
VI
XII
motorV
VII
n.amb.
XI
n.sol.tr.
n.sp.tr.V
n.pon.sen.V
thalamus
opticchiasma
p.VII
p.III
mes.tr.V
inte
rnal
caps
ule
n.mes.tr.V
sp.tr.V
genu VII
IIIventricle
pons
V
VIIolivary nucl.
VI
facial nerve
olivary nucl.
genu VII
pons
vestibularnucl.
rostralcolliculus
crus cerebri
dorsal nucl.trapezoid body
Sensory (left) and Motor (right) Cranial Nerve Nuclei
Cranial Nerves and Their Functions:
Name andNumber
Brain RegionAssociated
With
Function(Functional
Components)
ClinicalExamination
Symptom SeenAfter Injury
Olfactory - I Cerebrum Smell (SVA) Owner’sObservations
Anosmia(Loss of Smell)
Optic - II Diencephalon Vision (SSA) Menace Response Anopsia(Loss of Vision)
Oculomotor - III Midbrain Eye Movement(SE, VE)
Horizontal EyeMovement; Pupil-lary Light Reflex
Strabismus: eyedeviated down &out. Large Pupil
Trochlear - IV Midbrain Eye Movement(Dorsal ObliqueMuscle: SE)
Extend head andlook for dorso-lateral strabismus
Cat: dorsal aspectof vertical pupildeviated laterally
Trigeminal - V Pons Masticatory Move-Ments, sensationFrom face (SE,GSA)
Jaw movementEye blink reflex
Bilateral damage =Dropped jaw,Asymmetricchewing, atrophy
Abducens - VI Medulla Eye Movement(Lateral RectusMuscle; SE)
Lateral EyeMovement
Double vision;Strabismus: eyedeviated medially
Facial - VII Medulla Facial Movement;Taste, rost. tongue(SE, SVA, VE)
Facial Movement Facial paralysis,drooling
Vestibulocochlear- VIII
Medulla Hearing andBalance (SSA)
Horizontal andVertical Eye Movement
Deafness,Head tilt,nystagmus
Glossopharyngeal- IX
Medulla Tongue andPharynx (GVA,VE, SVA)
Pharyngeal gagreflexes
Choking,SwallowingDifficulty
Vagus - X Medulla Pharynx, Larynx,Heart, Viscera(SE, VE, GVA ...)
Gag reflexes,Blood Pressure,Heart Rate
Hoarseness,Inspiratorydyspnea
Spinal Accessory- XI
Medulla Trapezius, + three.neck mm. (SE)
Neck movement Weakenedturning of neck
Hypoglossal - XII Medulla Tongue Muscles(SE)
Tonguemovement
Deviation ofTongue towardSide of lesion
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50
Lecture 7
Vestibular SystemIntroduction:
The vestibular system is responsible for maintaining normal position of the eyes and head asexternal forces tend to displace the head from its “normal” position. Located within the inner ear, thevestibular apparatus is the sense organ that detects linear and angular accelerations of the head andrelays this information to brainstem nuclei that elicit appropriate postural and ocular responses.
Note: Because [force = mass • acceleration ] and because head mass is constant, detecting headacceleration 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 thatcontain 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 semicircularcanal is orthogonal to the other two
Schematic diagram of the osseous labyrinth containing the membranous labyrinth. Thevestibule relationship (left) and the semicircular canal relationship (right) are shown.
Membranous Labyrinth — consists of interconnected tubes and sacs that are filled withendolymph, a fluid high in potassium. (Fluid outside the membranous labyrinth is perilymph, whichis low in potassium and high in sodium like typical extracellular fluids.)
boneperilymph fluid
memb. labyrinthendolymph fluid
otolith memb.macula
cupulamembrane
crista ampularis semicircular
duct
UTRICLE
BONE
51
The membranous labyrinth, which containsthe sense organ receptor cells, consists of the follow-ing components:
1) Cochlear Duct — related to hearing (willbe discussed later).
2) Utricle — larger of two sacs located in thevestibule
3) Saccule — smaller of two sacs located inthe vestibule
4) 3 Semicircular Ducts — each duct islocated within one of the semicircular canals. Eachduct has a terminal enlargement called an ampullawhich contains a crista ampullaris, a small crestbearing sensory receptor cells.
Vestibular Apparatus:
Vestibular apparatus is a collective term for sensory areas within the membranous labrinthresponsible 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 linearacceleration in the vertical plane (up and down).
3) crista ampullaris — one per semicircular duct ampulla; each detects angular accelerationdirected along the plane of the duct.
Schematic illustraion of a macula, including neurons of the vestibular nerve. Two typesof receptor (hair) cells have stereocilia that extend into the overlying otolith membrane.
kinocilium
efferent
otolith membrane
vestibular nerve
vestibular ganglion
bipolar
CNS
Ducts
52
Signal Transduction:All components of the vestibular appa-
ratus (each macula & crista ampullaris) havethe same kind of sensory epithelium, composedof supporting cells and receptor (hair) cells.From the apical surface of each hair cell,stereocilia protrude into an overlaying mem-branes.
Membrane movement results in deflec-tion of stereocilia. Deflection toward thekinocilium mechanically opens ion channels.This allows potassium ions to flow from theendolymph into the hair cell thus depolarizingthe receptor cell membrane.
This depolarization (receptor potential)cause release of glutamate from the basolateralcell membrane of the receptor cell. Thegluatamate neurotransmitter triggers actionpotentials in afferent axons of the vestibularnerve.
Deflection away from the kinociliumcloses ion channels and reduces glutamaterelease.
Crista Ampullaris. Stereocilia areembedded in a gelatinous membrane called acupula. The cupula is moved by fluid inertiawhen the head rotates in the plane of a semicir-cular duct. The direction of head rotation isindicated by the relative amount of activityfrom the three semicircular ducts.
Macula. Stereocilia are embedded in agelatinous membrane termed the otolith mem-brane because it contains calcium concretions (“ear stones”). Being denser than surrounding en-dolymph, the otolith membrane has more inertia than the fluid and it lags during linear accelerationor 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 ncreaseor decrease in the rate of spontaneous activity.
2) Vestibular organs of each side are mirror images, a shift toward the kinocilia on oneside results in a shift away from the kinocilia on the other side. Thus, spontaeousactivity, which is bilaterally balanced under normal postural conditions, is quicklyimbalanced during head acceleration.
kinocilia
stereocilia
+++++
+
hair cell
tip-link
hyperpolarizedreceptor (hair) cell
depolarized
resting state (tonically active)time
on off
stimulus off
Rate of firing — vestibular nerve axon
stimulus
on
one Action Potential
53
CNS Connections:Vestibular nerve fibers (axons from neuron cell bodies of the vestibular ganglion) travel fromthe inner ear to the brain. They synapse in vestibular nuclei of the brainstem and in the nodulusor flocculus of the cerebellum.
Vestibular nuclei:Four vestibular nuclei are located bilaterally in the medulla oblongata and pons. They receiveinput 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), and4) 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)
medial
rostral
lateral
caudal
oculomotor
trochlear
abducent
thalamus
cerebellarpeduncles
lateral vestibulospinal tract
reticulospinal tracts
medial longitudinal fasiculus (mlf)
Spinal Cord
III
IV
VI
54
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 vestibu-
lar nerve and decreased frequency in the left. Vestibular nuclei on the right side dominate activity inthe 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 balancedon 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 nucleiare common. Such lesions produce imbalanced neural activity which leads to a vestibularsyndrome.
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. Thisimbalance causes reflexes to be expressed as if there were an “acceleration” toward thenormal 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 toangular acceleration;
• opticokinetic nystagmus — is generated by cerebral cortex when focusing onmoving objects, e.g., train passenger focussing ontelephone poles.
55
Lecture 8
Posture & MovementIn veterinary neurology, abnormalities of posture & movement are more important than sensorydisorders because animals readilty express motor behavior but hardly at all report their feelings.
Preview: Posture/Movement Hierarchy
Spinal Cord and Cranial Nerve Motor NucleiLocal reflex—useful response to a stimulus (determined by local interneuronal circuits).
HindbrainStanding 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).
MidbrainOrientation—orienting head/eyes/ears toward abrupt visual/auditory stimuli (tectum).Specific movements—moving individual joints (via red nucleus and rubrospinal tract).
ForebrainInherent 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
----------------------------------------------------------------------------------------------------------- HindbrainReticular 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 previouslyTwo 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.
56
-------------------------------------------------------------------------------------------------------------MidbrainRed nucleus
The nucleus gives rise to the rubrospinal tract—the principal descending tract for voluntarymovement 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 ofcerebral 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 lateralfuniculus. Rubrospinal fibers synapse on spinal interneurons and produce independent movements ofshoulder/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 nigraFunctions 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 primatesresults in Parkinson's Disease (hypokinesia, rigidity, tremor).
------------------------------------------------------------------------------------------------------------ForebrainSubthalamus
Functions like a basal nucleus (see below). It play a role in producing rhythmic movements such as are employed inlocomotion. In primates, lesions (damage) to subthalamus result in involuntary release of large flailing movements(hemiballismus).
Basal nucleiThree basal nuclei (caudate, putamen, & pallidum or globus pallidus) are associated with move-
ment. The nuclei do not give rise to descending tracts. Instead they participate in forebrain circuits inwhich they communicate with cerebral cortex via thalamic nuclei.
Damage to basal nuclei impairs coordinated movement by affecting the magnitude, timing andsequencing of individual components of a movement. (In domestic animals, lesions of the basalnuclei usually result in circling to the affected side.)
StriateBody
LentiformNucleus
Caudate
Putamen
Globus Pallidus
Amygdaloid
Claustrum
Anatomically, the term "Basal Nuclei"refers to non-cortical gray matter of thetelencephalon. There are five major nuclei (andseveral smaller ones).
The major nuclei can be anatomicallysubgrouped in different ways:
1] Striate body (gray matter connectingcaudate & putamen produce striations in theintervening internal capsule).
2] Lentiform nucleus (the putamen andglobus pallidus together have the shape (form)of a lens.
Physiologically, only caudate, putamen,and globus pallidus play a motor role.
57
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 cortexMotor-related areas of cerebral cortex:
• motor area—located around the cruciate sulcus; principal source of output for all voluntarymovement; 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-callinglearned, rapid-sequence movements (particularly involving distal muscles).
• supplementary motor area—located medial to premotor area; active when thinkingabout 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 oblon-gata. Most axons decussate at the medullary-spinal junction (lateral corticospinal tract); some crossat the level of termination in the cord (ventral corticospinal tract). The tract controls particularlymusculature 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 modifysensory 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 componentsof posture/movement/locomotion. Naturally, this system is most important in domestic animals. Theprincipal tracts are: rubrospinal tract, pontine reticulospinal tract, and medullary reticulospinal tract.
Voluntary movement:Urge —> Decision —> Selection (what) —> Execution (how)
[limbic system] [association neocortex] [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 byneck 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); denerva-
tion atrophy of skeletal muscles with time.
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P.T.
Globuspallidus
Thalamus
Motor-related Neocortex
Purpose
Association Neocortex &
Limbic Drive
RedNucleus
ReticularFormation
alpha and gamma(final common pathway)neurons in motor nuclei
local interneurons
Ex.-P.T.
Ex-P.T. = Extra-pyramidal Tracts
P.T. = Pyramidal Tracts
ReflexMovement
Tectum
VestibularNuclei
Spinal&
BrainstemReflexes
Pons Medulla
Caudateand
Putamen
Movement Initiation Schema
NOTE:Substantia nigra andsubthalamus are alsoinvolved in basal nucleiloops.
`2 4315
Descending Tracts: 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
Voluntary Movement
2
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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 pro-duced (e.g., synergists are excited & antagonists are inhibited) Thus, most descending path-way axons synapse on interneurons. However, a minority of descending axons synapse di-rectly on motor neurons (e.g., vestibulospinal axons; a minority of pyramidal tract axonssynapse directly on motor neurons that innervate digits in primates and raccoons).
• Both voluntary and reflex pathways compete for control of the same interneurons andmotor neurons. Thus voluntary neurons must suppress reflex neurons, and vice versa, to gaincontrol of motor units.
• Neurons initiate a voluntary movement by exciting a particular pattern of motor unitsat a certain intensity
— while the movement is underway, feedback from proprioceptors influences subse-quent neuronal activity in motor centers to effect the desired movement;
— the cerebellum influences neuronal activity in the initiating motor centers (thecerebellum continuously modulates neuronal activity, based on information about motorcommands and proprioceptive feedback about position and acceleration).
ADDENDUM
Movement and Posture Overview
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Lecture 9
Cerebral Hemisphere and CortexCerebral Hemisphere
Right & left cerebral hemispheres are derived from the embryonic telencephalon. They arecomposed 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 cerebralhemisphere. Basal nuclei include: caudate nucleus, putamen, pallidum, claustrum.
White Matter:Myelinated axons which connect cerebral cortex with other brain regions. Three cat-
egories of white matter fibers are recognized:
Projection Fibers — fibers that leave the cerebral white matter. Projection fibers formthe 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 cerebralhemispheres. The largest bundle forms the corpus callosum.
Association Fibers—fibers that connect regions of the cerebral cortex within onehemisphere. 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 rhinencephalonbecause 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 organizedhorizontally 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 fine-movements, and in learning and intelligent behavior. It is most abundant in the human brain. It formsabout 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 den-
drites 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 asinterneurons, receiving input from cortical afferent fibers and synapsing on output neurons (pyrami-dal 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 layernon-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 fea-tures (axons; cell bodies; & whole neurons). The six layers are numbered at the left and named at theright. P = pyramidal cell; S = granule (stellate) cell.
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Horizontal Layers of Cerebral CorticalThe 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 thick-ness among cortical regions (e.g., a sensory region has a thick internal granule layer; a motor area hasa 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 output4] Inner granule layer — interneurons for specific afferent input5] Inner pyramidal layer — large cells; projection & long association output6] Multiform layer — variably shaped cells; projection & long association output
Cell Column (Vertical) Organization of Cerebral CorticalThe 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 afunctional unit because all cells within an individual column are activated by the same particularfeature of a stimulus. The vertical organization is the result of neuronal connections within a corticalcolumn:
— non-specific input to the column terminates in the molecular layer on distal dendrites ofpyramidal cells, to provide background excitation to the column;
— specific thalamic input terminates in the internal granule layer, exciting interneurons whichexcite 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 cellscolumns constitute thefunctional units of cerebralcortex. Usually the func-tional columns are notanatomically distinct, butin the case of the massivesensory input from ratvibrissae, the cell columnsper vibrissae are morpho-logically evident and givethe impression of a “bar-rel”.
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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 andspinal cord (corticospinal tracts).
Somatotopic organization = organization based on regional organization of thebody (e.g., neck is near the head; hindlimb is near the tail; etc.). The organizationcan be represented by an animunculus, which appears distorted because amount ofcortex is proportional to density of innervation, not area of body surface.
Primary sensory areas: receive specific afferents of a given modality from the thalamus orgeniculate bodies:
• somesthetic (somatosensory) area — receives specific tactile input as well as informationrelated to pain, temperature and pressure sensation. The area issomatotopically organized around the coronal sulcus.
• visual area — receives visual input. The area is retinotopically organized in the occipitallobe around the marginal sulcus.
• auditory area — receives auditory input. The area is cochleotopically organized around theapex 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 areasare 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 areasare involved with thought, planning, memory, speech, creativity, etc. Association areas comprise 20% of thecanine brain and 85% of the human brain.
Note: In humans, language processing (written, vocal, signing) occurs in one cerebralhemisphere (left hemisphere in 95% of right handed and 70% of left handed persons) and visual-spatial processing (shapes, symbols, patterns, configuration analysis) is dominant in the otherhemisphere. Handedness is also a representation of hemispheric dominance.
Methods of Determining Cortical Function:
Destructive Lesions — information obtained by producing experimental lesions and byobserving patients whose lesions can be confirmed at necropsy. Findings include:
Somesthetic area — loss of the fine aspects of discrimination (e.g., cats loose theability to discriminate various degrees of texture roughness)
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Auditory Area — bilateral lesions cause difficulty in localizing sounds and themeaning (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 causescontraction of contralateral muscles in a somatotopic pattern.
Electrical Recording — following a stimulus the corresponding primary sensory areasbecome excited first. Next sensory information is relayed to association areas of cortex.
Primary auditory area — high frequency tones; activate neurons in the caudal sylviangyrus; low frequency tones activate neurons in the rostral sylvian gyrus(tonotopic organization).
Primary Visual Area—cell columns respond to edges, flashes, colors, andintensities 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, neuronswhich are active utilize more glucose and thus take up more of the 2-deoxyglucose. Theseneurons become highly radioactive and can be localized with autoradiographic techniques.
Figure 3: Diagram of a right cerebralhemisphere illustrating locations ofthe primary motor area and variousprimary sensory areas.
Figure 4: A schematic diagramillustrating a left cerebralhemisphere of a cat. Represen-tation of the motor area andsomethetic are is shown by ananimunculus in each case. Theanumunculus displays the theamount of cortical surfacedevoted to each region of thebody. Notice that the hindlimbsand tail extends onto the medialsurface of the hemisphere.
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Lecture 11
Nociception II1. The Spinocervicothalamic (Spinocervical) Pathway--this pathway appears to play an equallyimportant role in pain transmission in carnivores (it is less well developed in humans and in otherdomestic 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 tosynapse 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 tothe contralateral thalamus where they terminate on 4th order neurons.
F. The axons of these 4th order neurons project to the somatosensory area of the cerebralcortex.
Spinothalamic Tract
midline
BRAIN
Pelvic limb neuron Thoracic limb neuron
Dorsomarginal Nuc.
Spinal Cord
Spinothalamic Pathway (pain & temperature)
midline
BRAIN
C-1,2
Pelvic limb neuron Thoracic limb neuron
Lateral Cervical Nuc.
Spinocervicothalamic TractDorsal hornMediallemniscusto thalamus
Spinal Cord
Spinocervicothalamic Pathway (touch and pain)
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 thespinothalamic pathway (3 neuron pathway) is the presence of an additional neuron (located inthe 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 fromphysical damage by the environment or by excessive stress of the body tissues.
B. Acute Pain (Prolonged, subchronic, e.g. surgical pain; inflammatory pain)—elicited bysubstantial injury of body tissue and activation of nociceptive transducers at the site of localtissue damage. The local injury alters the response characteristics of nociceptors, theircentral connections and the autonomic nervous system in the region. This type of pain isseen 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 commonlytriggered by an injury or disease, but may be perpetuated by factors other than the cause ofthe pain. Because chronic pain is unrelenting (lasting months or longer), it is likely thatstress, environmental, and affective factors may be superimposed on the original damagedtissue and contribute to the intensity and persistence of the pain.
Note: The central (CNS) and peripheral (PNS) nervous systems are dynamic, not static, and aremodulated by tissue damage and injury. In the spinal cord, immune-like glial cells(astrocytes & microglia) are activated in response to subcutaneous inflammation, nervetrauma, and tumors. These glia are involved in the creation and maintenance ofpathological 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 canexert a strong control over the spinal cord. Reynolds was the first to demonstrate in 1969 that potentanalgesia could be produced by electrical stimulation of the midbrain in freely moving animals. Wenow know that narcotic drugs (e.g. morphine), acupuncture, certain types of hypnosis and electricalstimulation in selected brain regions will activate this endogenous analgesia system resulting in aprofound reduction in pain sensation.
Components:
1. Midbrain Periaqueductal Gray (PAG)—the region surrounding the mesencephalicaqueduct. It contains a high density of opiate receptors and has direct connections with the spinalcord and the nucleus raphe magnus. Activation of this region by an opiate drug, acupuncture or directstimulation activates a descending pathway that excites neurons in the nucleus raphe magnus andconsequently 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 thatcomprise this nucleus contain high levels of the indoleamine neurotransmitter, serotonin and theysend their axons to the spinal cord dorsal horn, where they synapse on projection neurons in themarginal nucleus and nucleus proprius. Release of serotonin causes inhibition of pain transmissionneurons 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 synapseon 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 andlocus coeruleus. These nuclei in turn send descending axonal projections via the dorsolateralfuniculus 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 thatfemale animals have a separate descending system from the PAG that is sensitive to estrogen. Thisunique 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. Thispain enhancement system appears to help maintain chronic pain status. We are just beginning tolearn about this system which also seems to be centered in the brainstem. The periaqueductal grayand the raphe magnus have collections of two physiologicallydifferent types of neurons that appear to be related, on the onehand, to pain enhancement and, on the other hand, to painsuppression.
nucleusraphemagnus
midbrain
ponsmedulla oblongataperiaqueductal
gray
locuscoeruleus
periaqueductalgray
locuscoeruleus
nucleusraphe
magnus
spinal corddorsal 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 systeminclude activation of the body’s endogenous pain modulatory systems, causing a releaseof nor-epinephrine, opioid substances and other neurotransmitters, thereby alteringnociceptive processing and perception. (for additional information, see the review byMittleman and Gaynor, JAVMA 217:1201, 2000).
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Ib
Ia
II
III
IV
A
slow pain nociceptorsthermoreceptors
secondary spindle endingsencapsulated receptors in
joints and skin
tendon organs
annulospiral spindle endings
hair follicle receptorsfree ending mechanoreceptorspricking pain receptors
GVE Postganglionic
Extrafusal muscle fibers—large motor units
Intrafusal muscle fibers
Extrafusal muscle fibers—small motor units
ALPHA
BETA
GAMMA
DELTA
GVE Preganglionic
C
B
Size Range of Peripheral Nerve Fibers
Efferent Fibers Fiber Diameter Afferent Fibers 20 µm
— — —
16 µm — — —
12 µm — — — — —
6 µm — —
3 µm — —
1 µm non-myelinated
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.
Schematic illustration of free nerve endings.
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Lecture 10
Nociception IOverview 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 toremove the pain stimulus. It is a complex sensory experience with many subjective compo-nents: 1) discriminative; 2) learning and memory—associate pain with certain events; 3) un-pleasantness, displeasure and 4) suffering, escape.
B. Noxious—a stimulus that damages or threatens damage to tissue, it can be mechanical, thermalor 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) attachedto “A delta” and “C” peripheral nerve fibers. The term “Nociception” is often used interchangablywith the term “Pain”, but technically refers to the transmission of nociceptive information to thebrain without reference to the production of emotional or other types of response to the noxiousstimulus.
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 normallyinnocuous (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 (hyperventi-
lation), increased sweating, salivation.3) Lameness4) 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 chemi-cal, mechanical or thermal stimuli.
1. Receptors — free nerve endings (unmyelinated terminals which contain synapticvesicles). Damage to tissue causes the release of a number of mediators that activatenociceptor free nerve endings. These mediators include ATP from damaged cells andbradykinin from blood (Fig. 2 ). In response to activation these terminals may actuallyrelease their transmitters (substance P, CGRP and other peptides) into the extracellularfluid in the area that they are located, this amplifies the pain sensation (Substance P forexample causes neurogenic inflammation by inducing mast cell degranulation).
Fig. 2: Influence of inflammatory mediators upon the activity of a “c-fiber” nociceptorfollowing injury. Following injury a variety of mediators are secreted by bloodvessels and other cells in the region which activate pain terminals by increasingconductance of sodium (gNA) or calcium (gCa2+) channels or by activating secondmessenger systems (adenylate cyclase, AC, etc.). Pain terminals then conduct anelectrical signal to the spinal cord.
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Fig. 3: Diagram of a nociceptor show-ing the cell body and processes.
2. Peripheral nociceptors have their cell bodyor soma in a dorsal root or cranial nerveganglia. The cell body gives rise to: 1) aperipheral process or primary afferentaxon that innervates skin, muscle, viscera,etc. as a free nerve ending and 2) a centralprocess that terminates in the spinal cord dorsal horn or in the brain stem.
Pain Sensitivity: Pain receptors become sensitized after tissue damage. When tissueis damaged or a noxious stimulus is repeated nociceptors exhibit sensitization inthat there can be a reduction in the threshold for activation, an increase in responseto a given stimulus, or the appearance of spontaneous activity. This sensitizationresults from the actions of second messenger systems activated by the release ofinflammatory mediators (bradykinin, histamine, prostaglandins, serotonin) at thesite of injury. This causes some of the features of hyperalgesia produced by tissuedamage 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: Aδ and C fibers can be classified into various types based on their functional properties. Forexample C fibers can be divided into: C-mechanical/heat nociceptors; C PolymodalNociceptors (sensitive to heat, mechanical & chemicals) and Cold Nociceptors.
4. Primary Reponse Characteristics (code intensity of stimulus):
Figure 4: Response characteristics of C polymodal (mechanoheat) nociceptors.
action potentials:
innocuousbrushing
innocuouspressure
lightpinch
hardpinch
Mechanical Stimulation:
30° C40° C 45° C 50° C
action potentials:
Thermal Stimulation:
68
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B. Central Transmission: Pain is transmitted from Primary Afferent Axons (axons from cellbodies in a spinal ganglion) —> the spinal cord dorsal horn (marginal nucleus or nucleusproprius) —> thalamus —> cerebral cortex
Pain sensation is conveyed from the spinal cord by several central nervous systempathways, the two most important in animals are: (1) the Spinothalamic Path-way and (2) the Spinocervicothalamic Pathway.
1. The Spinothalamic Pathway—this pathway is classically considered to be the major painrelay system in mammals. Although this pathway clearly plays an important role in carnivores, thespinocervicothalamic pathway (discussed in pain lecture 2) plays an equally important role in paintransmission in dogs and cats. The organization of the spinothalamic pathway can be summarizedas follows:
(A). 1st Order Neuron—Cell body located in a spinal (dorsal root) ganglion; its peripheralprocess is associated with the receptor, while its central process enters the gray matter of thecord to synapse in the marginal nucleus (lamina I), substantia gelatinosa (lamina II) anddeeper 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 excita-tory amino acid transmitters.
Fig. 5: Diagram illustrating the termination sites of nociceptive fibers in themarginal nucleus and nucleus proprius.
(B). 2nd Order Neuron—cell body located in the marginal nucleus and the nucleus pro-prius. The axons of second order neurons cross the midline (decussate) and join other axons whichalso carry pain sensation. These axons collectively form a tract in the ventral part of the lateralfuniculus called the Spinothalamic Tract (Fig. 6 ). The axons of 2nd order neurons in this painpathway 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 thalamusis 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 terminatingin the medial thalamus mediate the motivational-affective aspects of pain (eg. relationship betweenemotion [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 (pre-frontal, insular and cingulate cortex).
Note: An animal becomes aware of painful stimuli at the level of the thalamus, thecerebral cortex is required for localization of the pain to a specific bodyregion. It should also be noted that in addition to pain the spinothalamic pathwayconveys temperature sensation.
Fig. 6: Simplified diagrams illustrating the main features of thespinocervicothalamic pathway and the spinothalamic pathway.
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Lecture 12
CerebellumObjectives:
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 ofmuscle activation during movement.
2. Maintenance of Equilibrium (in conjunction with the vestibular system).
3. Regulation of Muscle Tone—modulates spinal cord and brain stem mechanismsinvolved 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; itis 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 hypoto-nia, hypermetria, and intention tremor.
C. Flocculonodular Lobe = vestibulocerebellum — associated with the vestibularsystem; 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 underlyinginterpositus nucleus — participates in the control of an evolving movement by utilizing propriocep-tive sensory information generated by the movement itself to correct errors in the movement.
C. Hemispheres — the largest and most lateral part of the cerebellum, associatedwith the dentate nucleus — influences the output of the motor cortex and thus permits fine, delicateadjustments 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 entirelyafferent 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 predomi-nantly 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 largeneuronal cell bodies, termed Purkinje cells.
3. Granule Cell Layer — the deepest layer of cerebellar cortex found adjacent to the whitematter; 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 nuclei2. Granule Cells — intrinsic cells of the cerebellar cortex, utilize glutamate as an excitatory
transmitter; excite Purkinje cells via parallel fibers3. Basket Cells — inhibitory interneurons; utilize GABA to inhibit Purkinje cells4. Climbing Fibers — arise from the olivary nucleus and terminate on Purkinje cells;
thought to utilize glutamate and aspartate as excitatory transmitters5. 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 dorsalspinocerebellar and ventral spinocerebellar tracts); terminate predominately in the rostral lobe.
[Makes cerebellum aware of ongoing movements via proprioceptive inputfrom 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 viapontocerebellar 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 main-taining posture and balance.
2. Interpositus Nucleus Projections: (via rostral peduncle)— go to red nucleus to influence rubrospinal tract activity; the projections make correc-
tions 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 cerebellarcortex) result in symptoms that occur because the cerebellum’s normal function is interrupted. Thusataxia, dysmetria, and intention tremor are the result of interference with the cerebellums normal rolein the coordination of movement and in the maintanence of equilibrium and appropriate muscle tone.
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Cerebellar disorders usually result from:1. Tumors2. Viral Infections (encephalitis) -- which may occur in utero3. Heavy metal poisoning4. Genetic disorders
1. Small lesions may produce no signs or only transient symptoms. The cerebellum seems tohave a relatively large margin of physiologic safety built into the system. Small deficits can often becompensated for by other parts of the brain.
2. Lesions of the cerebellar hemispheres result in loss of muscular coordination and jerkypuppet-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 swayingof the body while walking).
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Lecture 13
Diencephalon and HypothalamusObjectives:
1) To become familiar with the four major divisions of the diencephalon2) 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 diencephalonb. 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 movementsb. Lesions in primates lead to hemiballism (a violent form of hyperkinesia)
3. Thalamus — largest component of the diencephalona. 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.
Fig. 1. Schematic diagram illustrating the components of the diencephalon.
hypo-thalamus
optic chiasm
tuber cinereum
mamillary body
neurohypophysisadenohypophysis
habenula
caudal commissure
pineal glandthalamus
fornix
rostralcommissure
lamina terminalis
midbrain
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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 pituitarygland (neurohypophysis) where ADH is released and enters the blood.
2) Paraventricular Nucleus — contains neurons that produce predominatelyoxytocin
3) Suprachiasmatic Nucleus — appears to be the hypothalamic nucleuscritically involved in controlling circadian rhythms (endogenousbiological rhythms that have a period of about 24 hours). The nucleussynchronizes 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 bundleb. Limbic System via the fornixc. Retina via direct branches of the optic nerve and tractd. 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 systemd. To the pituitary gland
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Figure 2: Regions of the hypothalamus and pituitary gland in midsagittal view. Note the tubercinereum forms the floor of the hypothalamus between the optic chiasm & mammillary bodies. Thehypothalamus is divided in a rostrocaudal direction into 3 subdivisions: supraoptic, tuberal andmammillary, respectively.
5. Relationship to Pituitary Gland: [The pituitary gland lies beneath the brainand is formed by 2 distinct parts: a neuralpart, the neurohypophysis, and a glandularcomponent derived from oral epithelium,called the adenohypophysis.]
The hypothalamus controls the endocrinesystem via two different routes:
a. Directly by secretion of neuroendo-crine products into the general circulation viathe vasculature of the posterior pituitarygland (ADH and oxytocin).
b. Indirectly by secretion of releasingfactors into the local hypophyseal portalvenous plexus (which carries these releasingfactors from the base of the hypothalamus[an area know as the eminence] to the ante-rior pituitary). The hypothalamus thus con-trols anterior pituitary hormone synthesis viathese releasing factors.
Fig. 3. Projections from the hypothalamus tothe pituitary gland. The hypothalamus isconnected directly via the axons of the su-praoptic and paraventricular nuclei and indi-rectly 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 paraventricularnuclei of the hypothalamus. Functions: acts on uterine smooth muscle to stimulate myometrial con-tractions and accelerates parturition (thus oxytocin or synthetic derivatives of oxytocin can be used toinduce parturition, eg. in the mare). Activates milk letdown reflex in response to suckling (inducescontraction of myoepithelial cells in mammary gland).
B. Vasopressin (ADH): Produced by: neurons in the supraoptic nucleus. Function: toincrease reabsorption of water in the kidneys (via collecting ducts and convoluted tubules). Thus it de-creases urine production and conserves body water. Capillary density of the supraoptic nucleus ishigher 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 afailure 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 releas-ing factors which either stimulate or inhibit the release of hormones from the anterior pituitary gland.
Disease: Hyperadrenocorticoidism often accompanies tumors of theadenohypophysis which produce excess adrenocorticotropic hormone.
Symptoms: Extremely hungry; hair loss from the body; enlarged liver; lameness withskeletal muscle atrophy.
3. Control of the Autonomic Nervous SystemStimulate 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 withabscesses 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 bodytemperature.
b. Caudal hypothalamus — heat conservation center: cool blood, pyrogenic sub-stances or input from cold receptors causes shivering and vasoconstriction which serve to increasebody temperature.
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Disease: damage to the rostral hypothalamus can cause hyperthermia (fever) while dam-age or lesions to the caudal hypothalamus can cause hypothermia (decreasedbody temperature); e.g., cattle with abscesses of the pituitary gland that effectthe 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 cir-cuits 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 oftendepressed and hold head and neck extended as if “star gazing”.
Fig. 4. The effect ofdiscrete bilateral le-sions in specific hypo-thalamic areas on ap-petite in the cat. Le-sions of the ventrolat-eral nuclei producehyperphagia, while le-sions of the extremelateral hypothalamusproduce loss of appe-tite (Anorexia).
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Lecture 14
Olfaction and The Limbic SystemObjectives:
1. To understand the anatomical organization of the olfactory system2. To understand the concept of the “limbic” system3. 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 olfac-tory epithelium. The nonmyelinated axons of these neurons gather into bundles that collectively formthe olfactory nerve. Olfactory nerve bundles penetrate the cribiform plate of the ethmoid bone to enterthe olfactory bulb.
4. Second Order Neurons = mitral cells in the olfactory bulb. The axons of these cells formthe olfactory tracts (striae).
[Histologically, the olfactory bulb features several layers, including from superficial to deep, aglomerular layer, where olfactory nerve fibers synapse on the dendrites of mitral cells; a mitral celllayer and a granule cell layer.]
5. The olfactory tract terminates by bifurcating into a medial and lateral olfactory stria whichproject, respectively, to the septal area (olfactovisceral reflexes) and piriform cortex (consciousawareness of olfaction).
Fig. 1. Cellularcomponents of theolfactory mucosaand olfactorybulb.
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Fig. 2. The olfactory epithelium. A) Schematic illustration of the olfactory epithelium, showing the major celltypes. The inset shows the location of putative 7 transmembrane odorant receptors (7TMr) on cilia of olfactoryreceptor neurons. B) Hypothesized olfactory receptor-transduction mechanisms. Odor molecules bind to spe-cific 7TMr proteins located in the cilia. These 7TMrs are thought to be coupled to G proteins that activate ei-ther 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 ionslead to membrane depolarization and the generation of action potentials that are conducted along olfactorynerve 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 thatthe limbic structures which surrounded the brainstem were involved in emotions. This hypothesis was subsequently foundto be correct and these structures together with certain components of the hypothalamus, thalamus and epithalamus werecollectively called the.Limbic System
The Limbic System:1. Functions:
In domestic animals the limbic system is concerned with1) emotions of importance to survival (emotions associated with self preserva-
tion, such as escape, defense, feeding, etc.; and emotions associated with species preservation such asterritorial 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) neurotransmittersB. Low threshold for seizure activityC. 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 includingthe cingulate gyrus and septum (septal area) are shown and the hippocampus has been dissected out todisplay its anatomical location. B. Parts of the cortex and diencephalon have been removed to illus-trate 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 illustratedby sham rage— which occurs following removal of the cerebral cortex from a cat or dog. It is charac-terized by: lashing of the tail, vigorous arching of the back, clawing and attempts to bite, and auto-nomic responses. It is called sham rage because unlike genuine rage, the anger occurs spontaneouslyor can be triggered by mild tactile or other nonnoxious stimuli.
Hippocampus — a three layered cortical structure (archicortex) which has long been thought to be animportant cortical region for associative learning and memory (particularly memory acquisition orshort term memory). Both amnesia patients and animals with hippocampal damage exhibit ‘time-de-pendent impairments’ in behavioral tasks generally described as associative or relational in nature. It isalso 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 be-havioral processes including emotions, relief of fear, docile behavior and stress, as well as, a role inautonomic regulation (e.g., water/food intake, hibernation, etc.). Stimulation induces docile behaviorand can suppress many autonomic responses. Lesions result in rage and aggressive behavior and cantrigger many autonomic responses.
Amygdala — a highly differentiated region near the temporal pole of the mammalian cerebralhemispere. It is a basal nucleus that is implicated in a bewildering variety of behavioral and regula-tory functions. These include emotion and memory, social behaviors such as reproduction, fear andaggression, and modulation of the autonomic and neuroendocrine systems. Many amgdala effects ap-pear opposite to those of the septum. For instance, lesions result in docile behavior, while stimulationproduces rage and aggressive behavior.
[Note: Recent evidence indicates that the amygdala is neither a structural nor a functional co-hesive unit, but rather it consists of different parts performing different functions. For instance, thecentral nucleus of the amygdala projects to visceral areas of the brainstem and is a specialized auto-nomic projecting motor region. In contrast the cortical amydala together with the nucleus of the lat-eral 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 be-cause of its interconnections with other limbic structures, simulation of the hypothalamus producesmany of the behaviors seen with stimulation of other limbic sites. Thus stimulation reveals rage andaggression 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 infor-mation can gain access to the limbic system.
Also:Rhinencephalon (nose-brain) — includes the piriform lobe and olfactory bulb. It is con-
cerned with olfaction and is a major component of the limbic system where it functions together withother limbic structures in affective behavior (urges, behavioral drives).
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Cochlea and Auditory PathwaysAnatomical Considerations
External ear:The external auditory meatus (canal) is formed by auricular and an nu lar cartilages, plus a short contribution
from the temporal bone.
Middle ear: Air-fi lled tympanic cavity (including a ventrally expanded bulla) that fea tures: — four openings (three sealed by membranes): • auditory tubeauditory tube opening (not sealed) connects middle ear to the nasopharynx; • tympanic membranetympanic membrane (ear drum) separates tympanic cavity from external auditory meatus; • oval (vestibular) windowoval (vestibular) window separates the tympanic cavity from perilymph in the vestibule; • round (cochlear) windowround (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 refl exly 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 effi ciency of sound trans mis sion. (Pressure oscillations in air (sound waves) are very in ef fi ciently converted to pressure waves in fl uid, only 0.1% of the force is normally
transmitted.) Middle ear components convert large amplitude, low force input into low am pli tude, high force output. (The middle ear matches low impedance input to high impedance output.) Note: The tym panic mem brane occupies a large area and undergoes a large excur-sion, offering low re sis tance to being vibrated (by air pres sure waves). The mem brane of the oval win dow has a small area and makes small excursions against high re sis tance load (it must push against in com press ible per i lymph fl uid 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 mem brane (yielding a 60-fold force gain in the cat).
Inner ear: The inner ear consists of the cochlea and vestibular apparatus. The co chlea is a component of
os seous lab y rinthos seous lab y rinth that contains per i lymph and the co chle ar duct. The cochlear duct is a com po nent of mem bra nous lab y rinthmem bra nous lab y rinth and contains en dolymph.
The cochlea makes 3.25 turns in the dog (2.5 in man) around a core of bone (called the modiolus) through which the cochlear nerve passes. The entire complex resembles a snail’s shell (whence the term cochlea is derived).
Within the cochlea, the cochlea duct (scala media) separates two peri lymph chambers: the scala vestibuli, which con tacts the oval window membrane, and the scala tympani, which contacts the round win dow mem brane.
Perilymph can fl ow from one scala to the other through an opening (helicotrema) at the apex of the cochlea. The he li cot rema is non-functional with respect to the physi ol ogy of hearing, it merely
precludes per i lymph stagnation.
Lecture 15
Cochleabisected
cochlear nervespiral ganglion
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The cochlear duct (scala media) is triangular in cross-section. A thinvestibular membrane separates cochlear duct from scala vestibuli, presenting an ionic barrier between perilymph & endolymph. Vestibular membrane can be ignored in regard to the mechanics of hearing.
An osseous spiral osseous spiral lamina and basilar membrane separate cochlear duct from the scala tympani. Within the cochlear duct, a spiral organspiral 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 fi bers that extend outward from the osseous spiral lamina. The fi bers 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.)
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.
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.
Scalavestibuli
Scalatympani
Cochlearduct
BasilarmembraneSpiral
ganglionOsseousspirallamina
Spiralligament
Striavascularis
Vestibularmembrane
BONE
tectorialmembrane
reticularmembrane
inner outersensory hair cells
Limbusaxons
SpiralOrgan
BASEof cochlea
APEXof cochlea
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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 fl uid 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+ chan nels 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 dis place ment modulates an on-going K+ cur rent from the en dolymph through the hair cell to the perilymph. Hair cell ex cit abil i ty 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 amplifi es sound or imparts vibration to perilymph through temporal bone contact.
Scala vestibuli
Scala tympani
Cochlear ductExternalAuditoryMeatus
MiddleEar
View from Scala tympani
oval window
vestibular membrane
basilar membrane
osseous spiral lamina
tympanicmembrane
BONE
incusstapesmalleus
round window
helicotrema
basilar membrane
Scala tympani
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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:
pitchpitch = 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 de ter min ing which fi bers 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 in creas es, the peak amplitude of basi lar mem brane displacement re gresses, from the apex (longest fi bers) toward the base (shortest fi bers) 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 fi ring and the frequency of their action po ten tials. Increased volume (amplitude) will re-sult in greater excursion of the basilar membrane, greater dis place ment 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 dif fer ence be tween 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.)
Perilymph&
Extracellular
K+
Endolymph
K+
K+
K+pump
+ + + + + + + + + +_ _ _ _ _ _ _ _
+++++++
+++++++
________
________
90mV
40mV
_ _ _ _ _ _ _ _+ + + + + + + + + +
++++
____
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Auditory Pathway
Cochlear nerve fi bers synapse in dorsal and ventral cochlear nuclei, typically each fi ber 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 fi bers 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 fi bers of the trapezoid body); dorsal nucleus of the trapezoid body; nuclei of the lateral lemniscus; and caudal colliculus.
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 fi ring 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).
CaudalColliculus
MedialGeniculate
AuditoryCortex
Trapezoid Body
Cochlear Nerve
LateralLemniscus
Brachium ofCaudal Colliculus
Internal Capsule
Nuclei ofLateral Lemniscus
Dorsal Nucleus ofTrapezoid body
Dorsaland
VentralCochlear Nuclei
commissure ofcaudal colliculus
commissureof laterallemniscus
SylvianSulcus
Ventral Nuclei of Trapezoid Body
White
MatterG
rayMatter
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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 refl ex 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 refl ex turning of refl ex turning of the head, ears and eyesthe 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 soundpatterns of sound and direction of pitch change, i.e., elements of melody, patterns of sound and direction of pitch change, i.e., elements of melody, patterns of soundspeech, 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 signifi cancesignifi cance with a particular sound pattern.
auditoryassociationcortex
primaryauditory cortex
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Visual SystemEYEBALL — 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.
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 myeli-
nated axons that comprise the optic nerve. Photo-
receptor cells are absent at the optic disc (blind
spot). Retinal vessels enter at the disc and course
along the retinal surface.
Cornea
Sclera
Optic nerve
Lens
Ciliary body
Retina
Optic discora serrata
area centralis
Iris
Fundus of Right Eye
vessel
Tapetumlucidum
Optic discAreacentralis(visual streak)
RETINA
Lecture 16
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Photoreceptor cells:
There are two populations
of photoreceptor cells: rods &
cones. The outer segments of
rods & cones contain stacked
membranous discs that are
continually produced,
sloughed, and phagocytized by
pigmented epithelium. The
discs contain the photosensi-
tive pigment (retinal) that
intercepts photons.
Photoreceptor cells are
excited (depolarized) in the
dark and inhibited (repolar-
ized) by light (photons).Excitation (depolarization)spreads electrotonically andtriggers proportional release ofglutamate neurotransmitterwhich either excites or inhibitsthe bipolar cells they synapse on.
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 andthey synapse on ganglion cells (as well as some amacrine cells).
Bipolar cells associated with rods form convergent circuits (spatial summation), which improvesvision in dim light but at the expense of image resolution. Bipolar cells associated with cones formrelay circuits (temporal summation) which provides good visual detail but requires bright light.
Sclera
Choroid
Retina
RetinalLayers:
1. pigmented epithelium
2. rods & cones
3. ext. limiting membrane
4. outer nuclear
5. outer plexiform
6. inner nuclear
7. inner plexiform
8. ganglion cell
9. optic n. fiber10. int. limiting membrane
bipolarcells
horizontal c.amacrine c.
radialglialcell
(astrocyte)
area centralis
Rod Cone
Outersegment
Innersegment
outer limitingmembrane
mito
chon
dria
disks
nucleus
RODS
• 95% of photoreceptor cells
(in human retina)
• widely disributed
throughtout the retina
• single population all contain-
ing rhodopsin (protein +
retinal) and the same wave-
length (color) sensitivity
• functional in dim light
• participate in highly conver-
gent 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
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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 homeo-
stasis. Processes of these cells form the internal and external limiting membranes.
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).
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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).
Binocular vision,
which is important for
depth perception,
requires visual field
overlap so that
individual objects can
be viewed simulta-
neously by both eyes.
For binocular
vision to occur, the
visual cortex in one
cerebral hemisphere
must receive informa-
tion 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 corre-
sponding 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).
optic radiation
(internal capsule)
Visualcortex
Rostralcolliculus
Pretectalregion
Optic tract
Lateralgeniculate
Optic chiasma
Optic nerve
Brachiumof the rostral colliculus
OVERLAP
Visual Fields
Left field Right field
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Conscious Visual Pathway
Optic tract fibers synapse in the lateral geniculate nucleus, which exhibits a retinotopic organi-
zation 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, affect-
ing 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.
Reflex Visual Pathways
Axons participating in subconscious visual reflexes leave the optic tract and travel in the bra-
chium 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.)
Color VisionHumans 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 ororange-red.
All of several horses tested could distinguish red and blue from gray. Somebut 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., catand pig. Nocturnal animals are completely color blind (rat, hampster, etc.).
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Pupil Size — Reflex Pathways
Pupil (light sensitive) constriction
Pupil (emotion-related) dilation
Optic chiasma
Optic tract
Pretectal region andCaudal commissure
Oculomotor nucleus
ciliary nerve
ciliary ganglion
oculomotor nerve
cranial cervicalganglion
cervicalsympathetictrunk
Cervical spinal cord
Spinal cord segment T-1
Lateralgeniculate
Optic nerve
plexus oninternal carotid A.
Brachiumof rherostralcolliculus
Retina
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 iscontrolled by the cerebral cortex.
