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Dr.

Colin Haile
Neuroscience Winter 2004
Lecture Notes: III
LECTURE 25: The 12 Cranial Nerves

• There are 12 pairs of cranial nerves, which leave the brain


and pass through foramina and fissures in the skull.
• All the nerves are distributed in the head and neck, except CNX (vagus), which
also supplies structures in the thorax and abdomen.

• 1. Olfactory 7. Facial
• 2. Optic 8. Vestibulocochlear
• 3. Oculomotor 9. Glossopharyngeal
• 4. Trochlear 10. Vagus
• 5. Trigeminal 11. Accessory
• 6. Abducent 12. Hypoglossal

Organization of the Cranial Nerves


• The olfactory (CN I), optic (CN II), and vestibulocochlear (CN VIII) nerves
are entirely sensory.
• The oculomotor (CN III), trochlear (CN IV), abducent (CN VI), accessory
(CN XI) and hypoglossal (CN XII) nerves are entirely motor.
• The trigeminal (CN V), facial (CN VII), glossopharyngeal (CN IX), and vagus
(CN X) nerves are both sensory and motor nerves.
• The cranial nerves have central motor and/or sensory nuclei within the brain
and peripheral nerve fibers that emerge from the brain and exit from the skull to
reach their effector or sensory organs.
Cranial Nerves Grouped Functionally
• Nerves I, II, and VIII are devoted to special sensory input.
• Nerves III, IV, and VI control eye movements and pupillary constriction.
• Nerves XI, and XII are pure motor
– (XI: sternocleidomastoid and trapezius, XII: muscles of the tongue).
• Nerves III, VII, IX, and X carry parasympathetic fibers.
Motor Nuclei of the Cranial Nerves
• The somatic motor and branchiomotor nerve fibers of a cranial nerve are the
axons of nerve cells situated within the brain.
• These nerve cell groups form motor nuclei and they innervate striated muscle.
• Each nerve cell with its processes is referred to as a lower motor neuron.
• Such a nerve cell is, therefore, equivalent to the motor cells in the anterior
gray columns of the spinal cord.
• The motor nuclei of the cranial nerves receive impulses from the cerebral cortex
through corticonuclear (corticobulbar) fibers.

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• These fibers originate from the pyramidal cells in the inferior part of the
precentral gyrus (area 4) and from the adjacent part of the postcentral gyrus.
• The corticonuclear fibers descend through the corona radiata and the genu of
the internal capsule.
• They pass through the midbrain just medial to the corticospinal fibers in the
basis pedunculi and end by synapsing either directly with the lower motor
neurons within the cranial nerve nuclei or indirectly through the internuncial
(inter) neurons. (2nd Order neuron)
• The corticonuclear fibers thus constitute the first-order neuron, and the lower
motor neurons constitute the third-order neuron.
• Bilateral connections are present for all the cranial motor nuclei except for part
of the facial nucleus (VII) that supplies the muscles of the lower part of the face
and a part of the hypoglossal nucleus (XII) that supplies the genioglosus muscle.
General Visceral Motor Nuclei
• The general visceral motor nuclei form the cranial outflow of the
parasympathetic portion of the autonomic nervous system.
• They are the:
– Edinger-Westphal nucleus of the oculomotor nerve
– superior salvatory and lacrimal nuclei of the facial nerve
– inferior salivatory nucleus of the glossopharyngeal nerve
– dorsal motor nucleus of the vagus
• These nuclei receive numerous afferent fibers including descending pathways
from the hypothalamus.
Sensory Nuclei of the Cranial Nerves
• These include somatic and visceral afferent nuclei.
• The sensory or afferent parts of a cranial nerve are the axons of nerve cells
outside the brain and are situated in ganglia on the nerve trunks (equivalent
to posterior root ganglion of a spinal nerve) or may be situated in a sensory
organ, such as the nose, eye, or ear.
• These cells and their processes form the first-order neuron.
• The central processes of these cells enter the brain and terminate by
synapsing with cells forming the sensory nuclei.
• These cells and their processes form the second-order neuron.
• Axons from these nuclear cells now cross the midline and ascend to other
sensory nuclei, such as the thalamus, where they synapse.
• The nerve cells of these nuclei form the third-order neurons and their axons
terminate in the cerebral cortex.
Cranial Nerve I: Olfactory Nerve
The olfactory nerves arise from the olfactory receptor nerve cells in the olfactory
mucous membrane located in the upper part of the nasal cavity above the level of
the superior concha.
• The olfactory receptor cells are scattered among supporting cells.
• Each receptor cell consists of a small bipolar nerve cell with a course
peripheral process that passes to the surface of the membrane and a fine
central process.

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• From the coarse peripheral process a number of short cilia arise, the
olfactory hairs, which project into the mucus covering the surface of the
mucous membrane.
• These projecting hairs react to odors in the air and stimulate the olfactory
cells.
• The fine central processes form the olfactory nerve fibers.
• Bundles of these nerve fibers pass through the openings of the cribriform
plate of the ethmoid bone to enter the olfactory bulb.
• The olfactory nerve fibers are unmyelinated and are covered with Schwann
cells.
Olfactory Bulb
• This ovoid structure possesses several types of nerve cells, the largest of
which is the mitral cell.
• The incoming olfactory nerve fibers synapse with the dendrites of the mitral
cells and form rounded areas known as synaptic glomeruli.
• Smaller nerve cells called tufted cells and granular cells also synapse with the
mitral cells.
• The olfactory bulb receives axons from the contralateral olfactory bulb
through the olfactory tract.
• A narrow band of white matter that runs from the posterior end of the
olfactory bulb beneath the inferior surface of the frontal lobe of the brain is
the olfactory tract.
Olfactory Tract
• It consists of the central axons of the mitral and tufted cells of the bulb and
some centrifugal fibers from the opposite olfactory bulb.
• As the olfactory tract reaches the anterior perforated substance it divides
into medial and lateral olfactory striae.
• The lateral stria carries the axons to the olfactory area of the cerebral cortex,
namely the periamygdaloid and prepiriform areas.
• The medial olfactory stria carries the fibers that cross the median plane in
the anterior commissure to pass to the olfactory bulb of the opposite side.
• The periamygdaloid and prepiriform areas of the cerebral cortex are often
known as the primary olfactory cortex.
• The entorhinal area (area 28) of the parahippocampal gyrus, which receives
numerous connections from the primary olfactory cortex, is called the
secondary olfactory cortex.
• These areas of the cortex are responsible for the appreciation of olfactory
sensations.
• In contrast to ALL other sensory pathways the olfactory afferent pathway
has only two neurons and reaches the cerebral cortex without synapsing on
thalamic nuclei.
• The primary olfactory cortex sends nerve fibers to many other centers within
the brain to establish connections for emotional and autonomic responses to
olfactory sensations.

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Key Points: Cranial Nerve I
• 1.) Olfactory receptor cells are first-order neurons that project to the mitral
cells of the olfactory bulb.
• 2.) Mitral cells are the principal cells of the olfactory bulb.
– They are excitatory and glutamatergic.
– They project through the olfactory tract and lateral olfactory stria to
the primary olfactory cortex and amygdala.
• 3.) The primary olfactory cortex (Brodmann’s area 34) consists of the
piriform cortex that overlies the uncus.
Cranial Nerve II: Optic Nerve
• The fibers of the optic nerve are the axons of the cells in the ganglionic layer
of the retina.
• They converge on the optic disc and exit from the eye, about 3 or 4mm to the
nasal side of its center, as the optic nerve.
• The fibers of the optic nerve are myelinated, but the sheaths are formed from
oligodendrocytes rather than Schwann cells, since the optic nerve is
comparable to a tract within the CNS.
• The optic nerve leaves the orbital cavity through the optic canal and unites
with the optic nerve of the opposite side to form the optic chiasma.
• The optic chiasm is situated at the junction of the anterior wall and floor of
the third ventricle.
• Its anterolateral angles are continuous with the optic nerves and the
posterolateral angles are continuous with the optic tracts.
Optic Chiasm
• In the chiasma, the fibers from the nasal (medial) half of each retina,
including the nasal half of the macula, cross the midline and enter the optic
tract of the opposite side.
• The fibers from the temporal (lateral) half of each retina, including the
temporal half of the macula, pass posteriorly in the optic tract of the same
side.
Optic Tract
• The optic tract emerges from the optic chiasma and passes posterolaterally
around the cerebral peduncle.
• Most of the fibers terminate by synapsing with nerve cells in the lateral
geniculate body, which is a small projection from the posterior part of the
thalamus.
• A few of the fibers pass to the pretectal nucleus and the superior colliculus of
the midbrain and are concerned with light reflexes.
Lateral Geniculate Body (nucleus)
• The lateral geniculate body is a small, oval swelling projecting from the
pulvinar of the thalamus.
– It consists of six layers of cells upon which synapse the axons of the
optic tract.
• The axons of the nerve cells within the geniculate body leave it to form the
optic radiation.

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Optic Radiation
• The fibers of the optic radiation are the axons of the nerve cells of the lateral
geniculate body.
• The tract passes posteriorly through the retrolenticular part of the internal
capsule and terminates in the visual cortex (area 17).
• The visual association cortex (areas 18 and 19) is responsible for recognition
of objects and perception of color.
Neurons of the Visual Pathway and Binocular Vision
• Four neurons conduct visual impulses to the visual cortex:
– Rods and cones (specialized neurons in the retina)
– Bipolar neurons (which connect the rods and cones to the ganglion
cells)
– Ganglion cells (whose axons pass to the lateral geniculate body)
– Neurons of the lateral geniculate body (pass to the cerebral cortex).
Binocular Vision
• In binocular vision, the right and left fields of vision are projected on
portions of the BOTH retinae.
• The image of an object in the right field of vision is projected on the nasal
half of the right retina and the temporal half of the left retina.
• In the optic chiasma, the axons from these two retinal halves are combined to
form the left optic tract.
• The lateral geniculate body neurons now project the complete right field of
vision upon the visual cortex of the left hemisphere and the left visual field on
the visual cortex of the right hemisphere.

• The lower retinal quadrants (upper field of vision) project on the lower wall
of the calcarine sulcus, while the upper retinal quadrants (lower field of
vision) project on the upper wall of the sulcus.
• The macula lutea is represented on the posterior part of area 17 and the
periphery of the retina is represented anteriorly.
Visual Reflexes
• If a light is shone into one eye the pupils of both eyes normally constrict.
• The pupil upon which the light is shone is called the direct light reflex.
• Constriction of the opposite pupil even though no light fell upon that eye is
called the consensual light reflex.
• The afferent impulses travel through the optic nerve, optic chiasma, and
optic tract.
• Here a small number of fibers leave the optic tract and synapse on nerve cells
in the pretectal nucleus which lies close to the superior colliculus.
The impulses are passed by axons of the pretectal nerve cells to the parasympathetic
nuclei (Edinger-Westphal nuclei) of the third cranial nerve on both sides.
• Here the fibers synapse and the parasympathetic nerves travel through the
CN III to the ciliary ganglion in the orbit.
• Finally, postganglionic parasympathetic fibers pass through the short ciliary
nerves to the eyeball and the constrictor pupillae muscle of the iris.

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• Both pupils constrict in the consensual light reflex because the pretectal
nucleus sends fibers to the parasympathetic nuclei on both sides of the
midbrain.
• The fibers that cross the median plane do so close to the cerebral aqueduct in
the posterior commissure.
Accommodation Reflex
• Accommodation is the adjustment of the eyes for various distances.
• Accommodation occurs as contraction of the ciliary muscle results in a thickening
of the lens and an increase in refractive power.
• It is mediated by the Edinger-Westphal nucleus via CNIII.
• The visual cortex is connected to the eye field of the frontal cortex.
• From here, cortical fibers descend through the internal capsule to the oculomotor
nuclei in the midbrain.
• The oculomotor nerve travels to the medial recti muscles.
• Some of the descending cortical fibers synapse with the parasympathetic nuclei
(Edinger-Westphal nuclei) of CNIII on both sides.
• The fibers then synapse and the parasympathetic nerves travel through the CNIII
to the ciliary ganglion in the orbit.
• Postganglionic parasympathetic fibers then pass through the short ciliary nerves to
the ciliary muscle and the constrictor pupillae muscle of the iris.
Corneal Reflex
• Light touching of the cornea or conjunctiva results in blinking of the eyelids.
• Afferent impulses from the cornea or conjunctiva travel through the
ophthalmic division of the trigeminal nerve (CNV) to the sensory nucleus of
the trigeminal nerve.
• Interneurons connect with the motor nucleus of CNVII on both sides through the
medial longitudinal fasciculus.
• The CNVII and its branches supply the orbicularis oculi muscle, which causes the
closure of the eyelids.
Visual Body Reflexes
• The automatic scanning movements of the eyes and head made when reading, the
automatic movement of the eyes, head, and neck toward the source of the visual
stimulus, and the protective closing of the eyes and even the raising of the arm
for protection are REFLEX ACTIONS that involve the following of reflex
arcs.
• The visual impulses follow the optic nerves, optic chiasma, and optic tracts to the
superior colliculi.
• Here the impulses are relayed to the tectospinal and tectobulbar (tectonuclear)
tracts and to the neurons of the anterior gray columns of the spinal cord and
cranial motor nuclei.
Pupillary Skin Reflex
• The pupil will dilate if the skin is painfully stimulated by pinching.
• The afferent sensory fibers are believed to have connections with the efferent
preganglionic sympathetic neurons in the lateral gray columns of the first and
second thoracic segments of the spinal cord.

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• The white rami communicantes of these segments pass to the sympathetic trunk
and the preganglionic fibers ascend to the superior cervical sympathetic ganglion.
• The postganglionic fibers pass through the internal carotid plexus and the long
ciliary nerves to the dilator pupillae muscle of the iris.
Key Points: Optic Nerve II
• CNII is a special somatic afferent (SSA) nerve that subserves vision and
pupillary light reflexes.
• It is NOT a true peripheral nerve, but is a tract of the diencephalon.
• A transected optic nerve cannot regenerate.
Cranial Nerve III: Oculomotor Nerve
• The oculomotor nerve is entirely motor in function.
• It has two motor nuclei:
• (1) the main oculomotor nucleus and
• (2) the accessory parasympathetic nucleus
• The main oculomotor nucleus is situated in the anterior part of the gray matter
that surrounds the cerebral aqueduct of the midbrain.
• It lies at the level of the superior colliculus.
Oculomotor Nerve
• The nucleus consists of groups of nerve cells that supply all the extrinsic
muscles of the eye except the superior oblique and the lateral rectus.
• The outgoing nerve fibers pass anteriorly through the red nucleus and emerge on
the anterior surface of the midbrain in the interpeduncular fossa.
• The accessory parasympathetic nucleus (Edinger-Westphal nucleus) is situated
posterior to the main oculomotor nucleus.
• The axons of the nerve cells (preganglionic), accompany the other oculomotor
fibers to the orbit.
• Here they synapse in the ciliary ganglion and postganglionic fibers pass through
the short ciliary nerves to the constrictor pupillae of the iris and the ciliary
muscles.
• The accessory parasympathetic nucleus receives corticonuclear fibers for the
accommodation reflex and fibers from the pretectal nucleus for the direct and
consensual light reflexes.
• The oculomotor nerve emerges on the anterior surface of the midbrain. It passes
forward between the posterior cerebral and the superior cerebellar arteries.
• It then continues into the middle cranial fossa in the lateral wall of the cavernous
sinus.
• Here, it divided into a superior and an inferior ramus, which enter the orbital
cavity through the superior orbital fissure.
• The oculomotor nerve supplies the following extrinsic muscles of the eye:

• Levator palpebrae superioris


• Superior rectus
• Medial rectus
• Inferior rectus
• Inferior oblique

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• It also supplies through its branch to the ciliary ganglion and the short
ciliary nerves parasympathetic nerve fibers to the intrinsic muscles of the
eye; the constrictor pupillae of the iris and ciliary muscles.
• The oculomotor nerve is therefore ENTIRELY motor and is responsible for:

• lifting the upper eyelid


• turning the eye upward, downward and medially
• constricting the pupil
• accommodating the eye
Key Points: Oculomotor nerve (CNIII)
• CNIII is a general somatic efferent (GSE), general visceral efferent (GVE)
nerve.
• Oculomotor paralysis (palsy) is seen with transtentorial herniation (e.g.
tumor subdural or epidural hematoma).
• Transtentorial (uncal) herniation.
– Increased supratentorial pressure (e.g. tumor) forces the hippocampal
uncus through the tentorial notch and compresses or stretches the
oculomotor nerve.
• Aneurysms of carotid and posterior communicating arteries often compress
CNIII within the cavernous sinus or interpeduncular cistern.
• They usually affect the peripheral pupilloconstrictor fibers first.
• Diabetes Mellitus (diabetic ocular palsy) often effects the oculomotor nerve.
It damages the central fibers and spares the pupilloconstrictor fibers.
Cranial Nerve IV: Trochlear Nerve
• The trochlear nucleus is situated in the anterior part of the gray matter that
surrounds the cerebral aqueduct of the midbrain.
• It lies inferior to the oculomotor nucleus at the level of the inferior colliculus.
• The nerve fibers, after leaving the nucleus, pass posteriorly around the
central gray matter to reach the posterior surface of the midbrain.
• It lies inferior to the oculomotor nucleus at the level of the inferior colliculus.
• The nerve fibers, after leaving the nucleus, pass posteriorly around the
central gray matter to reach the posterior surface of the midbrain.
• The trochlear nucleus receives corticonuclear fibers from both cerebral
hemispheres.
• It receives the tectobulbar fibers, which connect it to the visual cortex
through the superior colliculus.
• It also receives fibers from the medial longitudinal fasciculus, by which it is
connected to the CNIII, CNIV and VIII cranial nerves.
• The trochlear nerve, the most slender of the cranial nerves, and the only one
to leave the posterior surface of the brainstem, emerges from the midbrain
and immediately decussates with the nerve of the opposite side.

• CNIV passes forward through the middle cranial fossa in the lateral wall of
the cavernous sinus and enters the orbit through the superior orbital fissure.
• The nerve supplies the superior oblique muscle of the eyeball.
• CNIV is entirely motor and assists in turning the eye downward laterally.

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Key Points: Trochlear Nerve CNIV
• The trochlear nerve is a general somatic efferent (GSE).
• The trochlear nerve is a PURE MOTOR NERVE that innervates the
superior oblique muscle.
• This muscle depresses, intorts, and abducts the eye.
• CNIV paralysis results in:
• Extorsion of the eye and weakness of downward gaze.
• Vertical diplopia, which increases when looking down.
• Head tilting to compensate for extorsion (may be misdiagnosed as
idiopathic torticollis).
• Head trauma: because of its course around the midbrain, the trochlear nerve
is particularly vulnerable to head trauma.
• The trochlear decussation underlies the superior medullary velum.
• The trauma at this site often results in bilateral fourth-nerve palsies.
• Pressure against the free border of the tentorium (herniation) may injure the
nerve.

LECTURE26: Cranial Nerves: V-VIII

Trigeminal Nerve (CNV)


• The trigeminal nerve is the LARGEST cranial nerve and contains both sensory
and motor fibers (trigeminal is Latin for “born three at a time”).
• It is the sensory nerve to the greater part of the head and the motor nerve to
several muscles, including muscles of mastication.
• The trigeminal nerve has four nuclei:

• 1. Main sensory nucleus


• 2. Spinal nucleus
• 3. Mesencephalic nucleus
• 4. Motor nucleus
Main Sensory Nucleus
• This nucleus lies in the posterior part of the pons, lateral to the motor nucleus.
• It is continuous below with the spinal nucleus.
Spinal Nucleus
• The spinal nucleus is continuous superiorly with the main sensory nucleus in
the pons and extends inferiorly through the whole length of the medulla
oblongata and into the upper part of the spinal cord as far as the second cervical
segment.
Mesencephalic Nucleus
• This nucleus is composed of a column of unipolar nerve cells situated in the
lateral part of the gray matter around the cerebral aqueduct.
• It extends inferiorly into the pons as far as the main sensory nucleus.
Motor Nucleus
The motor nucleus is situated in the pons medial to the main sensory nucleus.
Sensory Components of the Trigeminal Nerve (CNV)

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• The sensations of pain, temperature, touch and pressure from the skin of the
face and mucous membranes travel along axons whose cell bodies are situated in
the trigeminal sensory ganglion.
Sensory Components of the Trigeminal Nerve (CNV)
• The central processes of these cells form the large sensory root of the trigeminal
nerve.
• About half the fibers divided into ascending and descending branches when
they enter the pons.
• The remainder ascend or descend without division.
• The ascending branches terminate in the mains sensory nucleus and the
descending branches terminate in the spinal nucleus.
Sensory Components of the Trigeminal Nerve (CNV)
• The sensations of touch and pressure are conveyed by nerve fibers that terminate
in the main sensory nucleus.
• The sensation of pain and temperature pass to the spinal nucleus.
• The sensory fibers form the ophthalmic division of the trigeminal nerve
terminate in the inferior part of the spinal nucleus.
• Fibers from the maxillary division terminate in the middle of the spinal nucleus
and fibers from the mandibular division end in the superior part of the spinal
nucleus.
• Proprioceptive impulses from the muscles of mastication and from the facial
and extraocular muscles are carried by fibers in the sensory root of the
trigeminal nerve that have bypassed the trigeminal ganglion.
• The cell bodies of these cells are unipolar cells and are located in the
mesencephalic nucleus.
• The axons of the neurons in the main sensory and spinal nuclei, and the central
processes of the cells in the mesencephalic nucleus, cross the median plane and
ascend as the trigeminal lemniscus to terminate on the nerve cells of the ventral
posteromedial nucleus of the thalamus.
• The axons of these cells now travel through the internal capsule to the
postcentral gyrus (areas, 3,1 and 2) of the cerebral cortex.
Motor Component of the Trigeminal Nerve
• The motor nucleus receives corticonuclear fibers from both cerebral
hemispheres.
• It also receives fibers from the reticular formation, the red nucleus, the tectum
and the medial longitudinal fasciculus.
• It also receives fibers from the mesencephalic nucleus, thereby forming a
monosynaptic reflex arc.
• The cells of the motor nucleus give rise to the axons that form the motor root.
• The motor nucleus supplies the muscles of mastication, the tensor tympani, the
tensor veli palatini and the mylohyoid and the anterior belly of the digastric
muscle.
Course of the Trigeminal Nerve
• The trigeminal nerve leaves the anterior aspect of the pons as a small motor
root and a large sensory root.

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• The large sensory root expands to form the crescent-shaped trigeminal ganglion
that lies within a pouch of dura mater called the trigeminal or Meckel’s cave.
• The ophthalmic, maxillary, and mandibular nerves arise from the anterior
border of the ganglion.
• The ophthalmic nerve (V1) contains only sensory fibers and leaves the skull
through the superior orbital fissure to enter the orbital cavity.
• The maxillary nerve (V2) also contains only sensory fibers and leaves the skull
through the foramen rotundum.
• The mandibular nerve (V3) contains both the sensory and motor fibers and
leaves the skull through the foramen ovale.
• The sensory fibers to the skin of the face from each division supply a distinct
zone with little or no overlap of the dermatomes.
• As noted previously, the motor fibers in the mandibular division are mainly
distributed to muscles of mastication.
Key Points: Trigeminal Nerve (CNV)
• The trigeminal nerve is a special visceral efferent (SVE) and general somatic
afferent (GSA) nerve.
• It has three divisions: ophthalmic (CNV1), maxillary (CNV2), and mandibular
(CNV3).
• The somatic visceral efferent portion of the nerve innervates the muscles of
mastication.
• The general somatic afferent component provides sensory innervation to the
face, mucous membranes of the nasal and oral cavities and frontal sinus,
hard palate, and deep structures of the head.
• Lesions of CNV may result in loss of general sensation (hemianesthesia) from
the face and mucous membranes of the oral and nasal cavities.
• Loss of the corneal reflex (afferent limb, CN V-1).
• Flaccid paralysis of the muscles of mastication.
• Deviation of the jaw to the weak side as a result of the unopposed action of the
opposite lateral pterygoid muscle.
• Paralysis of the tensor tympani muscle, which leads to hypoacusis (partial
deafness to low-pitched sounds).
• Trigeminal neuralgia (tic douloureux) which is characterized by recurrent
paroxysms of sharp, stabbing pain in one or more branches of the nerve.
Abducent Nerve (CN VI)
The abducent nerve (CNVI) is a small motor nerve that supplies the lateral rectus
muscle of the eyeball.
Abducent Nerve Nucleus
• The small motor nucleus is situated beneath the floor of the upper part of the
fourth ventricle, close to the midline.
• The nucleus receives afferent corticonuclear fibers from both cerebral
hemispheres.
• It receives the tectobulbar tract from the superior colliculus, by which the visual
cortex is connected to the nucleus.
• Fibers of the abducent nerve pass anteriorly through the pons and emerge in the
groove between the lower border of the pons and the medulla oblongata.

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• It passes forward through the cavernous sinus, laying below and lateral to the
internal carotid artery.
• The nerve then enters the orbit through the superior orbital fissure.
• The abducent nerve is entirely a motor nerve and supplies the lateral rectus
muscle which is responsible for turning the eye laterally.
Deficits of horizontal gaze after damage to the abducens/MLF system
Horizontal Gaze Palsy
Abducent Nerve (CNV): Key Points
• The abducent nerve is a pure general somatic efferent (GSE) nerve that
innervates the lateral rectus muscle, which abducts the eye.
• CNVI paralysis is the most common isolated palsy that results from the long
peripheral course of the nerve.
• It is seen in patients with meningitis, subarachnoid hemorrhage, late-stage
syphilis, and trauma.
Facial Nerve (CN VII)
• The facial nerve is both a motor and a sensory nerve.

• The facial nerve has three nuclei


– 1. main motor nucleus
– 2. parasympathetic nuclei
– 3. sensory nucleus
Main Motor Nucleus
• The main motor nucleus lies deep in the reticular formation of the lower part
of the pons. The part of the nucleus that supplies the muscles of the upper part of
the face receives corticonuclear fibers from both cerebral hemispheres.
• The part of the nucleus that supplies the muscles of the lower part of the face
receives only corticonuclear fibers from the opposite cerebral hemisphere.
• These pathways explain the voluntary control of facial muscles.
• Involuntary pathways involve a separate pathway and control mimetic or
emotional changes in facial expression which is mediated by the reticular
formation.
Parasympathetic Nuclei
• The parasympathetic nuclei lie posterolateral to the main motor nucleus.
• They include the superior salivatory and lacrimal nuclei.
• The superior salivatory nucleus receives afferent fibers from the hypothalamus
through the descending autonomic pathways.
• Information concerning taste also is received from the nucleus of the solitary
tract from the mouth cavity.
The lacrimal nucleus receives afferent fibers from the hypothalamus for emotional
responses and from the sensory nuclei of the trigeminal nerve for reflex lacrimation
secondary to irritation of the cornea or conjunctiva.
Sensory Nucleus
• The sensory nucleus is the upper part of the nucleus of the tractus solitarius
and lies close to the motor nucleus.
• Sensations of taste travel through the peripheral axons of nerve cells situated in
the geniculate ganglion on the seventh cranial nerve.

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• Geniculate ganglionic processes synapse on nerve cells in the nucleus of tractus
solitarius.
• Efferent fibers cross the median plane and ascend to the ventral posterior
medial nucleus of the opposite thalamus and also a number of hypothalamic
nuclei.
• From the thalamus, the axons of the thalamic cells pass through the internal
capsule and corona radiata to end in the taste area of the cortex in the lower
part of the postcentral gyrus.
Course of the Facial Nerve
• The facial nerve consists of a motor and sensory root. The fibers of the motor
root first travel posteriorly around the medial side of the abducent nucleus.
• Then they pass around the nucleus beneath the colliculus facialis in the floor of
the fourth ventricle and finally pass anteriorly to emerge from the brainstem.
• The sensory root (nervus intermedius) is formed of the central processes of the
unipolar cells of the geniculate ganglion.
• It also contains the efferent preganglionic parasympathetic fibers from the
parasympathetic nuclei.
• The two roots of the facial nerve emerge from the anterior surface of the
brain between the pons and the medulla oblongata.
• They pass laterally in the posterior cranial fossa with the vestibulocochlear nerve
and enter the internal acoustic meatus in the petrous part of the temporal bone.
• At the bottom of the meatus, the nerve enters the facial canal and runs laterally
through the inner ear.
• On reaching the medial wall of the tympanic cavity, the nerve expands to form
the sensory geniculate ganglion and turns sharply backward above the
promontory.
At the posterior wall of the tympanic cavity the facial nerve turns downward on the
medial side of the aditus of the mastoid antrum, descends behind the pyramid, and
emerges from the stylomastoid foramen.
Distribution of the Facial Nerve
• The motor nucleus supplies the muscles of facial expression, the auricular
muscles, the stapedius, the posterior belly of the digastric, and the stylohyoid
muscles.
• The superior salivatory nucleus supplies the submandibular and sublingual
salivary glands and the nasal and palatine glands.
• The lacrimal nucleus supplies the lacrimal gland.
• The sensory nucleus receives taste fibers from the anterior two-thirds of the
tongue, the floor of the mouth, and the palate.
Key Points: Facial Nerve (CN VII)
• The facial nerve mediates facial movements, taste, salivation, lacrimation and
general sensation from the external ear.
• An upper motor neuron (UMN) lesion (stroke involving the internal capsule)
results in contralateral weakness of the lower face, with sparing of the upper
face.
• A lower motor neuron (LMN) lesion (e.g. Bell’s Palsy) results in paralysis of
the facial muscles in both the upper and lower face.

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• A lesion of the facial nerve cause:
• Flaccid paralysis of the muscles of the face.
• Loss of the corneal reflex (efferent limb) which may lead to corneal ulceration.
• Loss of taste (ageusia=gustatory anesthesia) from the anterior two-thirds of the
tongue which may result from damage to the chorda tympani.
• Hyperacusis (increased acuity to sounds) as a result of stapedius paralysis.
• Bell’s palsy (peripheral facial paralysis) which is caused by trauma or infection
and involves the upper and lower face.
• Crocodile tears syndrome (lacrimation during eating) which is a result of
aberrant regeneration after trauma.
• Supranuclear (central) facial palsy, which results in contralateral weakness of
the lower face, with sparing of the upper face.
• Bilateral facial nerve palsies, which occur in Guillain-Barre syndrome.
• Mobius’ syndrome which consists of congenital facial diplegia (CNVII) and
convergent strabismus (CNVI).
Vestibulocochlear Nerve (CN VIII)
• CN VIII consists of two distinct parts the vestibular nerve and the cochlear
nerve, which are concerned with the transmission of afferent information from
the internal ear to the CNS.
Vestibular Nerve
• The vestibular nerve conducts nerve impulses from the utricle and saccule that
provide information concerning the position of the head.
• The nerve also conducts impulses from the semicircular canals that provide
information concerning movements of the head.
• The nerve fibers of the vestibular nerve are the central processes of nerve cells
located in the vestibular ganglion, which is situated in the internal acoustic
meatus.
• They enter the anterior surface of the brainstem in a groove between the lower
border of the pons and the upper part of the medulla oblongata.
• When they enter the vestibular nuclear complex, the fibers divide into short
ascending and long descending fibers.
• A small number of fibers pass directly to the cerebellum through the inferior
cerebellar peduncle, bypassing the vestibular nuclei.
The Vestibular Nuclear Complex
• This complex consists of a group of nuclei situated beneath the floor of the fourth
ventricle.
• These include:
– Lateral vestibular nucleus
– Superior vestibular nucleus
– Medial vestibular nucleus
– Inferior vestibular nucleus
• The vestibular nuclei receive afferent fibers from the utricle and saccule and the
semicircular canals through the vestibular nerve, and fibers from the
cerebellum through the inferior cerebellar peduncle.
• Efferent fibers from the nuclei pass to the cerebellum through the inferior
cerebellar peduncle.

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• Efferent fibers also descend uncrossed to the spinal cord from the lateral
vestibular nucleus and form the vestibulospinal tract.
• Efferent fibers pass to the nuclei of the oculomotor, trochlear, and abducent
nerves through the medial longitudinal fasciculus.

• These connections enable the movements of the head and the eyes to be
coordinated so that visual fixation on an object can be maintained.
• Information received from the internal ear can assist in maintaining balance by
influencing the muscle tone of the limbs and trunk.
• Ascending fibers also pass upward from the vestibular nuclei to the cerebral
cortex, to the vestibular area in the postcentral gyrus, just above the lateral
fissure.
• These fibers relay in the ventral posterior nuclei of the thalamus.
• The cerebral cortex serves to orient the individual consciously in space.
Cochlear Nerve
• The cochlear nerve conducts nerve impulses concerned with sound from the
organ of Corti in the cochlea.
• The fibers of the cochlear nerve are the central processes of nerve cells located in
the spiral ganglion of the cochlea.
• They enter the anterior surface of the brainstem at the lower border of the pons
on the lateral side of the emerging facial nerve and are separated from it by the
vestibular nerve.
• On entering the pons the nerve fibers divide, one branch entering the posterior
cochlear nucleus and the other branch entering the anterior cochlear nucleus.
• The anterior and posterior cochlear nuclei are situated on the surface of the
inferior cerebellar peduncle.
• They receive afferent fibers from the cochlea through the cochlear nerve.
• The cochlear nuclei send axons (second-order fibers) that run medially through
the pons to end in the trapezoid body and the olivary nucleus.
• Here they are relayed in the posterior nucleus of the trapezoid body and the
superior olivary nucleus on the same side or the opposite side.
• The axons now ascend through the posterior part of the pons and midbrain and
form a tract known as the lateral lemniscus.
• Each lateral lemniscus, consists of third-order neurons from both sides.
• As these fibers ascend, some of them relay in small groups of nerve cells, known
as the nucleus of the lateral lemniscus.

On reaching the midbrain, the fibers of the lateral lemniscus either terminate in the
nucleus of the inferior colliculus or are relayed in the medial geniculate body and pass
to the auditory cortex of the cerebral hemisphere through the acoustic radiation of the
internal capsule.
• The primary auditory cortex (areas 41 and 42) includes the gyrus of Heschl on
the upper surface of the superior temporal gyrus.
• The recognition and interpretation of sounds on the basis of past experience
take place in the secondary auditory area.

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• Many collateral branches are given off to the reticular activating system of the
brainstem.
• The tonotopic organization present in the organ of Corti is preserved within the
cochlear nuclei, the inferior colliculi, and the primary auditory area.
Descending Auditory Pathways
• Descending fibers originating in the auditory cortex and in other nuclei in the
auditory pathway accompany the ascending pathway.
• These fibers are bilateral and end on nerve cells at different levels of the auditory
pathway and on the hair cells of the organ of Corti.
• These fibers serve as a feedback mechanism and inhibit the reception of sound.
• They also have a role in the process of auditory sharpening, suppressing some
signals and enhancing others.
Course of the Vestibulocochlear Nerve
(CN VIII)
• The vestibular and cochlear parts of the nerve leave the anterior surface of the
brain between the lower border of the pons and the medulla oblongata.
• They run laterally in the posterior cranial fossa and enter the internal acoustic
meatus with the facial nerve.
• The fibers are then distributed to the different parts of the internal ear.
Key Points: Vestibulocochlear Nerve (CNVIII)
• CN VIII has two functional divisions: the vestibular nerve, which maintains
equilibrium and balance, and the cochlear nerve, which mediates hearing.
• A lesion of the vestibular nerve results in disequilibrium, vertigo and
nystagmus (constant involuntary movements of the eyes).
• Lesions involving the cochlear nerve cause hearing loss (sensorineural
deafness).
• Irritative lesions cause tinnitus (ear ringing).
• An acoustic neuroma (schwannoma) is a Schwann cell tumor of the cochlear
nerve that causes deafness.

LECTURE 27: Cranial Nerves IX-XII


Glossopharyngeal Nerve (CN IX)
• The glossopharyngeal nerve is a motor and a sensory nerve.
• The glossopharyngeal nerve has three nuclei:
– Main motor nucleus
– Parasympathetic nucleus
– Sensory nucleus
Main Motor Nucleus
• The main motor nucleus lies deep in the reticular formation of the medulla
oblongata and is formed by the superior end of the nucleus ambiguus.
• It receives corticonuclear fibers from both cerebral hemispheres.
• The efferent fibers supply the stylopharyngeus muscle.
Parasympathetic Nucleus
• The parasympathetic nucleus is also called the inferior salivatory nucleus.
• It receives afferent fibers from the hypothalamus through the descending
autonomic pathways.

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• It also receives information from the olfactory system through the reticular
formation.
• Information concerning taste also is received from the nucleus of the solitary
tract from the mouth cavity.
• The efferent preganglionic parasympathetic fibers reach the otic ganglion
through the tympanic branch of the glossopharyngeal nerve, the tympanic
plexus and the lesser petrosal nerve.
• The postganglionic fibers pass to the parotid salivary gland.
Sensory Nucleus
• This is part of the nucleus of the tractus solitarius.
• Sensations of taste travel through the peripheral axons of cells situated in the
ganglion on the glossopharyngeal nerve.
• The central processes of these cells synapse on nerve cells in the nucleus.
• Efferent fibers cross the median plane and ascend to the ventral group of nuclei
of the opposite thalamus, and also a number of hypothalamic nuclei.
• From the thalamus, the axons of the thalamic cells pass through the internal
capsule and corona radiata to end in the lower part of the postcentral gyrus.
• Afferent information that concerns common sensation enters the brainstem
through the superior ganglion of the glossopharyngeal nerve, but ends in the
spinal nucleus of the trigeminal nerve.
• Afferent impulses from the carotid sinus, a baroreceptor situated at the
bifurcation of the common carotid artery, also travel with the glossopharyngeal
nerve.
• They terminate in the nucleus of the tractus solitarius and are connected to the
dorsal motor nucleus of the vagus nerve.
• The carotid sinus reflex that involves the glossopharyngeal and vagus nerves
assists in the regulation of arterial blood pressure.
Course of the Glossopharyngeal Nerve
• The glossopharyngeal nerve leaves the anterolateral surface of the upper part of
the medulla oblongata as a series of rootlets in a groove between the olive and
the inferior cerebellar peduncle.
• It passes laterally in the posterior cranial fossa and leaves the skull through the
jugular foramen.
• The superior and inferior glossopharyngeal sensory ganglia are situated on the
nerve here.
The nerve then descends through the upper part of the neck in company with the internal
jugular vein and the internal carotid artery to reach the posterior border of the
stylopharyngeus muscle which it supplies.
• The nerve then passes forward between the superior and middle constrictor
muscles of the pharynx to give sensory branches to the mucous membrane of
the pharynx and the posterior third of the tongue.
Glossopharyngeal Nerve (CN IX): Key Points
• The glossopharyngeal nerve is primarily a sensory nerve.
• Along with CNX, CNXI, and CNXII, it mediates taste, salivation and
swallowing.

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• It mediates input from the carotid sinus, which contains baroreceptors that
monitor arterial blood pressure.
• It also mediates input from the carotid body, which contains chemoreceptors
that monitor the CO2 and O2 concentration in the blood.
• Loss of general sensation in the pharynx, tonsils, fauces and back of the
tongue.
• Loss of taste from the posterior one-third of the tongue.
• Glossopharyngeal neuralgia, which is characterized by severe stabbing pain in
the root of the tongue.
Vagus Nerve (X)
• The vagus nerve is a motor and sensory nerve.

• The vagus nerve has three nuclei:


– Main motor nucleus
– Parasympathetic nucleus
– Sensory nucleus
Main Motor Nucleus
• The main motor nucleus lies deep in the reticular formation of the medulla
oblongata and is formed by the nucleus ambiguus.
• It receives corticonuclear fibers from both the cerebral hemispheres.
• The efferent fibers supply the constrictor muscles of the pharynx and the
intrinsic muscles of the larynx.
Parasympathetic Nucleus
• This nucleus forms the dorsal nucleus of the vagus and lies beneath the floor of
the lower part of the fourth ventricle posterolateral to the hypoglossal nucleus.
• It receives afferent fibers from the hypothalamus through the descending
autonomic pathways.
• It also receives other afferents, including those from the glossopharyngeal nerve
(carotid sinus reflex).
• The efferent fibers are distributed to the involuntary muscle of the bronchi,
heart, esophagus, stomach, small intestine, and large intestine as far as the
distal one third of the transverse colon.
• This nucleus is the lower part of the nucleus of the tractus solitarius.
• Sensations of taste travel through the peripheral axons of nerve cells situated in
the inferior ganglion on the vagus nerve.
• The central processes of those cells synapse on nerve cells in the nucleus.
• Efferent fibers cross the median plane and ascend to the ventral group of nuclei
of the opposite thalamus as well as to a number of hypothalamic nuclei.
• From the thalamus, the axons of the thalamic cells pass through the internal
capsule and corona radiata to end in the postcentral gyrus.
• Afferent information concerning common sensation enters the brainstem
through the superior ganglion of the vagus nerve but ends in the spinal nucleus
of the trigeminal nerve.
Course of the Vagus Nerve

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• The vagus nerve leaves the anterolateral surface of the upper part of the medulla
oblongata as a series of rootlets in a groove between the olive and the inferior
cerebellar peduncle.
• The nerve passes laterally through the posterior cranial fossa and leaves the
skull through the jugular foramen.
• The vagus nerve possesses two sensory ganglia, a rounded superior ganglia,
situated on the nerve within the jugular foramen, and a cylindrical inferior
ganglion, which lies on the nerve just below the foramen.
• Below the inferior ganglion the cranial root of the accessory nerve joins the
vagus nerve and is distributed mainly in its pharyngeal and recurrent
laryngeal branches.
• The vagus nerve descends vertically in the neck within the carotid sheath with
the internal jugular vein and the internal and common carotid arteries.
• The right vagus nerve enters the thorax and passes posterior to the root of the
right lung contributing to the pulmonary plexus.
• It then passes on to the posterior surface o the esophagus and contributes to the
esophageal plexus.
• It enters the abdomen through the esophageal opening of the diaphragm.
• The posterior vagal trunk (which is the name given to the right vagus) is
distributed to the posterior surface of the stomach and by a large celiac branch
to the duodenum, liver, kidneys, and small and large intestines as far as the
distal third of the transverse colon.
• The wide distribution is accomplished through the celiac, superior mesenteric,
and renal plexuses.

• The left vagus nerve enters the thorax and crosses the left side of the aortic
arch and descends behind the root of the left lung contributing to the
pulmonary plexus.
• The left vagus then descends on the anterior surface of the esophagus
contributing to the esophageal plexus.
• It enters the abdomen through the esophageal opening of the diaphragm.
• The anterior vagal trunk divides into several branches, which are distributed to
the stomach, liver, upper part of the duodenum, and head of the pancreas.
Vagus Nerve (CN X): Key Points
• CN X mediates phonation, swallowing (with CN IX,XI and XII) elevation of
the palates, taste, and cutaneous sensation from the ear.
• It innervates the viscera of the neck, thorax, and abdomen.
• Lesions of CN X produce ipsilateral paralysis of the soft palate, pharynx, and
larynx that leads to dysphonia (hoarseness), dyspnea, dysarthria, and
dysphagia.
• Loss of the gag (palatal) reflex (efferent limb).
• Anesthesia of the pharynx and larynx that leads to unilateral loss of the cough
reflex.
• Aortic aneurysms and tumors of the neck and thorax that frequently compress
the vagal nerve.

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• Complete laryngeal paralysis which can be rapidly fatal if it is bilateral
(asphyxia).
• Parasympathetic (vegetative) disturbances, including bradycardia (irritative
lesion), tachycardia (destructive lesion) and dilation of the stomach.
• The oculocardiac reflex, in which pressure on the eye slows the heart rate
(afferent limb of CN V-1 and efferent limb of CN X).
• The carotid sinus reflex, in which pressure on the carotid sinus slows the heart
rate (bradycardia).
Accessory Nerve (CN XI)
The accessory nerve is a motor nerve that is formed by the union of a cranial and a
spinal root.
Cranial Root
• The cranial root is formed from the axons of nerve cells of the nucleus
ambiguus.
• The nucleus receives corticonuclear fibers from both cerebral hemispheres.
The efferent fibers of the nucleus emerge from the anterior surface of the medulla
oblongata between the olive and the inferior cerebellar peduncle.
Course of the Cranial Root
• The nerve runs laterally in the posterior cranial fossa and joins the spinal root.
• The two roots unite and leave the skull through the jugular foramen.
• The roots then separate and the cranial root joins the vagus nerve (CN X) and is
distributed in its pharyngeal and recurrent laryngeal branches to the muscles of
the soft palate, pharynx, and larynx.
Spinal Root
• The spinal root is formed from axons of nerve cells in the spinal nucleus which
is situated in the anterior gray column of the spinal cord in the upper five
cervical segments.
• The spinal nucleus is thought to receive corticospinal fibers from both cerebral
hemispheres.
• The nerve fibers emerge from the spinal cord midway between the anterior and
posterior nerve roots of the cervical spinal nerves.
• The fibers form a nerve trunk that ascends into the skull through the foramen
magnum.
• The spinal root passes laterally and joins the cranial root as they pass through
the jugular foramen.
• After a short distance, the spinal root separates from the cranial root and ruins
downward and laterally and enters the deep surface of the sternocleidomastoid
muscle, which it supplies.
• The accessory nerve thus brings about movements of the soft palate, pharynx,
and larynx and controls the movement of two large muscles in the neck.
Accessory Nerve (CN XI): Key Points
• The CN XI mediates head and shoulder movement and innervates the laryngeal
muscles.
• It has a cranial division (accessory) and a spinal division (spinal portion).

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• The CN XI mediates head and shoulder movement and innervates the
laryngeal muscles.
• It has a cranial division (accessory) and a spinal division (spinal portion).
• Lesions of the accessory nerve cause:
• Paralysis of the sternocleidomastoid muscle that results in difficulty in
turning the head to the contralateral side.
• Paralysis of the trapezius muscle that results in shoulder droop and
inability to shrug the shoulder.
• Paralysis of the larynx if the cranial root is involved.
• Corticobulbar fibers project predominantly to the contralateral hypoglossal
nucleus.
• An upper motor neuron (UMN) lesion causes deviation of the protruded
tongue to the weak (contralateral) side.
• A lower motor neuron (LMN) lesion causes deviation of the protruded
tongue to the weak (ipsilateral) side.
Hypoglossal Nerve (CN XII)
• The hypoglossal nerve is a purely motor nerve and supplies all the intrinsic
muscles of the tongue, styloglossus, hyoglossus, and the genioglossus muscles.
Hypoglossal Nucleus
• The hypoglossal nucleus is situated close to the midline immediately beneath
the floor of the lower part of the fourth ventricle.
• It receives corticonuclear fibers from both cerebral hemispheres.
• However, the cells responsible for supplying the genioglossus muscle only
receive corticonuclear fibers from the opposite cerebral hemisphere.
• The hypoglossal nerve fibers pass anteriorly through the medulla oblongata
and emerge as a series of roots in the groove between the pyramid and olive.
• The hypoglossal nerve fibers emerge on the anterior surface of the medulla
oblongata between the pyramid and the olive.
• It crosses the posterior cranial fossa and leaves the skull through the
hypoglossal canal.
• The nerve passes downward and forward in the neck between the internal
carotid artery and the internal jugular vein until it reaches the lower border
of the posterior belly of the digastric muscle.
• Here it turns forward and crosses the internal and external carotid arteries
and the loop if the lingual artery.
• It passes deep to the posterior of the mylohyoid muscle lying on the lateral
surface of the hyoglossus muscle.
• The nerve then sends branches to the muscles of the tongue.
• In the upper part of its course, the hypoglossal nerve is joined by C1 fibers
from the cervical plexus.
• The hypoglossal nerve thus controls the movements and shape of the tongue.
Hypoglossal Nerve (XII): Key Points
• The hypoglossal nerve mediates tongue movement.
• It arises from the hypoglossal nucleus of the medulla and exits the medulla in
the preolivary sulcus.

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• It exits the skull through the hypoglossal canal, and it innervates the intrinsic
and extrinsic muscles of the tongue.
• Extrinsic muscles are genioglossus, styloglossus, and hyoglossus.
• Lesions of the hypoglossal nerve results in hemiparalysis of the tongue.
• Protrusion causes the tongue to point toward the weak side because of the
unopposed action of the opposite genioglossus muscle.
Clinical Notes
• General Considerations:

• Bilateral corticonuclear connections are present for all the cranial motor
nuclei except that part of the facial nucleus that supplies the muscles of the
lower part of the face and that part of the hypoglossal nucleus that supplies
the genioglossus muscle.
• The cranial nerves that possesses afferent sensory fibers have cell bodies that
are found in ganglia along the course of the nerves.
• These are equivalent to the posterior root ganglia.
• In the case of the olfactory nerves, the cells are the olfactory receptors.
• In situations where the cranial nerve nuclei are close together, it is very rare
for a disease process to affect one nucleus only.
• For example, the cell groups of the nucleus ambiguus serve the
glossopharyngeal, the vagus, and the cranial root of the accessory nerve, and
functional loss involving all three nerves is a common finding.
Anosmia
• Bilateral anosmia is caused by disease of the olfactory mucous membrane,
such as the common cold or allergic rhinitis.
• Unilateral anosmia can result from disease affecting the olfactory nerves,
bulb or tract.
• A lesion of the olfactory cortex on one side is unlikely to produce complete
anosmia because fibers from each olfactory tract travel to both cerebral
hemispheres.
• Fractures of the anterior cranial fossa involving the cribriform plate of the
ethmoid could tear the olfactory nerves.
• Cerebral tumors of the frontal lobes or meningiomas of the anterior cranial
fossa can produce anosmia by pressing upon the olfactory bulb or tract.
Lesions of the Visual Pathway
• Lesions of the optic pathway may have many pathological causes.
• Expanding tumors of the brain and neighboring structures, such as the
pituitary gland and the meninges, and cerebrovascular accidents are
commonly responsible.
• The most widespread effects on vision occur where the nerve fibers of the
visual pathway are tightly packed together, such as in the optic nerve or the
optic tract.

• Lesions of the visual pathway result in……


Circumferential Blindness
• This may be caused by hysteria or optic neuritis.

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• Optic neuritis may occur following spread of infection from the sphenoid and
ethmoid sinuses.
• The nerve is infected as it passes through the optic canal to enter the orbital
cavity.
Total Blindness of One Eye
This would follow complete section of one optic nerve.
Nasal Hemianopia
This would follow a partial lesion of the optic chiasm on its lateral side.
Bitemporal Hemianopia
• This would follow a sagittal section of the optic chiasma.
• This condition is most commonly produced by a tumor of the pituitary gland
exerting pressure on the optic chiasma.
Contralateral Homonymous Hemianopia
• This would follow division of the optic tract or optic radiation or destruction
of the visual cortex on one side.
• The lesion would produce the same hemianopia for both eyes or,
homonymous hemianopia.
Oculomotor Nerve (CNIII)
• The oculomotor nerve supplies all the extraocular muscles except the
superior oblique and the lateral rectus.
• It also supplies the striated muscle of the levator palpebrae superioris and
the smooth muscle concerned with accommodation, namely the sphincter
pupillae and the ciliary muscle.
Conditions most commonly affecting the oculomotor nerve are diabetes, aneurysm,
tumor, trauma, inflammation, and vascular disease.
Trochlear Nerve (CN IV)
• The trochlear nerve supplies the superior oblique muscle, which rotates the
eye downward and laterally.
• Conditions mostly affecting the trochlear nerve include stretching or
bruising as a complication of head injuries, cavernous sinus thrombosis,
aneurysm of the internal carotid artery, and vascular lesions of the dorsal
part of the midbrain.
Abducent Nerve (CN VI)
• The abducent nerve supplies the lateral rectus muscle, which rotates the eye
laterally.
• Lesions of the abducent nerve include damage due to head injuries,
cavernous sinus thrombosis or aneurysm of the internal carotid artery, and
vascular lesions of the pons.
Internuclear Ophthalmoplegia
• Lesions of the medial longitudinal fasciculus will disconnect the oculomotor
nucleus that innervates the medial rectus muscle from the abducent nucleus
that innervates medial rectus muscle.
• Bilateral internuclear ophthalmoplegia can occur with MS, occlusive
vascular disease, trauma, or brainstem tumors.
• Unilateral internuclear ophthalmoplegia can follow an infarct of a small
branch of the basilar artery.

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Trigeminal Nerve (CN V)
• The trigeminal nerve has sensory and motor roots.
• The sensory root passes to the trigeminal ganglion, from which emerge the
ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions. The motor
root joins the mandibular division.
Trigeminal Neuralgia
• Pain is felt most commonly over the skin areas innervated by the mandibular
and maxillary divisions of the trigeminal nerve.
• Only rarely is pain felt in the area supplied by the ophthalmic division.
Facial Nerve (CN VII)
The facial nerve supplies the muscle of facial expression, supplies the anterior two-
thirds of the tongue with taste fibers, and is secretomotor to the lacrimal,
submandibular, and sublingual glands.
Bell’s Palsy
• Bell’s Palsy is a dysfunction of the facial nerve and is usually unilateral.
• The swelling of the nerve within the body canal causes pressure on the nerve
fibers.
• This results in a temporary loss of function of the nerve producing a lower
motor neuron type of facial paralysis.
• The cause of Bell’s palsy is not known but has been attributed to trauma or
infection.
Vestibulocochlear Nerve (CN VIII)
• The vestibulocochlear nerve innervates the utricle and saccule, which are
sensitive to static changes in equilibrium.
• The semicircular canals, which are sensitive to changes in dynamic
equilibrium.
• And the cochlea which is sensitive to sound.
Disturbances of vestibular Nerve Function
• Disturbances of vestibular nerve function include giddiness (vertigo) and
nystagmus.
• The causes of vertigo include diseases of the labyrinth such as Meniere’s
disease.
• Lesions of the vestibular nerve, the vestibular nuclei, and the cerebellum can
also be responsible.
• MS, tumors, and vascular lesions of the brainstem also cause vertigo.
Disturbance of Cochlear Nerve function
• Disturbances of cochlear nerve function are manifested as deafness and
tinnitus.
• Loss of hearing may be due to:
– a defect of the auditory conducting mechanism in the middle ear
– damage to the receptor cells in the spiral organ of Corti in the cochlea
– a lesion of the cochlear nerve
– a lesion of the central auditory pathways
– or the cortex of the temporal lobe
Glossopharyngeal Nerve (CN IX)

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• The glossopharyngeal nerve supplies the stylopharyngeus muscle and send
secretomotor fibers to the parotid gland.
• Sensory fibers innervate the posterior one-third of the tongue for general
sensation and taste.
• Isolated lesions of the glossopharyngeal nerve are rare and usually also
involve the vagus nerve.
Accessory Nerve (CN XI)
• The accessory nerve supplies the sternocleidomastoid and the trapezius
muscles by means of its spinal root.
• Lesions of the spinal part of the accessory nerve will result in paralysis of the
sternocleidomastoid and trapezius muscles.
• The sternocleidomastoid muscle will atrophy and there will be weakness in
turning the head to the opposite side.
• The trapezius muscle will also atrophy and the shoulder will droop on that
side.
• There will also be weakness and difficulty in raising the arm above the
horizontal.
• Lesions of the spinal part of the accessory nerve may occur anywhere along
its course and may result from:
• Tumors
• Trauma such as stab or gunshot wounds to the neck
Hypoglossal Nerve (CN XII)
• The hypoglossal nerve supplies the intrinsic muscles of the tongue and the
styloglossus, hyoglossus, and the genioglossus muscles.
• Lesions of the hypoglossal nerve may occur anywhere along its course and
may result from tumor, demyelinating diseases, syringomyelia, and vascular
accidents.
• Injury of the nerve in the neck may also follow stab and gunshot wounds.

LECTURE 29: Thalamus


Gross Anatomy of the Thalamus
• There are two thalami and one is situated on each side of the third ventricle.
• The anterior end of the thalamus is narrow and rounded and forms the posterior
boundary of the interventricular foramen.
• It is the largest division of the diencephalon.
• It plays an important role in the integration of the sensory and motor systems.
• The thalamus is a large, egg-shaped (or potato-shaped) mass of gray matter that
forms the major part of the diencephalon.
• The posterior end is expanded to form the pulvinar, which overhangs the
superior colliculus.
• The medial surface of the thalamus forms part of the lateral wall of the third
ventricle and is connected to the opposite thalamus by a band of gray matter
called the interthalamic connection or interthalamic adhesion.
Subdivisions of the Thalamus
• The thalamus is covered on its superior surface by a thin layer of white matter
called the stratum zonale.

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• On its lateral surface by another layer the external medullary lamina.
• The gray matter of the thalamus is divided by a vertical sheet of white matter,
the internal medullary lamina, into medial and lateral halves.
• The internal medullary lamina consists of nerve fibers that pass from one
thalamic nucleus to another.
• Anterosuperiorly, the internal medullary lamina splits so that it is Y-shaped.
• The thalamus thus is subdivided into three main parts: the anterior part lies
between the limbs of the Y and the medial and lateral parts lie on the sides of
the stem of the Y.
• Each of the three parts of the thalamus contains a group of thalamic nuclei.
• Smaller nuclear groups are situated within the internal medullary lamina, and
some are located on the medial and lateral surfaces of the thalamus.
Anterior Portion
• The anterior portion of the thalamus contains the anterior thalamic nuclei
which receives the mamillothalamic tract from the mammillary nuclei.
• These anterior thalamic nuclei also receive reciprocal connections with the
cingulate gyrus and hypothalamus.
The function of the anterior thalamic nuclei is closely associated with that of the limbic
system and is concerned with emotional tone and the mechanisms of recent memory.
Papez Circuit
Medial Portion
• The medial portion of the thalamus contains the large dorsomedial nucleus and
several smaller nuclei.
• The dorsomedial nucleus has two-way connections with the whole prefrontal
cortex of the frontal lobe of the cerebral hemisphere.
• It also has a similar connections with the hypothalamic nuclei.
• It is interconnected with all other groups of thalamic nuclei.
• It is responsible for the integration of a large variety of sensory information,
including somatic, visceral, and olfactory information, and the relation of this
information to one’s emotional feelings and subjective states.
• It receives input from the amygdala, substantia nigra, and temporal neocortex.
• If the medial portion is damaged or destroyed, then memory loss occurs
(Wernicke-Korsakoff syndrome).
• The mediodorsal nucleus plays a role in the expression of affect, emotion and
behavior (limbic function).
Dorsal Tier of the Nuclei
• The dorsal tier of the nuclei include the lateral dorsal nucleus, the lateral
posterior nucleus and the pulvinar.
Pulvinar
• The pulvinar is the largest thalamic nucleus.
• It has reciprocal connections with the association cortex of the occipital,
parietal and posterior temporal lobes.
• It receives input from the lateral and medial geniculate bodies and the superior
colliculus.
• It plays a role in the integration of visual, auditory, and somesthetic input.
• Destruction of the pulvinar will result in sensory dysphasia.

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Ventral Tier of the Nuclei
• Ventral anterior nucleus: This nucleus is connected to the reticular formation,
the substantia nigra, the corpus striatum, and the premotor cortex
(Brodmann’s area 6) as well as to many of the other thalamic nuclei.
• Since this nucleus lies on the pathway between the corpus striatum and the
motor areas of the frontal cortex it influence the activities of the motor cortex.
• Ventral lateral nucleus: this nucleus receives input from the cerebellum
(dentate nucleus), globus pallidus, and substantia nigra, and a minor input
from the red nucleus.
• Its main projections pass to the motor and premotor regions of the cerebral
cortex.
Ventral posterior nucleus: this nucleus is subdivided into the ventral posteromedial
nucleus and the ventral posterolateral nucleus.
The ventral posteromedial nucleus receives the ascending trigeminal (CNV) and
gustatory (CNIX) pathways, while the ventral posterolateral nucleus receives the
important ascending sensory tracts the medial and spinal lemnisci.
• These include the intralaminar nuclei, the midline nuclei, the reticular nucleus
and the medial and lateral geniculate bodies.
Intralaminar Nuclei
• Intralaminar nuclei are small collections of nerve cells within the internal
medullary lamina.
• They receive afferent fibers from the reticular formation as wells as fibers from
the spinothalamic and trigeminothalamic tracts.
• They send efferent fibers to other thalamic nuclei, which in turn project to the
cerebral cortex, and fibers to the corpus striatum.
• These nuclei influence levels of consciousness and alertness.
Reticular Nucleus
• The reticular nucleus is a thin layer of nerve cells sandwiched between the
external medullary lamina and the posterior limb of the internal capsule.
• Afferent fibers converge on this nucleus from the cerebral cortex and the
reticular formation and its output is mainly to other thalamic nuclei.
• The function of this nucleus is concerned with intercommunication between the
cortex that regulates thalamic activity.
• The reticular nucleus surrounds the thalamus as a thick layer of gama-
aminobutyric acid (GABA)-ergic neurons.
• It lies between the external medullary lamina and the internal capsule.
• It receives excitatory collateral input from corticothalamic and
thalamocortical fibers.
• It projects inhibitory fibers to thalamic nuclei from which it receives input.
• It is thought to play a role in normal electroencephalogram readings.
Medial Geniculate Body
• The medial geniculate body forms part of the auditory pathway and is a
swelling on the posterior surface of the thalamus beneath the pulvinar.
• Afferent fibers to the medial geniculate body form the inferior brachium and
come from the inferior colliculus.
• The medial geniculate body is an auditory relay nucleus.

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• It receives auditory input through the brachium of the inferior colliculus and
projects to the primary auditory cortex (Brodmann’s areas 41 and 42).
Lateral Geniculate Body
• Efferent fibers leave the medial geniculate body to form the auditory radiation,
which passes to the auditory cortex of the superior temporal gyrus.
• The lateral geniculate body forms part of the visual pathway and is a swelling
on the undersurface of the pulvinar of the thalamus.
• The lateral geniculate body is a visual relay nucleus.
• It receives retinal input through the optic tract and projects to the primary
visual cortex (Brodmann’s area 17).
Connections to the Thalamus
Every thalamic nucleus (except the reticular nucleus) sends axons to different parts
of the cerebral cortex and every part of the cerebral cortex sends reciprocal fibers
back to the thalamic nuclei.
This would indicate that information received by the thalamus is always shared with the
cerebral cortex and that the cortex and thalamus can modify each other’s activities.
• The thalamus is an important relay station for two sensory-motor axonal loops
involving the cerebellum and the basal nuclei:
• 1. the cerebellar-rubro-thalamic-cortical-ponto-cerebellar loop and
• 2. the corticalstriatal-pallidal-thalamic-cortical loop, both are necessary for
normal voluntary movement.
Functions of the Thalamus
• The thalamus is made up of complicated collections of nerve cells that are
centrally placed in the brain and are interconnected.
• A vast amount of sensory information of all types (except smell, CN I)
converges on the thalamus and is integrated through the interconnections
between nuclei then distributed to other parts of the CNS.
Connections of the Thalamus
• Anatomically and functionally the thalamus and the cerebral cortex are closely
linked.
• The cortex is required for the interpretation of sensations based on past
experiences.
• The thalamus is required for the appreciation of crude sensations.
• The thalamus possesses certain very important nuclei whose connections have
been clearly established.
• These include the ventral posteromedial nucleus, the ventral posterolateral
nucleus, the medial geniculate body and the lateral geniculate body.
• The ventroanterior and the ventrolateral nuclei of the thalamus form part of the
basal nuclei circuit and thus are involved in the performance of voluntary
movement.
• These nuclei receive input from the globus pallidus and send fibers to the
prefrontal, supplemental, and premotor areas of the cerebral cortex.
• The large dorsomedial nucleus has extensive connections with the frontal lobe
cortex and hypothalamus.
• There is considerable evidence that this nucleus lies on the pathway that is
concerned with subjective feeling states and the personality of the individual.

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• The intralaminar nuclei are closely connected with the activities of the reticular
formation and they receive much of their information from the source.
• Their strategic position enables them to control the level of overall activity of
the cerebral cortex.
• The intralaminar nuclei are thus able to influence the level of consciousness
and alertness in an individual.
Clinical Notes
• Since the thalamus is such an important relay and integrative center, it follows
that disease of this area of the CNS will have profound effects.
• The thalamus may be invaded by neoplasms, subject to ischemia or damaged
by hemorrhage.
Lesions of the Thalamus
• Lesions usually result from thrombosis or hemorrhage of one of the arteries
supplying the thalamus (posterior communicating, posterior cerebral,
anterior choroidal arteries).
• Damage to the ventral posteromedial nucleus and the ventral posterolateral
nucleus will result in the loss of MANY forms of sensation, including light
touch, tactile localization and discrimination, and muscle joint sense from the
opposite side of the body.
• Due to its central location, a thalamic lesion results in dysfunction of neighboring
structures, producing symptoms and signs that overshadow those produced by
thalamic disease.
• A vascular lesion of the thalamus may also involve the midbrain, with resulting
coma, or a lateral extension of thalamic disease may involve the internal capsule
and produce extensive motor as well as sensory deficits.
Thalamic Pain
• Thalamic pain may occur as the patient is recovering from a thalamic infarct.
• Spontaneous pain, which is often excessive (thalamic overreaction), occurs on
the opposite side of the body.
• The painful sensation may be aroused by light touch or by cold, and may fail
to respond to powerful analgesic drugs.
Thalamic Syndrome
• Thalamic syndrome is characterized by immediate hemianesthesia, with the
threshold of sensitivity to pinprick, heat and cold rising later.
• The sensations are unpleasant.
• The syndrome usually appears during recovery from a thalamic infarct.
Thalamic Hand
• The contralateral hand is held in an abnormal posture in some patients with
thalamic lesions.
• The wrist is pronated and flexed, the metacarpophalangeal joints are flexed,
and the interphalangeal joints are extended.
• The fingers can be moved actively, but the movements are slow.
• The condition is due to altered muscle tone in the different muscle groups.

LECTURE 30: Hypothalamus

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• Although small (0.3% of total brain) the hypothalamus is a very important part
of the CNS.
• It controls the autonomic nervous system and the endocrine system and thus
indirectly controls body homeostasis.
• It is well placed for this purpose lying in the center of the limbic system.
• It is the site of numerous converging and diverging neuronal pathways.
• In essence it subserves three systems: the autonomic system, endocrine system
and limbic system.
• The hypothalamus is part of the diencephalon that extends from the region of
the optic chiasm to the caudal border of the mammillary bodies.
• It lies below the thalamus and forms the floor and the inferior part of the
lateral walls of the third ventricle.
• Anterior to the hypothalamus is the preoptic area often included in the
description of the hypothalamus.
• Caudally, the hypothalamus merges into the tegmentum of the midbrain.
• The lateral boundary of the hypothalamus is formed by the internal capsule.
• Viewed ventrally, the hypothalamus is seen to be related to the optic chiasm, the
tuber cinereum and the infundibulum and the mammillary bodies.
• The hypothalamus is composed of small nerve cells that are arranged in groups
or nuclei, many of which are not clearly segregated from one another.
Hypothalamic Nuclei
• For descriptive purposes the nuclei are divided by an imaginary parasagittal
plane into medial and lateral zones.
• Lying within the plane are the columns of the fornix and the mammillothalamic
tract.
Medial Zone
• The medial zone contains:

– Part of the preoptic nucleus


– Anterior nucleus
– Part of the suprachiasmatic nucleus
– Paraventricular nucleus
– Dorsomedial nucleus
– Ventromedial nucleus
– Infundibular (arcuate) nucleus
– Posterior nucleus
Lateral Zone
• The lateral zone contains:
– Part of the preoptic nucleus
– Part of the suprachiasmatic nucleus
– Supraoptic nucleus
– Lateral nucleus
– Tuberomammillary nucleus
– Lateral tuberal nuclei

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Some nuclei overlap both zones thus most nuclei of the hypothalamus have ill-
defined boundaries.
Hypothalamic Lines of Communication
• The hypothalamus receives information from the rest of the body through
nervous connections, bloodstream and cerebrospinal fluid.
• The neurons of the hypothalamic nuclei respond and exert their control via the
same routes.
• The CSF serves as a conduit between the neurosecretory cells of the
hypothalamus and distant sites of the brain.
Afferent Nervous Connections of the Hypothalamus
The hypothalamus, which lies in the center of the limbic system receives many afferent
fibers from the viscera, the olfactory mucous membrane, the cerebral cortex and the
limbic system.
Somatic and visceral afferents. General somatic sensation, gustatory and visceral
sensations reach the hypothalamus through collateral branches of the lemniscal
afferent fibers and the tractus solitarius, and through the reticular formation.
• Visual afferents leave the optic chiasma and pass to the suprachiasmatic
nucleus.
• Olfaction travels through the medial forebrain bundle.
• Auditory afferents have not been identified but auditory stimuli does influence
the activities of the hypothalamus.
• Corticohypothalamic fibers arise from the frontal lobe of the cerebral cortex
and pass directly to the hypothalamus.
• Hippocampohypothalamic fibers pass from the hippocampus through the
fornix to the mammillary body.
• Amygdalohypothalamic fibers pass from the amygdaloid complex to the
hypothalamus through the stria terminalis and through a route inferior to the
lentiform nucleus.
• Thalamohypothalamic fibers arise from the dorsomedial and midline thalamic
nuclei.
• Tegmental fibers arise from the midbrain.
Efferent Pathways to the Hippocampus
• Descending fibers to the brainstem and spinal cord influence the peripheral
neurons of the autonomic nervous system.
• They descend through a series of neurons in the reticular formation.
• The hypothalamus is connected to the parasympathetic nuclei of the
oculomotor, facial, glossopharyngeal, and vagus nerves in the brainstem.
• In a similar manner, the reticulospinal fibers connect the hypothalamus with
sympathetic cells of origin in the lateral gray horns of the first thoracic
segment to the second lumbar segment of the spinal cord and the sacral
parasympathetic outflow at the level of the second, third and fourth sacral
segments of the cord.
• The mammillothalamic tract arises in the mammillary body and terminates in
the anterior nucleus of the thalamus.
• Here the pathway is relayed to the cingulate gyrus.

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• The mammillotegmental tract arises from the mammillary body and terminates
in the cells of the reticular formation in the tegmentum of the midbrain.
• The hypothalamus has multiple efferent connections with the limbic system.
Connections of the Hypothalamus with the Hypophysis Cerebri
• The hypothalamus is connected to the hypophysis cerebri (pituitary gland) by
two pathways:
• 1. nerve fibers that travel from the supraoptic and paraventricular nuclei to
the posterior lobe of the hypophysis
• 2. long and short portal blood vessels that connect sinusoids in the median
eminence and infundibulum with capillary plexuses in the anterior lobe of the
hypophysis.
• These pathways enable the hypothalamus to influence the activities of the
endocrine glands.
Hypothalamohypophyseal Tract
• The hormones vasopressin and oxytocin are synthesized in the nerve cells of the
supraoptic and paraventricular nuclei.
• The hormones are passed along the axons together with carrier proteins called
neurophysins and are released at the axon terminals.
• Here the hormones are absorbed into the bloodstream in fenestrated capillaries
of the posterior lobe of the hypophysis.
• The hormone vasopressin (antidiuretic hormone) is produced mainly in the
nerve cells of the supraoptic nucleus.
• Its function is to cause vasoconstriction.
• It also has an important antidiuretic function, causing an increased absorption
of water by the kidney.
• Oxytocin is produced mainly in the paraventricular nucleus.
• Oxytocin stimulates the contraction of the myoepithelial cells that surround the
alveoli and ducts of the breast.
• Toward the end of pregnancy oxytocin is produced in large amounts and
stimulates labor contractions of the uterus.
• Later, when the baby suckles at the breast, a nervous reflex from the nipple
stimulates the hypothalamus to produce more of the hormone.
• This promotes contraction of the myoepithelial cells and assists in the
expression of the milk from the breasts.
• vasopressin is a hormone formed in the supraoptic and paraventricular nuclei
of the hypothalamus and transported to the posterior lobe of the hypophysis
through the hypothalamohypophyseal tract.
• It has an antidiuretic and pressor effect that elevates blood pressure by
increasing the reabsorption of water by the kidneys and thereby decreasing
the production of urine (antidiuretic).
• Neurosecretory cells situated mainly in the medial zone of the hypothalamus
are responsible for the production of the releasing hormones and release-
inhibitory hormones.
• The hormones are packaged into granules and transported along the axons of
these cells into the median eminence and infundibulum.

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• Here, the granules are released are released by exocytosis onto fenestrated
capillaries at the upper end of the hypophyseal portal system.
• Oxytocin and vasopressin are transported down the axons of magnocellular
neurons of the supraoptic and paraventricular nuclei, reaching capillaries of the
posterior lobe.
• Parvocelluar neurons in the arcuate nucleus and nearby regions of the walls of
the third ventricle secrete releasing and inhibiting hormones in the median
eminence, where they gain access to the hypophyseal portal system and through
it reach the anterior lobe.
• The hypophyseal portal system is formed on each side from the superior
hypophyseal artery, which is a branch of the internal carotid artery.
• The artery enters the median eminence and divides into tufts of capillaries.
• These capillaries drain onto long and short descending vessels that end in the
anterior lobe of the hypophysis by dividing into vascular sinusoids that pass
between the secretory cells of the anterior lobe.
• The portal system carries the releasing hormones and the release-inhibiting
hormones to the secretory cells of the anterior lobe of the hypophysis.
• The releasing hormones stimulate the production and release of
adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH),
luteinizing hormone (LH), thyrotropic hormone or thyroid-stimulating
hormone (TSH), and growth hormone (GH).
• The release of inhibiting hormones inhibits the release of the melanocyte-
stimulating hormone (MSH) and luteotropic hormone (LTH) which is also
known as lactogenic hormone or prolactin.
• Stimulates the corpus luteum to secrete progesterone and the mammary gland
to produce milk.
• The growth hormone inhibitory hormone (somatostatin) inhibits the release of
growth hormone.
Functions of the Hypothalamus
• Autonomic Control
• The hypothalamus has a controlling influence on the autonomic nervous system
and integrates the autonomic and neuroendocrine systems, thus preserving
body homeostasis.
• Essentially, the hypothalamus should be regarded as a higher nervous center
for the control of lower autonomic centers in the brainstem and spinal cord.
Hypothalamic Electrical Stimulation Studies
Autonomic Control
• Electrical stimulation of the hypothalamus in animal experiments shows that the
anterior hypothalamic area and the preoptic area influence parasympathetic
responses.
• Stimulation induces the lowering of the blood pressure, slowing of the heart
rate, contraction of the bladder, increased motility of the gastrointestinal
tract, increased acidity of the gastric juice, salivation, and pupillary
constriction.
• Stimulation of the posterior and lateral nuclei causes sympathetic responses,
which include elevation of blood pressure, acceleration of the heart rate,

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cessation of peristalsis in the gastrointestinal tract, pupillary dilation, and
hyperglycemia.
Endocrine Control
• The nerve cells of the hypothalamic nuclei, by production the releasing factors
or release-inhibiting factors, control the hormone production of the anterior
lobe of the hypophysis (pituitary gland).
• The anterior lobe hormones include growth hormone (GH), prolactin,
adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH),
luteinizing hormone, and follicle-stimulating hormone (FSH).
• Some of these hormones act directly on body tissues, while others such as ACTH
act through an endocrine organ, which in turn produces additional hormones
that influence the activities of general body tissues.
• Each stage is controlled by negative and positive feed-back mechanisms.
Temperature Regulation
• The anterior portion of the hypothalamus controls those mechanisms that
dissipate heat loss.
• Experimental stimulation of this area causes dilation of skin blood vessels and
sweating, which lower the body temperature.
• Stimulation of the posterior portion of the hypothalamus results in
vasoconstriction of the skin blood vessels, inhibition of sweating, shivering in
which the skeletal muscles produce heat.
Regulation of Food and Water Intake
• Stimulation of the lateral region of the hypothalamus initiates the feeling of
hunger and results in an increased in food intake.
• This lateral region is referred to as the hunger center.
• Bilateral destruction of this center results in anorexia with the consequent loss
in body weight.
• Stimulation of the medial region of the hypothalamus inhibits eating and
reduces food intake.
• This area is referred to as the satiety center.
• Bilateral destruction of the satiety center produces uncontrolled voracious
appetite causing extreme obesity.
• Stimulation of the lateral hypothalamus causes an immediate increase in the
desire to drink water, the thirst center.
Emotion and Behavior
• Emotion and behavior are a function of the hypothalamus, the limbic system,
and the prefrontal cortex.
• The hypothalamus is the integrator of afferent information received form other
areas of the nervous system, and brings about the physical expression of
emotion.
• It can increase heart rate, elevate blood pressure, cause dryness of the mouth,
flushing or pallor of the skin, and sweating, and produce massive peristaltic
activity of the gastrointestinal tract.
Control of Circadian Rhythms
• The hypothalamus controls circadian rhythms, including body temperature,
adrenocortical activity, eosinophil count, and renal secretion.

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• Sleeping and wakefulness, although dependent on the activities of the thalamus,
the limbic system, and the reticular activating system, are also controlled by
the hypothalamus.
• Lesions of the anterior part of the hypothalamus seriously interfere with the
rhythm of sleeping and waking.
• The suprachiasmatic nucleus, which receives afferent fibers from the retina,
plays an important role in controlling biological rhythms.
• Nerve impulses generated in response to variations in the intensity of light are
transmitted via the suprachiasmatic nucleus to influence the activities of many
of the hypothalamic nuclei.
Pivotal Role of the Hypothalamus
• The hypothalamus can affect autonomic motor neurons both directly and
through visceral motor programs in the brainstem and spinal cord, and can
also influence visceral structures through its control over the pituitary gland.
• It can also stimulate somatic responses through connections with limbic
structures that interconnect the hypothalamus and neocortex.
• The latter are two-way connections, providing us a degree of voluntary control
over responses that may be physiologically desirable but do not fit the current
circumstances in some other way (e.g. “grin and bear it”).
• The cerebellum and basal ganglia also have connections with the
hypothalamus, but their roles in the planning and coordination of drive-related
activities are still poorly understood.
Clinical Notes
The Hypothalamus
• The activities of the hypothalamus are modified by information received along
numerous afferent pathways from different parts of the CNS---from the limbic
system and the prefrontal cortex—and by the plasma levels of circulating
hormones.
• It exerts its influence on bodily functions through the autonomic nervous system
and the endocrine system.
Clinical Disorders and the Hypothalamus
• The hypothalamus may be the site of inflammation, neoplasm, or a vascular
disorder.
• Because of its deep-seated central position, it can be pressed upon by tumors of
the surrounding brain tissue or may be compressed as the result of the
development of internal hydrocephalus.

Clinical Disorders and the Hypothalamus


• Its widespread influence on many homeostatic and behavioral functions means
that a lesion of the hypothalamus will produce a large number of different
syndromes.
• Therefore, it is important to remember that an acute lesion is more likely to
produce signs and symptoms whereas a slow growing tumor will most likely not.
Obesity and Wasting
• Severe obesity can occur as the result of hypothalamic lesions.
• It is generally associated with genital hypoplasia or atrophy.

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• Wasting is less common than obesity in hypothalamic disease.
• Severe cachexia is suggestive of damage to the hypophysis (pituitary gland).
Sexual Disorders
• In children there may be sexual retardation and rarely, sexual precocity with
hypothalamic lesions.
• After puberty, the patient with hypothalamic disease may have impotence or
amenorrhea.
Hyperthermia and Hypothermia
• Hyperthermia can follow lesions of the hypothalamus caused by head injury
or following surgical operations in the region of the hypothalamus.
• The patient with hyperthermia is otherwise normal and has no signs of malaise,
which occurs with pyrexia secondary to infections.
• Hypothermia also can follow a lesion of the hypothalamus.
Diabetes Insipidus
• This disease results from a lesion of the supraoptic nucleus or from the
interruption of the nervous pathway to the posterior lobe of the hypophysis.
• Characteristically, the patient passes large volumes of urine of low specific
gravity (polyuria).
• As a result, the patient is extremely thirsty and drinks large quantities of fluids
(polydipsia).
• The condition must be distinguished from diabetes mellitus (inadequate
production of insulin), in which there is glucosuria.
Disturbances of Sleep
The occurrence of either frequent short periods of sleep during the waking hours or
insomnia has been observed in patient with hypothalamic lesions.
Emotional Disorders
Attacks of unexplained weeping or laughter, uncontrollable rage, depressive
reactions, or even maniacal outbursts all have been observed ini patients with
hypothalamic lesions.

LECTURE 31: Autonomic Nervous System

• The autonomic nervous system exerts control over the functions of many organs
and tissues of the body, including heart muscle, smooth muscle, and the
exocrine glands.
• Along with the endocrine system, it brings about fine internal adjustments
necessary for the internal environment of the body.
• Like the somatic nervous system, the ANS has afferent, connector and efferent
neurons.
• The afferent impulses originate in visceral receptors and travel via afferent
pathways to the CNS where they are integrated through connector neurons at
different levels and then leave via efferent pathways to visceral effector organs.
• The majority of activities of the autonomic system do not affect consciousness.
• The efferent pathways of the autonomic system are made up of preganglionic
and postganglionic neurons.

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• The cell bodies of the preganglionic neurons are situated in the lateral gray
column of the spinal cord and in the motor nuclei of the CN III, CN VII,
CNIX, and CNX cranial nerves.
• The axons of these cell bodies synapse on the cell bodies of the postganglionic
neurons that are collected together to form ganglia outside the CNS.
• The control exerted by the ANS is rapid and widespread since one preganglionic
axon may synapse with several postganglionic neurons.
• Large collections of afferent and efferent fibers and their associated ganglia
form autonomic plexuses in the thorax, abdomen, and pelvis.
• The visceral receptors include chemoreceptors, baroreceptors, and
osmoreceptors.
• Pain receptors are present in viscera and certain types of stimuli, such as lack of
oxygen or stretch, can cause extreme pain.
Organization of the ANS
• The ANS is distributed throughout the central and peripheral nervous
systems.
• It is divided into three divisions, the sympathetic, parasympathetic and enteric
(GI tract) consisting of both afferent and efferent fibers.
Sympathetic Part of the ANS
• The sympathetic system is the larger of the two parts of the autonomic system
and is widely distributed throughout the body innervating:
• heart and lungs
• muscle in the walls of many blood vessels
• hair follicles
• sweat glands
• many abdominopelvic viscera.
• The function of the sympathetic system is to prepare the body for an
emergency.
• The heart rate is increased, arterioles of the skin and intestine are
constricted, those of the skeletal muscle are dilated, and the blood pressure is
raised.
• There is a redistribution of blood so that it leaves the skin and gastrointestinal
tract and passes to the brain, heart and skeletal muscle.
• Sympathetic nerves dilate the pupils, inhibit smooth muscle of the bronchi,
intestine, and bladder wall and close the sphincters.
• The hair is made to stand on end and sweating occurs.
• The sympathetic system consists of the efferent outflow from the spinal cord,
two ganglionated sympathetic trunks, important branches, plexuses, and
regional ganglia.
Efferent nerve Fibers (Sympathetic Outflow)
The lateral gray columns (horns) of the spinal cord from the first thoracic (T1)
segment to the second lumbar segment (L2,sometimes L3) possess the cell bodies of
the sympathetic connector neurons.
The myelinated axons of these cells leave the cord in the anterior nerve roots and pass
via the white rami communicantes (the white rami are white because the nerve

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fibers are covered with white myelin) to the paravertebral ganglia of the sympathetic
trunk.
• Once these fibers (preganglionic) reach the ganglia in the sympathetic trunk,
they are arranged in the following manner:
• They synapse with an excitor neuron in the ganglion.
• The gap between the two neurons is bridged by the neurotransmitter
acetylcholine (Ach).
• The postganglionic nonmyelinated axons leave the ganglion and pass to the
thoracic spinal nerves as gray rami communicantes (gray rami are gray
because the nerve fibers are devoid of myelin).
• They are distributed in branches of the spinal nerves to smooth muscle in the
blood vessel walls, sweat glands, and arrector muscles of hairs in the skin.

• They travel superiorly in the sympathetic trunk to synapse in ganglia in the


cervical region.
• The postganglionic nerve fibers pass via gray rami communicantes to join the
cervical spinal nerves.
• Many of the preganglionic fibers entering the lower part of the sympathetic trunk
from the lower thoracic and upper two lumbar segments of the spinal cord
travel caudally to synapse in ganglia in the lower lumbar and sacral regions.
• Here again, the postganglionic nerve fibers pass via gray rami communicantes
to join the lumbar, sacral, and coccygeal spinal nerves.
• They pass through the ganglia of the sympathetic trunk without synapsing.
• These myelinated fibers leave the sympathetic trunk as the greater splanchnic,
lesser splanchnic, and lowest or least splanchnic nerves.
• The greater splanchnic nerve is formed from branches from the fifth to the
ninth thoracic ganglia.
• It descends obliquely on the sides of the bodies of the thoracic vertebrae and
pierces the crus of the diaphragm to synapse with excitor cells in the ganglia of
the celiac plexus, the renal plexus, and the suprarenal medulla.
• The ratio of preganglionic to postganglionic sympathetic fibers is about 1:10
permitting a wide control of involuntary structures.
Afferent Nerve Fibers
• The afferent myelinated nerve fibers travel from the viscera through the
sympathetic ganglia without synapsing.
• They pass to the spinal nerve via white rami communicantes and reach their cell
bodies in the posterior root ganglion of the corresponding spinal nerve.
• The central axons then enter the spinal cord and may form the afferent component
of a local reflex arc or ascend to higher centers, such as the hypothalamus.
Sympathetic Trunks
The sympathetic trunks are two ganglionated nerve trunks that extend the whole length
of the vertebral column.
Parasympathetic Part of the ANS
• The activities of the parasympathetic part of the autonomic system are directed
toward conserving and restoring energy.

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• The heart rate is slowed, pupils are constricted, peristalsis and glandular
activity is increased, sphincters are opened, and the bladder wall is
contracted.
Efferent Nerve Fibers (craniosacral outflow)
• The connector nerve cells of the parasympathetic part of the ANS are located in
the brainstem and the sacral segments of the spinal cord.
• Those nerve cells located in the brainstem form nuclei in the oculomotor
(parasympathetic or Edinger-Westphal nucleus), the facial (superior
salivatory nucleus and lacrimatory nucleus) and the vagus nerves (dorsal
nucleus of the vagus).
• The axons of these connector nerve cells are myelinated and emerge from the
brain within the cranial nerves.
• The sacral connector nerve cells are found in the gray matter of the S2, S3, and
S4 sacral segments of the spinal cord.
• These cells are not sufficiently numerous to form a lateral gray horn, as do the
sympathetic connector neurons in the thoracolumbar region.
• The myelinated axons leave the spinal cord in the anterior nerve roots of the
corresponding spinal nerve.
• They then leave the sacral nerves and form the pelvic splanchnic nerves.
• The myelinated efferent fibers of the craniosacral outflow are preganglionic and
synapse in peripheral ganglia located close to the visceral they innervate.
• Acetylcholine is the neurotransmitter at these synapses.
• The cranial parasympathetic ganglia are the ciliary, pterygopalatine,
submandibular, and otic.
• In certain locations the ganglion cells are placed in nerve plexuses such as the
cardiac plexus, pulmonary plexus, myenteric plexus (Auerbach’s plexus) and
mucosal plexus (Meissner’s plexus).
• The last two plexuses are associated with the gastrointestinal tract.
• The pelvic splanchnic nerves synapse in ganglia in the hypogastric plexuses.
• Characteristically, the postganglionic parasympathetic fibers are
nonmyelinated and of relatively short length compared to sympathetic
postganglionic fibers.
The ratio of preganglionic to postganglionic fibers is about 1:3 or less, which is much
more restricted than in the sympathetic part of the system.
Afferent Nerve Flow
• The afferent myelinated fibers travel from the viscera to their cell bodies,
located either in the sensory ganglia of the cranial nerves or in the posterior
root ganglia of the sacrospinal nerves.
• The central axons then enter the CNS and take part in the formation of local
reflex arcs, or pass to higher centers of the ANS such as the hypothalamus.
• The afferent component of the autonomic system is identical to the afferent
component of somatic nerves, and it forms part of the general afferent segment
of the entire nervous system.
• The nerve endings in the autonomic afferent component are activated by stretch
or lack of oxygen NOT by sensations of heat or touch.
Large Autonomic Plexuses

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• An autonomic nerve plexus is a collection of nerve fibers that form a network,
nerve cells may be present within such a network.
• A ganglion is a knot-like mass of nerve cells found outside the CNS.
Autonomic Ganglia
• The autonomic ganglion is the site where preganglionic nerve fibers synapse on
postganglionic neurons.
• Ganglia are situated along the course of efferent nerve fibers of the ANS.
• The preganglionic fibers are myelinated, small, and relatively slow-conducting
B fibers.
• The postganglionic fibers are unmyelinated, smaller and slower-conducting C
fibers.
• In other ganglia they receive collateral branches and may serve some integrative
function.
• Many SIF cells contain dopamine which is thought to be their transmitter.
Ganglion Stimulating Agents
• Drugs such as nicotine, lobeline, and dimethylphenol piperazinium stimulate
sympathetic and parasympathetic ganglia by activating nicotinic receptors on
the postsynaptic membrane and producing a fast EPSP.
Ganglion Blocking Agents
• There are two types of ganglion blocking agents: depolarizing and
nondepolarizing.
• Nicotine acts as a blocking agent in high concentrations, by first stimulating the
postganglionic neuron and causing depolarization, and then by maintaining
depolarization of the excitable membrane.
• During this latter phase the postganglionic neuron will fail to respond to the
administration of any stimulant, regardless of the types of receptor it activates.
• Hexamethonium and tetraethylammonium block ganglia by competing with
acetylcholine at the nicotinic receptor sites.
Neurotransmission in the ANS
• Adrenergic neurons release norepinephrine.
• Cholinergic neurons release acetylcholine (ACh).
• Peptidergic neurons in the parasympathetic nervous system release peptides
such as vasoactive inhibitory peptide and substance P.
Receptor Types in the ANS
• Adrenergic receptors: α 1
– Located on vascular smooth muscle of the skin and splanchnic regions,
the GI and bladder sphincters, and the radial muscle of the iris.
– Produce EXCITATION (e.g. contraction or constriction).
– Equally sensitive to norepinephrine and epinephrine. (However, only
norepinephrine release from adrenergic neurons is present in high enough
concentrations to activate α 1 receptors.)
– Mechanism of action: formation of IP3 and increase of intracellular
Ca2+
Inositol triphosphate IP3/diacylglyceraol (DAG) System
• Transmitter binds to receptor

40
• Activation of G-protein activates phospholipase C causes

• Cleavage of phosphatidyl inositol (PI) into IP3 and DAG

• IP3 diffuses into the cytosol and binds to sites on the endoplasmic reticulum to
release calcium
• DAG remains in the plasma membrane and activates protein kinase C (PKC)

• Calcium (bound to calmodulin) activates a calcium/calmodulin dependent protein


kinase
• In the inositol-lipid pathway the binding of transmitter to a receptor activates a
G-protein, which in turn activates phospholipase C (PLC).
• This phospholipase cleaves phosphatidylinositol 1,4,5-bisphosphate (PIP2) into
two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol
(DAG).
• Inositol 4,5-trisphosphate is water soluble and can diffuse into the cytoplasm.
• There it binds to a receptor on the endoplasmic reticulum to release Ca2+ from
internal stores.
• Diacylglycerol, the other second messenger produced by the cleavage of PIP2
remains in the membrane where it activates protein kinase C (PKC).
• Membrane phospholipid is also necessary for this activation.
• Thus, PKC is active only when translocated from the cytoplasm to the
membrane.
• Some isoforms of PKC also require Ca2+ for activation.
• Calcium bound to calmodulin activates the calcium/calmodulin dependent
protein kinase.
Receptor Types in the ANS
• Adrenergic receptors: α 2
– Located in presynaptic nerve terminals, platelets, fat cells, and the walls of
the GI tract.
– Often produce inhibition of adenylate cyclase and decrease in cyclic
adenosine monophosphate (cAMP)
Adenylate Cyclase/cAMP Cascade
• Transmitter binds to receptor

• Stimulatory G protein binds to intracellular portion of receptor


• GTP displaces into α and beta/gamma subunits

• The α subunit associates with the intracellular domain of adenylate cyclase


causing activation of the enzyme and conversion of ATP to cAMP
• Hydrolysis of GTP leads to dissociation of the α subunit from the enzyme and re-
association with the beta/gamma subunit

• Dissociation of the transmitter with the receptor restores the original inactive state
of the complex

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• cAMP activates a cAMP dependent protein kinase
• Adenylyl cyclase converts ATP into cAMP.
• Four cAMP molecules bind to the two regulatory subunits of the cAMP-
dependent protein kinase, liberating the two catalytic subunits, which are then
free to phosphorylate specific substrate proteins that regulate a cellular response.
• Two kinds of enzymes regulate this pathway.
• Phosphodiesterases convert cAMP to AMP (which is inactive), and protein
phosphatases remove phosphate groups from the regulator (substrate) proteins
releasing inorganic phosphate, Pi.
Receptor Types in the ANS
• Adrenergic receptors: β 1
– Located in the sinoatrial (SA) node, atrioventricular (AV) node, and
ventricular muscle of the heart.
– Produce EXCITATION (e.g. increased heart rate, increased conduction
velocity, increased contractility).
– Sensitive to both norepinephrine and epinephrine, and are more sensitive
than the α 1 receptors.
– Mechanism of action: activation of adenylate cyclase and INCREASE in
cAMP.
• Adrenergic receptors: β 2
– Located on vascular smooth muscle of skeletal muscle, bronchial
smooth muscle, and in the walls of the GI tract and bladder.
– Produce RELAXATION (e.g. dilation of vascular smooth muscle, dilation
of bronchioles, relaxation of the bladder wall).
– Are more sensitive to epinephrine than to norepinephrine.
– Are more sensitive to epinephrine than the α 1 receptors.
– Mechanism of action: same as for β 1 receptors.
• Cholinergic receptors: Nicotinic
– Located in the autonomic ganglia of the sympathetic and parasympathetic
nervous system, at the NEUROMUSCULAR JUNCTION and in the
adrenal medulla.
– Activated by ACh or nicotine.
– Produce EXCITATION.
– Blocked by ganglionic blockers (e.g. hexamethonium) in the autonomic
ganglia, but not at the neuromuscular junction.
– Mechanism of action: ACh binds to α subunits of the nicotinic ACh
receptor.
• The nicotinic ACh receptors are ion channels for NA+ and K+.
• Cholinergic receptors: Muscarinic
– Located in the heart, smooth muscle, and glands.
– Are INHIBITORY in the heart (e.g. decrease heart rate and conduction
velocity in AV node).
– Are EXCITATORY in smooth muscle and glands (e.g. increase GI
motility and secretion).
– Activated by ACh and muscarine.
– Blocked by atropine.

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• Cholinergic receptors: Muscarinic
– Mechanism of action:
– Heart SA node: inhibition of adenylate cyclase, leads to opening of K+
channels, slowing of the rate of spontaneous Phase 4 depolarization, and
decrease heart rate.
– Smooth muscle and glands: formation of IP3 and increase in intracellular
Ca+.
Cholinergic Receptors
• Cholinergic receptors are divided into 2 general classes: nicotinic and
muscarinic.
• The nicotinic receptor is an integral membrane protein with five subunits.
• It is a directly gated ion channel which has 2 functions:
– It recognizes and binds the neurotransmitter
– Opens a channel in the membrane through which ions flow
Acetylcholine
• The receptor-channel complex consists of five subunits, all of which contribute to
forming the pore.
• When two molecules of ACh bind to portions of the alpha-subunits exposed to
the membrane surface, the receptor channel changes conformation.
• This opens a pore in the portion of the channel embedded in the lipid bilayer, and
both K+ and Na+ flow through the open channel down their electrochemical
gradients.
Nicotinic Acetylcholine Receptor
• Each subunit is composed of four membrane-spanning alpha-helices (labeled M1
through M4).
• The five subunits are arranged such that they form an aqueous channel, with the
M2 segment of each subunit facing inside and forming the lining of the pore.
Postganglionic Transmitters
• The action of norepinephrine on the receptor site of the effector cell is
terminated by reuptake into the nerve terminal, where it is stored in
presynaptic vesicles for reuse.
• Some of the norepinephrine escapes from the synaptic cleft into the general
circulation and is subsequently metabolized in the liver.
Blocking of Adrenergic Receptors
• α -adrenergic receptors can be blocked by agents such as phenoxybenzamine
and the β -adrenergic receptors can be blocked by agents such as propranolol.
• The synthesis and storage of norepinephrine at sympathetic endings can be
inhibited by reserpine.
Functions of the ANS
• The ANS, along with the endocrine system, maintains body homeostasis.
• The endocrine control is slower and exerts its influence by means of hormones
released into the bloodstream.
• The functions of the ANS are not directly conscious to us.
• We are not aware, for example, that our pupils are dilating or that our arteries
are constricting.

43
• The various activities of the autonomic and endocrine systems are integrated
within the hypothalamus.
• The sympathetic and parasympathetic components of the ANS cooperate in
maintaining the stability of the internal environment.
• The sympathetic part prepares and mobilized the body in an emergency, when
there is sudden severe exercise, fear or RAGE.
• The parasympathetic part aims at conserving and storing energy, for example,
in the promotion of digestion and the absorption of food by increasing the
secretions of glands of the gastrointestinal tract and stimulating peristalsis.
• The sympathetic and parasympathetic components of the ANS cooperate in
maintaining the stability of the internal environment.
• The sympathetic part prepares and mobilized the body in an emergency, when
there is sudden severe exercise, fear or RAGE.
• The parasympathetic part aims at conserving and storing energy, for example,
in the promotion of digestion and the absorption of food by increasing the
secretions of glands of the gastrointestinal tract and stimulating peristalsis.
• The sympathetic and parasympathetic parts of the autonomic system usually
have antagonistic control over a visceral organ.
• For example, the sympathetic activity will increase the heart rate whereas the
parasympathetic will slow the heart rate.
Differences Between the Sympathetic and Parasympathetic Systems
• The sympathetic efferent nerve fibers originate from nerve cells in the lateral
gray column of the spinal cord between the first thoracic and second lumbar
segments (the thoracic outflow).
• The parasympathetic efferent nerve fibers originate from nerve cells in the
CNIII, CNVII, CNIX, and CNX, cranial nerves and in the gray matter of the S2,
S3 and S4 sacral segments of the cord (the craniosacral outflow).
• The sympathetic ganglia are located either in the paravertebral sympathetic
trunks or in the prevertebral ganglia, such as the celiac ganglion.
• The parasympathetic ganglion cells are located as small ganglia close to the
viscera or within plexuses within the viscera.
• The sympathetic part of the autonomic system has long postganglionic fibers,
whereas the parasympathetic system has short fibers.
• The sympathetic part of the system has a widespread action on the body.
• It does this via preganglionic fibers synapsing on many postganglionic neurons
and the suprarenal medulla releasing the sympathetic transmitters epinephrine
and norepinephrine, which are distributed throughout the body through the
bloodstream.
• The parasympathetic part of the autonomic system has a more discrete control,
since the preganglionic fibers synapse on only a few postganglionic neurons
and there is no comparable organ to the suprarenal medulla.
• The sympathetic postganglionic endings liberate norepinephrine at most
endings and acetylcholine at a few endings (e.g. sweat glands).
• The parasympathetic postganglionic endings liberate acetylcholine.

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The sympathetic part of the autonomic system prepares the body for emergencies and
severe muscular activity, whereas the parasympathetic part conserves and stores
energy.
Clinical Notes
Sympathetic Injuries
• The sympathetic trunk in the neck can be injured by stab and bullet wounds.
• Traction injuries to the first thoracic root of the brachial plexus can damage
sympathetic nerves destined for the stellate ganglion.
• All these conditions can produce a preganglionic types of Horner’s syndrome.
• Injuries to the spinal cord or cauda equina can disrupt the sympathetic control
of the bladder.
Parasympathetic Injuries
The oculomotor nerve is vulnerable in head injuries (herniated uncus) and can be
damaged by compression by aneurysms in the junction between the posterior cerebral
artery and posterior communicating artery.
• The preganglionic parasympathetic fibers traveling in the oculomotor nerve
are situated in the periphery of the nerve and can be damaged.
• Surface aneurysmal compression characteristically causes dilatation of the pupil
and loss of the visual light reflexes.
• The autonomic fibers in the facial nerve can be damaged by fractures of the
skull involving the temporal bone.
• The vestibulocochlear nerve is closely related to the facial nerve in the internal
acoustic meatus so that clinical findings involving both nerves are common.
• Involvement of the parasympathetic fibers in the facial nerve may produce
impaired lacrimation in addition to paralysis of the facial muscles.
• The glossopharyngeal (CN IX) and vagus (CN X) nerves are at risk in stab and
bullet wounds of the neck.
• The parasympathetic secretomotor fibers to the parotid salivary gland leave
the glossopharyngeal nerve just below the skull so that they are rarely damaged.
The parasympathetic outflow in the sacral region of the spinal cord (S2, 3 and 4) may
be damaged by spinal cord and cauda equina injuries, leading to disruption of
bladder, rectal, and sexual functions.
Horner’s Syndrome
• Horner’s syndrome consists of:
– 1. constriction of the pupil (miosis)
– 2. slight drooping of the eyelid (ptosis)
– 3. enophthalmos (recession of eyeball into orbit)
– 4. vasodilation of skin arterioles
– 5. loss of sweating (anhydrosis)
• All resulting from an interruption of the sympathetic nerve supply to the head and
neck.
• Pathological causes include lesions in the brainstem or cervical part off the
spinal cord that interrupt the reticulospinal tracts descending from the
hypothalamus to the sympathetic outflow in the lateral gray column of the
first thoracic segment of the spinal cord.
• Such lesions include multiple sclerosis and syringomyelia.

45
• Traction on the stellate ganglion due to a cervical rib, or involvement of the
ganglion in a metastatic lesion, may interrupt the peripheral part of the
sympathetic pathway.
Frey’s Syndrome
• Frey’s syndrome sometimes follows penetrating wounds of the parotid gland.
• During the healing process, postganglionic parasympathetic secretomotor
fibers traveling in the auriculotemporal nerve grow out and join the distal end
of the great auricular nerve, which supplies the sweat glands of the overlying
facial skin.
• By this means, a stimulus intended for saliva production instead produces
sweat secretion.
• A similar syndrome may follow injury to the facial nerve (CNVII).
• During the process of regeneration, parasympathetic fibers normally destined
for the submandibular and sublingual salivary glands are diverted to the
lacrimal gland.
• This produces watering of the eyes associated with salivation the so called
crocodile tears.
Hirschsprung’s Disease (Megacolon)
• Hirschsprung’s disease is a congenital condition in which there is a failure of
development of the myenteric plexus (Auerbach’s plexus) in the distal part of
the colon.
• The involved part of the colon possesses no parasympathetic ganglion cells and
peristalsis is absent.
• This effectively blocks the passage of feces and the proximal part of the colon
becomes enormously distended.
Botulinum Toxin
• A very small amount of botulinum toxin binds irreversible to the nerve plasma
membranes and prevents the release of acetylcholine at cholinergic synapses
and neuromuscular junctions, producing an atropine-like syndrome with
skeletal muscle weakness.
Black Widow Spider Venom
• Black widow spider venom causes a brief release of acetylcholine at the nerve
endings followed by a permanent blockade.
Anticholinesterase Side-effects
• Acetylcholinesterase, which is responsible for hydrolyzing and limiting the
action of acetylcholine at nerve endings, can be blocked by certain drugs.
• Physostigmine, neostigmine, pyridostigmine and carbamate and
organophosphate insecticides are effective ACHE inhibitors.
• Their use results in the excessive stimulation of cholinergic receptors resulting in
the “SLUD syndrome”:

• Salivation
• Lacrimation
• Urination
• Defecation
Raynaud’s Disease

46
• This is a vasospastic disorder involving the digital arteries of the upper limbs.
• The disorder is usually bilateral and an attack is provoked by exposure to
cold.
• There is pallor or cyanosis of the fingers as well as severe pain.
• Gangrene of the tips of the fingers may occur.
• In mild cases of Raynaud’s disease the treatment is to avoid the cold and
nonsmoking (smoking causes vasoconstriction).
• In more severe cases, drugs that inhibit sympathetic activity, such as
reserpine, bring about arterial vasodilation with consequent increase in
blood flow to the fingers.
• Cervicothoracic preganglionic sympathectomy has been used in the past with
little benefit.

LECTURE 32: Neurotransmission I
• There are two forms of neurotransmission in the nervous system: electrical and
chemical.
Electrical Neurotransmission
• Not unique to the nervous system,
• Less common than chemical neurotransmission
• Characterized by rapid speed of transmission mediated by channels that connect
the cytoplasm of one cell to the other
Chemical Neurotransmission
• No continuity between the cytoplasms of the cells
• The neurons are separated by a cleft
• Involves neurotransmitter release and receptor activation
• Neurotransmitters can mediate either excitatory or inhibitory actions which is
determined by transmitter receptor
Electrical Synapses: Gap Junction
• At electrical synapses two cells are structurally connected by gap-junction
channels.
• A gap-junction channel is actually a pair of hemichannels, one in each apposite
cell, that match up in the gap junction through homophilic interactions.
• The channel thus connects the cytoplasm of the two cells and provides a direct
means of ion flow between the cells.
• This bridging of the cells is facilitated by narrowing of the normal intercellular
space.
• Each hemichannel, or connexon, is made up of six identical protein subunits
called connexins.
• Each connexin is about 7.5nm long and spans the cell membrane.
• The amino acid sequences of gap-junction proteins from many different kinds of
tissue all show regions of similarity.
• Channels connect the lipid bilayers of two cells.
• The channel in each cell joins a similar unit of another cells, forming an aqueous
pore connecting their cytoplasmic compartments.
• The pore may be closed by a twisting of one connexon that causes the six
subunits to pinch together.

47
• Diffusion of molecules typically happens in both directions, but not always.
• The names of various kinds of synapses—axosomatic, axondendritic, and axo-
axonic—identify the contacting regions of both the presynaptic and postsynaptic
neurons (the presynaptic element is identified first).
• Note that axodendritic synapses can occur on either the main shaft of a dendrite
branch or on a specialized input zone, the spine.
Synaptic Interactions
• Varieties of synapses made by axon terminals on various parts of neurons.
Electrical vs. Chemical Synapses
• At an electrical synapse some of the current injected into a presynaptic cell
escapes through resting ion channels in the cell membrane.
• However, some current also flows into the postsynaptic cell through gap-
junction channels, that connect the cytoplasm of the pre and postsynaptic cells.
• At chemical synapses all of the injected current escapes through ion channels in
the presynaptic cell.
• However, the resulting depolarization of the cell activated the release of
neurotransmitter molecules packaged in synaptic vesicles (open circles)
which then bind to receptors on the postsynaptic cell.
• This binding opens ion channels, thus initiating a change in membrane potential
in the postsynaptic cell.
• Chemical messengers must fulfill 4 criteria to be considered neurotransmitters:
• The molecules must be synthesized by the neuron
• It must be present in the presynaptic terminal and released in amounts
sufficient to exert an action on the postsynaptic neuron
• When applied exogenously (i.e. drug), it mimics exactly the action of the
endogenously released transmitter (i.e. it activates the same ion channels
or second messenger systems).
• A specific mechanism exists for removing it from its site of action (i.e.
the synaptic cleft).
• (1) Neurotransmitter (T) synthesis: synthesis of proteins occurs in the cell body
and these proteins are transported via axoplasmic transport to the axon terminal.
• T is stored in synaptic vesicles.
• An axon terminal can contain one or more types of T.
• (2) Release of transmitter into synaptic cleft: Ca2+ influx into the axon terminal
causes fusion of vesicle with presynaptic membrane and T is released into the
synaptic cleft.
• (3) Binding of T to receptor: T binds to cell surface proteins on postsynaptic cell
causing a structural change in the conformation of the receptor protein.
• (4) Inactivation of T: T can be degraded by extracellular enzymes.
• T can diffuse into the extracellular space or can be taken back up into
presynaptic terminal and re-packaged.
The Synapse
• The synapse is the characteristic substrate for communication between
neurons.
• It is the site where the electrical activity of a neuron brings on the release of a
neurotransmitter.

48
• The extracellular space between the pre-and postsynaptic cells is called the
synaptic cleft.
• The two most common morphologic types of synapses in the CNS are Gray type
I and type II.
• Type I synapses are usually excitatory, which are usually glutamatergic
synapses; type II synapses are usually inhibitory, which are usually
GABAergic.
• Difference include the shape of vesicles, prominence of presynaptic densities,
total area of the active zone, width of the synaptic cleft, and presence of a dense
basement membrane.
• Synaptic transmission at chemical synapses involves several steps:
• An action potential arriving at the terminal of a presynaptic axon causes voltage-
gated Ca2+ channels at the active zone to open.
• The influx of Ca2+ produces a high concentration of Ca2+ near the active zone,
which in turn causes vesicles containing neurotransmitter to fuse with the
presynaptic cell membrane and release their contents into the synaptic cleft
( a process termed exocytosis).
• The released neurotransmitter molecules then diffuse across the synaptic cleft
and bind to specific receptors on the post-synaptic membrane.
• These receptors cause ion channels to open (or close), thereby changing the
membrane conductance and membrane potential of the postsynaptic cell.
• The complex process of chemical synaptic transmission is responsible for the
delay between action potentials in the pre and post synaptic cells compared
with the virtually instantaneous transmission of signals at electrical synapses.
Synaptic Vesicle Proteins
• Separate compartments are assumed for (1) storage (where vesicles are tethered
to the cytoskeleton), (2) trafficking and targeting of vesicles to active zones, (3)
the docking of vesicles at active zones and their priming for release, and (4)
release.
• Some of these proteins represent the targets for neurotoxins that act by modifying
transmitter release.
• VAMP (synaptobrevin), SNAP-25, and syntaxin are the targets for tetanus and
botulinum toxins, two zinc-dependent metalloproteases, and are cleaved by
these enzymes.
• Alpha-Latrototoxin, a spider toxin that generates massive vesicle depletion and
transmitter release, binds to the neurexins.
• Synapsins are vesicle-associated proteins that are thought to mediate interactions
between the synaptic vesicle and the cytoskeletal elements of the nerve
terminal.
• The Rab proteins are involved in vesicle trafficking within the cell and also in
targeting of vesicles within the nerve terminal.
• The docking, fusion and release of vesicles involves distinct interactions
between vesicle proteins and proteins of the nerve terminal plasma membrane:
• VAMP (synaptobrevin) and synaptotagmin on the vesicle membrane,
and
• syntaxins and neurexins on the nerve terminal membrane.

49
• Synaptophysin, an integral membrane protein in synaptic vesicles, is
phosphorylated by tyrosine kinases and may regulate release.
Neurotransmitter Receptors
• Synaptic receptors have two major functions: recognition of specific
transmitters and activation of effectors.
• Receptors for neurotransmitters can be divided into 2 major families according to
how the receptor and effector functions are coupled.
• 1. Postsynaptic receptor gates an ion channel directly (ionotropic receptors).
• This family includes:
• nicotinic acetylcholine (Ach) receptor, the
• gamma-aminobutyric acid (GABA) receptor, the
• glycine receptor, the
• AMPA (kainate-quisqualate) and
• NMDA class of glutamate receptors.
• 2. Postsynaptic receptors modulate intracellular metabolism via a second
messenger (activation of G proteins which affect neuronal excitability in an
INDIRECT fashion).
• This family include:
• α and ß adrenergic receptors,
• serotonin,
• dopamine,
• muscarinic Ach receptors and
• receptors for neuropeptides.
G-protein Coupled Receptors
• The receptor molecule is coupled to its effector molecule by a guanosine
nucleotide-binding protein (G-protein).
• Activation of the effector component requires the participation of several distinct
proteins.
• Typically the effector is an enzyme that produces a diffusible second
messenger i.e. cyclic adenosine monophosphate (cAMP), diacylglycerol, or an
inositol polyphosphate.
• These second messengers trigger a biochemical cascade that changes the cell’s
biochemical state.
Receptor Gating Mechanisms
• A. Ionotropic receptors directly gate ion channels as part of a single
macromolecule that also forms the ion channel.
• The receptor, located on the extracellular side, and the ion channel pore,
embedded in the cell membrane, are formed within the same protein.
• B. Receptors that indirectly gate ion channels fall into two families.
• 1. Metabotropic G protein-coupled receptors activate ion channels and other
substrates indirectly by activating a GTP-binding protein that often engages a
second-messenger cascade.
• 2. Receptor tyrosine kinases modulate the activity of ion channels indirectly
through a cascade of protein phosphorylation reactions, beginning with
autophosphorylation of the kinase itself on tyrosine residues.
NeurotransmitteràChannel Interactions

50
• Direct gating of ion channels is mediated by ionotropic receptors.
• This type of receptor is an integral part of the same macromolecule that forms the
channel it regulates and thus is sometimes referred to as a receptor-channel or
ligand-gated channel.
• Many ionotropic receptors are composed of 5 subunits, each of which is thought
to contain four membrane-spanning α-helical regions.
• B. Indirect gating is mediated by activation of metabotropic receptors.
• This type of receptor is distinct from the ion channels it regulates.
• The receptor activates a GTP-binding protein (G protein), which in turn
activates a second-messenger cascade that modulates channel activity.
• Here the G protein stimulates adenylyl cyclase, which converts ATP to cAMP.
• The cAMP activates the cAMP-dependent protein kinase (cAMP-kinase),
which phosphorylates the channel (P), leading to a change in function.
Second Messenger Pathways
• There are four well-characterized second messenger pathways:

– cAMP cascade
– Inositol polyphosphate pathway
– Diacylglycerol
– Arachidonic acid
• Transmitter binds to receptor

• Stimulatory G protein binds to intracellular portion of receptor


• GTP displaces into α and beta/gamma subunits

• The α subunit associates with the intracellular domain of adenylate cyclase


causing activation of the enzyme and conversion of ATP to cAMP
• Hydrolysis of GTP leads to dissociation of the α subunit from the enzyme and re-
association with the beta/gamma subunit

• Dissociation of the transmitter with the receptor restores the original inactive state
of the complex

• cAMP activates a cAMP dependent protein kinase


• Adenylyl cyclase converts ATP into cAMP.
• Four cAMP molecules bind to the two regulatory subunits of the cAMP-
dependent protein kinase, liberating the two catalytic subunits, which are then
free to phosphorylate specific substrate proteins that regulate a cellular response.
• Two kinds of enzymes regulate this pathway.
• Phosphodiesterases convert cAMP to AMP (which is inactive), and protein
phosphatases remove phosphate groups from the regulator (substrate) proteins
releasing inorganic phosphate, Pi.
Inositol triphosphate IP3/diacylglyceraol (DAG) System
• Transmitter binds to receptor

• Activation of G-protein activates phospholipase C causes

51
• Cleavage of phosphatidyl inositol (PI) into IP3 and DAG

• IP3 diffuses into the cytosol and binds to sites on the endoplasmic reticulum to
release calcium
• DAG remains in the plasma membrane and activates protein kinase C (PKC)

• Calcium (bound to calmodulin) activates a calcium/calmodulin dependent protein


kinase
• In the inositol-lipid pathway the binding of transmitter to a receptor activates a
G-protein, which in turn activates phospholipase C (PLC).
• This phospholipase cleaves phosphatidylinositol 1,4,5-bisphosphate (PIP2) into
two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol
(DAG).
• Inositol 4,5-trisphosphate is water soluble and can diffuse into the cytoplasm.
• There it binds to a receptor on the endoplasmic reticulum to release Ca2+ from
internal stores.
• Diacylglycerol, the other second messenger produced by the cleavage of PIP2
remains in the membrane where it activates protein kinase C (PKC).
• Membrane phospholipid is also necessary for this activation.
• Thus, PKC is active only when translocated from the cytoplasm to the
membrane.
• Some isoforms of PKC also require Ca2+ for activation.
• Calcium bound to calmodulin activates the calcium/calmodulin dependent
protein kinase.
Arachidonic Acid Cascade
• Transmitter binds to receptor

• Activation of G-protein activates phospholipase A2 (PLA2)

• Hydrolysis of phosphatidyl inositol (PI)


• Release of arachidonic acid (second messenger)

• Conversion of arachidonic acid via multiple pathways to active metabolites called


eicosanoids
• Arachidonic acid is released when a phospholipase is activated by a histamine
receptor.
• The beta/gamma subunits of the G-protein activate phospholipase A2 (PLA2),
which hydrolyzes phosphatidylinositol (PI) in the plasma membrane.
• Once released, arachidonic acid is metabolized through several pathways.
• The 12 and 5-lipoxygenase pathways both produce several active metabolites.
• The cyclooxygenase pathway produces prostaglandins and thromboxanes.
• This enzyme is inhibited by indomethacin, aspirin and other nonsteroidal
anti-inflammatory drugs.

LECTURE 33: Neurotransmission II/Diseases of Neurotransmission

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Neurotransmitter Categories
• Monoaminergic pathways in the brain make use of monoamines as
neurotransmitters.
• They contain one amine group.
• Monoamines include dopamine, norepinephrine, epinephrine, and serotonin.
• Catecholaminergic pathways make use of a monoamine that contains a catechol
nucleus.
• Catecholamines include dopamine, norepinephrine, and epinephrine.
• In general, they include dopaminergic, noradrenergic (norepinephrinergic)
and adrenergic (epinephrinergic) pathways.
• Indolaminergic (serotonergic) pathways make use of a monoamine that contains
an indole nucleus.
• Serotonin is an indolamine.
• Cholinergic pathways make use of acetylcholine (ACh) as a neurotransmitter.
• Peptidergic pathways make use of peptides as neurotransmitters.
• Gamma-aminobutyric acid (GABA)-ergic pathways make use of GABA as a
neurotransmitter.
• Glutamatergic pathways make use of glutamate as a neurotransmitter.
• Glycinergic pathways make use of glycine as a neurotransmitter.
• L-Arginine-nitric oxide pathway makes use of the gaseous neurotransmitter
nitric oxide.
Neurotransmitters
• The particular transmitter used by a neuron is determined by a specific subset of
biosynthetic enzymes.
• These enzymes define the neurochemical identity of the neuron and endow the
cell with the property of being cholinergic, noradrenergic, dopaminergic,
glutamatergic etc.
Acetylcholine
• This transmitter is NOT derived from an amino acid.
• The precursor is CHOLINE which is derived from dietary sources and
delivered to neurons through the bloodstream.
• Acetylcholine was the FIRST neurotransmitter to be identified.
• It is used by the motor neurons in the ventral horn of the spinal cord.
• In the autonomic nervous system, it is the transmitter for all preganglionic
neurons and for the parasympathetic postganglionic neurons.
• Cholinergic neurons in the brain are distributed throughout the brainstem in
cranial nerve nuclei, the base of the forebrain and the basal ganglia.
Key enzyme for acetylcholine is: choline acetyltransferase (ChAT).
• Cholinergic receptors are divided into 2 general classes: nicotinic and
muscarinic.
• The nicotinic receptor is an integral membrane protein with five subunits.
• It is a directly gated ion channel which has 2 functions:
– It recognizes and binds the neurotransmitter
– Opens a channel in the membrane through which ions flow
• The receptor-channel complex consists of five subunits, all of which contribute to
forming the pore.

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• When two molecules of ACh bind to portions of the alpha-subunits exposed to
the membrane surface, the receptor channel changes conformation.
• This opens a pore in the portion of the channel embedded in the lipid bilayer, and
both K+ and Na+ flow through the open channel down their electrochemical
gradients.
Nicotinic Acetylcholine Receptor
• Each subunit is composed of four membrane-spanning alpha-helices (labeled M1
through M4).
• The five subunits are arranged such that they form an aqueous channel, with the
M2 segment of each subunit facing inside and forming the lining of the pore.
Cholinergic Pathways
• Major cholinergic pathways include:
– Septal nuclei which projects via the fornix to the hippocampal
formation.
– Basal nucleus of Meynert which is located in the substantia innominata
of the basal forebrain, between the globus pallidus and the anterior
perforated substance.
– The Basal nucleus of Meynert projects to the ENTIRE neocortex.
• The basal nucleus of Meynert receives input from the locus ceruleus, raphe
nuclei, substantia nigra, amygdaloid nucleus, and orbitofrontal and temporal
cortices.
• This nucleus degenerates in Alzheimer’s disease.
• The striatum (caudate nucleus and putamen) contains ACh in its local circuit
neurons.
– These neurons degenerate in Huntington’s and Alzheimer’s disease.
Catecholamines
• Catecholamines are a part of a group of transmitters known as biogenic amines.
• The precursor for catecholamines is TYROSINE which is obtained through
dietary sources and enters the brain via an uptake transport mechanism.
• Catecholamines are characterized by the presence of a catechol ring.
• There are specific enzymes involved in the synthesis of each catecholamine.
• The rate limiting step in the synthesis of dopamine and norepinephrine is the
enzyme TYROSINE HYDROXYLASE.
Dopamine
• Dopamine is a catecholamine and can be identified by the marker tyrosine
hydroxylase.
• It plays a role in cognitive, motor, and neuroendocrine functions and is the
neurotransmitter depleted in Parkinson’s disease.
• Moreover, it is INCREASED in a majority of cases of Schizophrenia
(dopamine hypothesis of schizophrenia).
• Dopamine is estimated to constitute as much as 80% of the total brain
catecholamine content. However, the total number of DA cells is rather small.
• Presynaptic dopamine receptors also modulate the rate of tyrosine
hydroxylation.
• These receptors are activated by DA release from the nerve terminal resulting in
feedback inhibition of dopamine synthesis.

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• These autoreceptors are important sites for pharmacological manipulation of DA
transmission.
• Dopamine is converted to dihydroxyphenylacetic acid (DOPAC) by
intraneuronal monoamine oxidase (MAO) after reuptake into the nerve terminal.
• Extracellular dopamine is converted to homovanillic acid (HVA) through the
sequential action of catechol-O-methyltransferase (COMT) and MAO.
• The primary metabolites of dopamine in the CNS are HVA and DOPAC.
• Accumulation of the metabolite HVA, in the brain or CSF has been used as an
index of the functional activity of dopaminergic neurons.
• Drugs which increase dopaminergic transmission increase HVA in the brain.
Dopamine: intracellular mechanisms
• DARPP-32 is a protein found in cells containing D1 receptors.
• When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32
can inhibit the action of protein phosphatase-1, an enzyme that
dephosphorylates some proteins (X) that have also been phosphorylated by
PKA.
• In this way, DARPP-32 may facilitate various effects of DA that are mediated by
D1 receptors and the activation of PKA.
Dopamine Pathways
• Nigrostriatal pathway: the substantia nigra projects to the striatum.
– Destruction of dopaminergic nigral neurons results in Parkinsonism.
• Mesolimbic Pathway: the ventral tegmental area projects to all cortical and
subcortical structures of the limbic system.
– This pathway is linked to motivational behavior and schizophrenia.
• Tuberohypophyseal (tuberoinfundibular) pathway: the arcuate nucleus of the
hypothalamus projects to the protal vessels of the infundibulum.
– Released dopamine inhibits the release of prolactin from the
adenohypophysis.
Norepinephrine
• Norepinephrine is a catecholamine that can be localized in the brain by the
marker dopamine β -hydroxylase.
• Norepinephrine is the transmitter of postganglionic sympathetic neurons.
• It plays a role in the genesis and maintenance of mood.
– The catecholamine hypothesis of mood disorders states that reduced
norepinephrine activity is related to depression, and that increased
norepinephrine activity is related to mania.
• Dopamine β -hydroxylase converts dopamine to norepinephrine.
• Unlike all other enzymes in the biosynthetic pathways of small-molecule
neurotransmitters, dopamine β -hydroxylase is membrane-associated.
• The hydroxylase is bound tightly to the inner surface of aminergic vesicles as a
peripheral protein.
• Consequently, norepinephrine is synthesized within vesicles and is the only
transmitter synthesized in this manner.
• The locus ceruleus (LC) contains the largest concentration of noradrenergic
neurons in the CNS.
• It is located in the pons and midbrain and projects to all parts of the CNS.

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• The LC receives input from the cortex, limbic system, reticular formation,
raphe nuclei, cerebellum, and spinal cord.
• There is a significant loss of noradrenergic neurons in Alzheimer’s and
Parkinson’s disease.
• Noradrenergic pathways play a role in anxiety and panic disorders.
Serotonin
• Tryptophan obtained from dietary sources is the main precursor for serotonin
synthesis.
• Synthetic enzyme for serotonin is tryptophan hydroxylase.
• Serotonin is metabolized via monoamine oxidase and its metabolite 5-
hydroxyindoleacetic acid (5-HIAA).
• 5-HT is an indolamine and can be identified by the marker tryptophan
hydroxylase.
• It plays an important role in influencing arousal, sensory perception, emotion,
and higher cognitive functions.
• The permissive serotonin hypothesis states that reduced 5-HT activity permits
reduced levels of catecholamines to cause depression and elevated levels to
cause mania.
• Severe depression and insomnia are associated with low 5-HT levels, and
mania is associated with high 5-HT activity.
• Dysfunction of 5-HT is believed to underlie obsessive-compulsive disorder.
Serotonin Transporter
• Serotonin uptake is a carrier-mediated process requiring the presence of NA+
and Cl- ions.
• Sodium binds first to the carrier, following by 5-HT (1).
• Chloride is needed for transport but not for transmitter binding.
• The carrier is translocated in the membrane by an unknown mechanism after
which 5-HT and the ions dissociate from their binding sites (2).
• Potassium then binds to the carrier (3) is translocated to the outside of the
membrane (4) and dissociates from the carrier to complete the cycle.
Serotonergic Pathways
• 5-HT neurons are only found in the raphe nuclei of the brainstem which project
diffusely to the entire CNS.
• Raphe nuclei of the medulla project to the dorsal horns of the spinal cord.
• Raphe nuclei of the pons project to the spinal cord and cerebellum.
• Raphe nuclei of the midbrain project to widespread areas of the diencephalon
and the telencephalon including the striatum.
• The pineal gland (epiphysis cerebri) contains the highest concentrations of 5-
HT in the body.
• It contains pinealocytes, which convert 5-HT to melatonin.
Amino Acid Transmitters
• Some neurotransmitters are universal cellular constituents.
• Glycine, glutamate and aspartate are 3 of the 20 common amino acids that are
incorporated into the proteins of all cells.
• Glutamate and aspartate are products of the citric acid cycle (Kreb’s) cycle.

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• GABA is synthesized from glutamate in a reaction catalyzed by the enzyme
glutamic acid decarboxylase or GAD.
• Amino acids may serve as neurotransmitters in some neurons and not others.
Glutamate
• Glutamate is the major excitatory transmitter of the brain: 60% of brain
synapses are glutamatergic.
• It is the neurotransmitter of the cerebellar granule cell, corticobulbar and
corticospinal tracts, and is used by dorsal root ganglion cells.
• Glutamate is involved in long-term potentiation (LTP) of hippocampal neurons
via N-methyl-D-aspartate (NMDA) receptors.
• It also plays a role in kindling-induce seizures and pain transmission (in A and
C fibers).
• Neocortical glutamatergic neurons project to the striatum, the subthalamic
nucleus, and the thalamus.
• The subthalamic nucleus projects glutamatergic fibers to the globus pallidus.
• Glutamate plays an important function in:

– the detoxification of ammonia in the brain


– is an important building block in the synthesis of proteins and peptides
including glutathione
– and is a precursor for the inhibitory neurotransmitter GABA
– Glutamate is synthesized in neural tissues by two major pathways:
– (A) from α-ketoglutarate and donor amino acids by means of transamination, and
– (B) from glutamine by the action of the enzyme glutaminase.
– In both neurons and astrocytes, glucose is converted to pyruvate by the process
of glycolysis.
– Pyruvate is then transaminated to alanine or, more typically, enters the citric acid
cycle either following conversion to acetyl CoA or by condensation with CO2 to
generate oxaloacetate.
– Following synaptic release, some neuronal glutamate is accumulated by
astrocytes where it can be converted to glutamine for storage.
– Glutamine and possibly alanine are released by astrocytes and taken up by
neurons for glutamate synthesis.

•AMPA, kainate, and NMDA receptors are all ionotropic receptors; they
belong to the ligand-gated channel receptor superfamily.
• They are all named after pharmacologic agonists to which they respond relatively
selectively.
NMDA Glutamatergic Receptor
• The NMDA receptor complex possesses a glutamate recognition site to which
receptor agonists and competitive antagonists bind, as well as other binding sites
for glycine, polyamines such as spermine and spermidine, phencyclidine
(PCP) and related drugs, Mg2+, and Zn2+.
• Channel opening permits an influx of Na+ and Ca2+ ions, and an efflux of K+
ions.
• (A) NMDA

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• (B) Kainate
• (C) AMPA
γ -aminobutyric acid (GABA)
• GABA can be localized by the marker glutamic acid decarboxylase.
• It is the major INHIBITORY neurotransmitter in the brain.
• It coexists with substance P and enkephalin
• Purkinje, stellate, basket, and Golgi cells of the cerebellar cortex are GABA-
ergic.
• GABA-ergic striatal neurons project to the globus pallidus and the substantia
nigra.
• GABA-ergic pallidal neurons project to the thalamus and nigral neurons project
to the thalamus.
• GABA is synthesized from glutamate by the enzyme glutamate
decarboxylase.
• The breakdown of GABA is catalyzed by GABA aminotransferase (GABA-T),
which forms succinic semialdehyde and regenerates the precursor glutamate
from α-ketoglutarate.
GABAa Receptor Complex
• The GABAa receptor complex has a GABA binding site that mediates the effects
of agonists and competitive antagonists, a Cl- channel, and modulatory binding
sites for benzodiazepines, barbiturates, picrotoxin, and certain anesthetics.
Opioid Peptide Transmitters
Opioid Peptides
• Endorphins: are derived from pro-opiomelanocortin (POMC) the precursor of
adrenocorticotropic hormone (ACTH).
• Endorphins include β -endorphin (the major endorphin found in the brain).
They play a major role in endocrine function.
• Endorphinergic neurons are found almost exclusively in the hypothalamus
(arcuate and premamillary nuclei).
• These neurons project to the hypothalamus, amygdala, nucleus accumbens,
septal area, thalamus, and locus ceruleus (midbrain and pons).
• Enkephalins: are derived from proenkephalin and are the most widely
distributed and abundant opioid peptides.
• They are found in the highest concentrations in the globus pallidus.
• Enkephalins are also synthesized in striatal neurons, which project to the
globus pallidus.
• Enkephalins are located mainly in local circuits of the limbic and striatal systems
and play a role in pain suppression in the dorsal horn of the spinal cord.
• Enkephalins are co-localized with dopamine, norepinephrine, ACh, and
GABA.
• Dynorphins are derived from prodynorphin and follow, in general, the
distribution map for enkephalin.
• Dynorphins have high concentrations in the hypothalamus and amygdala.
Nonopioid Neuropeptides
• Substance P: is an excitatory neurotransmitter and is contained in the dorsal root
ganglion cells, which project to the substantia gelatinosa.

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• It plays a role in pain transmission.
• Substance P is synthesized in striatal neurons, which project to the globus
pallidus and the substantia nigra.
• It is found in highest concentration in the substantia nigra (striatonigral and
pallidonigral tracts).
• Somatostatin: is also called somatotropin release-inhibiting factor.
• Somatostatinergic neurons are found in the anterior hypothalamus and in the
preoptic region, striatum, amygdala, cerebral cortex, and in dorsal root
ganglion cells.
• Somatostatinergic neurons from the anterior hypothalamus project their axons
to the median eminence, where somatostatin enters the hypophyseal portal
system and regulates the release of growth hormone (GH) and thyroid-
stimulating hormone (TSH).
• The concentration of somatostatin in the neocortex and hippocampus is
significantly reduced in Alzheimer’s disease.
• Nitric Oxide:
• NO is a recently discovered gaseous neurotransmitter that is produced when
nitric oxide synthase converts arginine to citrulline with the formation of NO.
• NO is located in the olfactory system, striatum, cortex, hippocampal
formation, supraoptic nucleus of the hypothalamus, and cerebellum.
• Nitric Oxide:
• NO is responsible for the smooth muscle relaxation of the corpus cavernosum
and thus penile erection by bringing an influx of blood.
• It also plays a role in memory formation (long-term potentiation in the
hippocampus).

Neurotransmitters III: Disorders of Chemical Neurotransmission


Disorders of the Cholinergic System
Myasthenia Gravis
• Myasthenia gravis is an autoimmune syndrome that occurs in the presence of
antibodies to the nicotinic ACh receptor.
• It is caused by the action of antibodies that reduce the number of receptors in the
neuromuscular junction, resulting in muscle paresis.
• Clinically, it involves extraocular and eyelid muscles (e.g., in diplopia, ptosis),
bulbar muscles (e.g., in nasal speech, jaw fatigue).
• (A) Normal turnover of randomly spaced ACh receptors takes place every 5-7
days.
• (B) In myasthenia gravis and in experimental myasthenia gravis, the cross-
linking of ACh receptors by the antibody facilitates the normal endocytosis
and phagocytic destruction of receptors, which leads to a two-to threefold
increase in the rate of receptor turnover.
• Binding of anti-receptor antibody activates the complement cascade, which is
involved in focal lysis of the postsynaptic membrane.
• This focal lysis is probably primarily responsible for the characteristic alterations
of postsynaptic membrane morphology observed in myasthenia.
Alzheimer’s Disease

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• Results from the degeneration of cortical neurons and cholinergic neurons found
in the basal nucleus of Meynert.
• It is associated with a 60-90% loss of choline acetyltransferase in the cerebral
cortex.
• Alzheimer’s disease is characterized histologically by the presence of
neurofibrillary tangles, senile (neuritic) plaques and granulovacuolar
degeneration.
• This disease is twice as common in women as in men.
• Senile plaques consist of degenerated nerve cell processes and a central core of
amyloid β -protein.
• Therapeutic strategies include inhibitors of acetylcholinesterase (e.g. Tacrine,
Piracetam).
Lambert-Eaton myasthenic Syndrome
• This syndrome is caused by a presynaptic defect of ACh release.
• It results in weakness in the limb muscles.
• Unlike myasthenia gravis, muscle strength improves with use in which the
muscle use results in fatigue.
• Lambert-Eaton myasthenic syndrome is associated with neoplasms (e.g. lung,
breast, prostate) in 50% of cases.
• It also leads to autonomic dysfunction, with dry mouth, constipation,
impotence, and urinary incontinence.
Norepinephrine
• Noradrenergic deficiency in the catecholamine hypothesis of depression:
– The catecholamine hypothesis of mood disorders states that reduced NE
activity is related to depression, and that increased NE activity is
related to mania.
– drugs which deplete monoamines (e.g. reserpine) induce symptoms of
depression.
• These symptoms are responsive to monoamine reuptake inhibitors (e.g.
imipramine) and tricyclic compounds.
• Norepinephrine dysfunction has also been implicated in anxiety disorders:
– Panic disorder
– Post-traumatic stress disorder
– Generalized anxiety disorder
– Social phobia
– Obsessive-compulsive disorder
– Panic attacks
Drug Misuse (Abuse)
Clonidine, an α-2-agonist counteracts withdrawal from drugs such as morphine and
heroin suggesting that norepinephrine transmission is involved in drug withdrawal
processes.
Disorders of the Dopaminergic System
Parkinson’s Disease
• Results from degeneration of dopaminergic neurons found in the pars compacta
of the substantia nigra.

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• Disease progression results in a reduction of dopamine in the striatum and in
the substantia nigra.
• Parkinson’s produces the formation of Lewy bodies, intraneuronal inclusions in
the substantia nigra.
• Clinical benefits derived from treatment with the dopamine precursor, L-DOPA
or dopamine receptor agonists (e.g. bromocriptine).
Schizophrenia
• Caused in part by overactivity of mesolimbic and/or mesocortical dopamine
transmission.
• Dopamine receptor antagonists (e.g. haloperidol, chlorpromazine) are often
very effective.
• Abnormalities in dopaminergic transmission may not account for all aspects
of schizophrenia.
Substance Misuse (Abuse)
• Dopamine has been implicated in mechanisms of reinforcement and reward.
• Cocaine inhibits dopamine re-uptake and amphetamine reverses the
dopamine reuptake transporter, are examples of highly addictive drugs.
• Heroin, nicotine and THC also increased DA neurotransmission.
Disorders of the Serotonergic System
Depression
• The permissive serotonin hypothesis states that reduced 5-HT activity permits
reduced levels of catecholamines to cause depression.
• Severe depression and insomnia are associated with low 5-HT levels and
mania is associated with high 5-HT activity.
• Dysfunction of 5-HT is believed to underlie obsessive-compulsive disorder.
• Tricyclic antidepressants and fluoxetine increase 5-HT availability by
blocking its reuptake.
Substance Misuse (Abuse)
• Psychedelic drugs such as the hallucinogens are structurally related to 5-HT
including LSD and MDMA (e.g. ecstasy).
Disorders of the GABAergic System
Epilepsy
• Markers of GABAergic function have been shown to be deficient in various
types of seizure disorders.
• Administration of GABA antagonists (e.g. bicuculline) produces behavioral
seizure activity whereas GABA agonists block seizures.
Anxiety
• Benzodiazepines (e.g. diazepam or Valium) enhance GABAergic activity and
are effective in the treatment of anxiety.
• This evidence has lent strong support for the hypothesis of an underactive
GABA system in anxiety disorders.
Huntington’s Disease
• A disorder of abnormal involuntary movement with additional cognitive
impairment.

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• This disorder results from a loss of ACh and GABA-containing neurons in the
striatum (caudate and putamen) and further loss of GABA in the substantia
nigra.
Disorders of the Glutamatergic System
Neurodegeneration and Neurotoxicity
• Stimulation of NMDA receptors allows direct influx of CA2+ into neurons.
• This is considered to be a critical event in processes related to neuronal
degeneration and excitotoxicity.
• High concentrations of intracellular Ca2+ may activate calcium dependent
proteases and phospholipases and may produce free radicals that are toxic to
the cell.
Stroke
• The neuronal damage induced by obstruction of blood flow to the brain has
been attributed to glutamate toxicity since many experimental paradigms of stroke
show increased glutamate release following hypoxia.
• Glutamate receptor antagonists have shown promise in experimental situations
and continue to be developed for use in humans with stroke.
Epilepsy
• Glutamate and related receptor agonists including NMDA and kainic acid
cause neuronal hyperexcitability and seizures in experimental animals.
• Glutamate receptor antagonists are under development as anticonvulsant drugs.
Disorders implicating Neuropeptides
Stress and Depression
• In depression, excessive secretion of ACTH by the pituitary leads to excessive
cortisol release from the adrenal cortex.
• The increased release of ACTH is a result of hypersecretion of corticotropin-
releasing factor (CRF) from the hypothalamus to the pituitary.
• Increased levels of CRF has been correlated with depression.

LECTURE 34: Learning and Memory


Outline
• 1. Introduction
• 2. Associative Learning: Classical and Operant
• 3. Cellular model of learning: Long-term potentiation (LTP)
• 4. Invertebrate model of learning (Aplasia Californica)
• 5. Pre-clinical models (rats!) used in learning and memory
• 6. Human memory: organization and neural substrates
• 7. Clinical applications
• 8. Conclusions

Associative Learning
• Classical Conditioning: conditioning based on reflexes.
• Operant Conditioning: conditioning based on consequences. Guided by
consequences the organism ‘operates’ on its environment to attain goals.
Reinforcement plays a large role.
Basics of Classical Conditioning

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• Unconditioned stimulus (UCS): something that elicits a response (i.e. food, eye
air-puff, shock)
• Unconditioned response (UCR): a reflex (i.e. salivation, eye blink, freezing)
• Conditioning stimulus (CS): a previously neutral stimulus that is given meaning
by being paired with the unconditioned stimulus (i.e. bell or light)
• Conditioned response (CR): multiple pairings between the UCS and CS changes a
UCR to a CR (i.e. bell or light alone elicits salivation or eye blink or freezing)
Classical Conditioning Formula
UCS (food)=UCR (salivation)
Bell+Food=salivation
CS+UCS=UCR
After multiple pairings you get:
UCR>CR or
Bell=salivation
CS=CR
Real-life Examples of Classical Conditioning
• K-Mart: Blue-light special?
• Pets: Fluffy bullets for the kitchen after hearing you open a can of cat food.
• Advertising (J.B.Watson)
Operant Conditioning
• Positive reinforcer: something that increases the rate or probability at which a
behavior occurs
• Negative reinforcer: something that removal of an aversive stimulus increases the
rate of behavior
• Extinction: is the disappearance of a learned behavior when a reinforcer is
withheld
• Punishment: an aversive stimulus aimed at reducing an unwanted behavior
Schedules of Reinforcement
• Fixed Ratio: a reinforcer is given after a specific number of responses. This
schedule is best for learning a new behavior.
• Fixed Interval: the first correct response after a set amount of time has passed is
reinforced. Time period is always the same.
• Variable Ratio: a reinforcer is given after a set number of correct responses. After
reinforcement the number of correct responses necessary for reinforcement
changes. This schedule is best for maintaining behavior.
• Variable Interval: the first correct response after a set amount of time has passed
is reinforced. After the reinforcement, a new time period is set.
Real-life applications of operant conditioning principles
• Systematic desensitization: used to eliminate phobias
• Token Economy: reinforce good behavior
• Biofeedback: used to control the autonomic system to treat hypertension, peptic
ulcers, asthma, peripheral temperature regulation and migraine headaches and
anxiety
• Programmed instruction in schools
Long-term Potentiation (LTP)

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• Long-term potentiation (LTP): is a long-lasting increase in synaptic efficacy in
response to high-frequency stimulation of afferent fibers.
• This increase in synaptic strength can last for minutes to weeks.
• LTP is a cellular model of learning.
LTP requires:
• Coincident pre-synaptic activity and post synaptic depolarization
• Activation of NMDA receptors
• Calcium entry into the post-synaptic cell
• Initiation of a variety of second-messengers
Is LTP a biological correlate that can explain learning and memory?
• Associative and spatial learning results in LTP
• Old rats have poor LTP and poor learning
• Genetically altered mice that have poor LTP do not learn well
• Block LTP you block memory
Behavioral Paradigms
• 1) Fear Conditioning
• Associative Learning
• 2) Passive Avoidance
• Associative Learning
• 3) Morris Water Maze
• Spatial Learning
• 4) T-maze
• Working Memory
• 5) Operant Conditioning
• Various types of learning
Human Memory
• Short Term (working) memory: minutes to hours
• Long Term memory: more than a day
• Declarative memory (explicit): conscious recall of factual information of past
experiences.
• -Episodic memory: personal information, personal experiences in a
temporal context (When did you go to college? What did you do last weekend?);
allows us to place facts and events in time and refer to them as needed.
• -Semantic memory: is a general knowledge of facts and concepts that can
be categorized (a cat is a mammal that has fur that is a carnivore that is a
vertebrate…) usually acquired by rote.
• Procedural (implicit) memory: motor skill memory or habits, once learned they
do not have to be learned again (riding a bike, walking, talking etc.).
Patient H.M.
• Underwent bilateral medial temporal lobe resection in 1953 to stop epileptic
seizures.
Result:
• Severe anterograde memory impairment and some retrograde
• Intact short-term memory
• Impaired long-term memory consolidation, memories before surgery intact

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• Normal motor learning (procedural or implicit learning)
• Take home message:

• Bilateral damage to the medial temporal lobe results in severe disruption in


declarative memory function for events occurring after damage.
• However, episodic and semantic memories of information and events that
occurred prior to surgery remain intact.
Declarative memory: hippocampus
Lateralization in the Hippocampus: Spacial Mapping
• We spend much of our time actively moving around our environment.
• This requires that we have a representation in our brain of the external
environment, a representation that can be used to find our way around.
• The right hippocampus seems to be critically involved in this representation.
• Whereas, the left hippocampus is concerned with verbal memory.
Emotional Memory: amygdala
Damage to the amygdala results in:
• Inability to recognize the expression of fear in human faces
• Deficits in memory of emotional material
• Electrical stimulation of the amygdala causes intense hallucinations accompanied
by fear
• Monkey lesions: unable to recognize the emotional significance of objects
Procedural (Implicit) memory: cerebellum, motor cortex, striatum
Working Memory: prefrontal cortex, parietal cortex
Memory Storage: Posterior Parietal Cortex
• Memories are not stored in one area of the brain.
• For example, a patient with associative agnosia can not NAME objects but they
can identify them by selecting a drawing or reproducing detailed drawings of the
object.
• A patient with apperceptive agnosia is unable to reproduce even simple drawings
but nevertheless can name the objects in the drawings.
Causes of Memory Loss
• Strokes
• Trauma
• Seizures (Epilepsy)
• Alzheimer’s Disease
• Dementia with Lewy bodies
• Parkinson’s disease with dementia
• Vascular dementia (ischemia)
• Progressive supranuclear palsy
• Encephalitis (herpes simplex encephalitis, inflammations)
• Wernicke-Korsakoff’s Syndrome
• Medications/drugs (benzodiazepines, opiates, ketamine, cholinergic antagonists,
alcohol)
Facilitation of Learning and Memory
Some drugs used to treat memory impairment include:

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– Cholinesterase inhibitors (tacrine, donepezil, rivastigmine)
– Cholinergic agonists (M1, nicotinic)
– Enhancement of Dopamine: MAO-B inhibitors (deprenyl), amphetamine,
methylphenidate (Ritalin)
– Agents that facilitate oxygen utilization (Ginkgo biloba)

LECTURE 35: Dementia and Aging: Alzheimer’s Disease and Other Disorders
Dementia
• Dementia refers to an acquired, generalized, and often progressive impairment
of cognitive function that affects the content, but not the level of
consciousness.
• Incidence increases with age: estimates show dementia to affect 5-20% of
individuals over the age of 65.
• Dementia reflects an underlying pathology that affects the cerebral cortex, its
subcortical connections, or both.
Minor changes in neurologic function, including alterations in memory and other
cognitive spheres, are associated with normal aging.
• Enlargement of ventricles and cerebral cortical sulci seen on CT or MRI scans
is also common with normal aging.
• These findings should not by themselves be considered indicative of
dementia.
• The most common problem in diagnosing dementia is distinguishing it from an
acute confusional state, such as that produced by drug intoxication.
• Another common problem is differentiating between dementia and so-called
pseudodementia produced by depression.
• It is important to establish that the patient’s previous level of functioning has
declined.
• Data that can help to establish the cause of dementia include:
• time course of deterioration
• associated symptoms such as headache
• gait disturbance
• incontinence
• family history of similar condition
• concurrent medial illness
• use of alcohol
• prescribed and unprescribed drugs
Dementia: Diagnosis
• General Physical Examination
• Mental Status Examination
• Neurologic Examination
• Laboratory Tests
Alzheimer’s Disease
• Alzheimer’s disease, is by far the single most frequent cause of dementia.
• AD becomes increasingly common with advancing age and has an equal
incidence in both sexes.

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• It is a slowly progressing disorder that cannot be diagnosed with certainty on
clinical grounds.
• AD is characterized by typical histopathologic features:
• neurofibrillary tangles
• neuritic plaques
• granulovacuolar degeneration
• Pick’s disease, a closely related dementing process in which atrophy is most
concentrated in the frontal and temporal lobes, may be clinically
indistinguishable from AD.
Pathogenesis
• Genetics: AD is usually sporadic, but a genetic basis can be identified in some
cases.
• Patients with trisomy 21 (Down’s syndrome) which is usually due to the
presence of three free copies of chromosome 21 but can also result from
translocation of the third copy to chromosome 12 or 21 have incidence of AD
beginning in the fourth decade.
• Familial Alzheimer’s disease with autosomal dominant inheritance has also been
documented and is genetically heterogenous.
Pathogenesis
• In some families there are associated mutations in the gene for amyloid
precursor protein (APP) on chromosome 21.
• These are missense mutations that result from single amino acid substitutions,
producing a protein with altered function.
• In another form of familial AD which has an especially early onset and more
virulent course is linked to mutations in the gene for presenilin 1, a
membrane protein on chromosome 14.
• Mutations in another transmembrane protein, presenilin 2 have been associated
with familial Alzheimer’s disease in a German population.
• Genetic factors may also modify susceptibility to AD without being directly
causal:
• In late-onset familial (and to a lesser extent sporadic) AD, the risk of
being affected and the age at onset are related to the number of other
apolipoprotein E e-4 (APOE) alleles on chromosome 19.
• How the APOE4 allele (or the absence) confers disease susceptibility is
unclear.
• It has been speculated that apolipoprotein E (APOE4) produced by astrocytes
may be taken up into neurons and interact abnormally with microtubule-
associated proteins (MAP), like tau, to produce paired helical filaments in
neurofibrillary tangles.
Role of β -amyloid: Amyloid β -protein (β Amyloid or Aβ )
• Aβ is deposited in neuritic plaques (as their principal constituent) and in
cerebral and meningeal blood vessels of patients with AD.
• Some cases of familial AD are associated with mutations affecting the amyloid
precursor protein (APP).
• These findings suggest that alterations in the metabolism of APP to Aβ may be
involved in the pathogenesis of AD.

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• In Down’s syndrome, the extra copy of chromosome 21, which codes for APP,
would be expected to cause increasing production of APP and its product Aβ .
• APP is a member of a family that includes the APP-like proteins APLP1 and
APLP2.
• It is encoded by a gene in the midportion of the long arm of human chromosome
21.
• APP exists in three principle isoforms of 695, 751, and 770 amino acids, each of
which contains Aβ amyloid.
β -Amyloid or Aβ
• APP is synthesized in the rough ER, glycosylated in the Golgi apparatus and
delivered to the cell surface as an integral membrane protein.
• Some of these molecules are cleaved within the Aβ sequence, thus preventing
the formation of the Aβ peptide.
A fraction of the APP within the plasmalemma is internalized in the cell to generate
various forms of Aβ amyloid (Aβ 1-40, Aβ 1-42, Aβ 1-43) as well as a truncated
form of the Aβ peptide (β 17-40).
• According to one model, a β -secretase cleaves APP at the N terminus of the
Aβ peptide sequence in the endosomal compartment and a γ -secretase
enzyme cleaves at the C terminus of the Aβ peptide at or near the cell
surface.
Aβ Amyloid: Aβ 1-42 is Neurotoxic
• The Aβ peptide is predominantly 40 amino acids in length (Aβ 1-40).
• However, Aβ 1-42 and Aβ 1-43 nucleate more rapidly into amyloid fibrils
than Aβ 1-40 does.
• In the cerebral cortices of individuals with AD or Down’s syndrome, Aβ
amyloid deposition begins with Aβ 1-42 and Aβ 1-43 not Aβ 1-40.
• The Aβ 1-42 fragment of the Aβ peptide appears to be neurotoxic by
mechanisms not fully understood as of yet.
Toxicity as a Cause of AD
• A role has been proposed for aluminum toxicity in the pathogenesis of AD.
• This is based on findings that the concentration of aluminum in the brain
increases with age, and aluminum is present in the neurofibrillary tangles
and neuritic plaques of brains from patients with AD.
• Aluminum-containing dialysates may be responsible for a dementia
associated with chronic hemodialysis.
• It is however, unlikely that exposure to aluminum in antacids, drinking water, or
cooking utensils increases the risk of AD.
• More research is needed to confirm the role of aluminum toxicity in AD.
Neurochemical Changes in AD
• Changes in several neurotransmitters and neuromodulator systems have been
fund in the brains of AD victims.
• The acetylcholine-synthesizing enzyme choline acetyltransferase is markedly
depleted in the cerebral cortex and hippocampus of patients with AD.
• Degeneration of the nucleus basalis of Meynert and of cholinergic septal-
hippocampal tract may underlie this abnormality.

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• Several neurotransmitters (acetylcholine, somatostatin, vasopressin, β -
endorphin, corticotropin, substance P) are depleted in the brains of patients
with AD.
• Specific neuronal systems have been identified in morphological and
neurochemical analyses as vulnerable in AD.
• The involvement of these bran regions and neural systems in AD is reflected
in the clinical signs of the disease.
• Comparison of a normal nerve cell and a neuron exhibiting abnormalities that
occur in AD.
• The principal components of senile plaques are neurofibrillary tangles in the
cell bodies, neuropil threads, and neurites as well as extracellular Aβ
amyloid.
• These lesions are surrounded by microglial cells and astrocytes.
• Many large β -amyloid containing plaques are present in the hippocampal
CA1 region and the subiculum (silver stain).
• Tissue which was silver-stained, was obtained from an 80 year old demented
woman with late-stage AD.
Clinical Findings
• Early Manifestations: Impairment of recent memory is typically the first sign
of AD—often noticed only by family members.
• As the memory disorder progresses, the patient become disoriented to time and
then to place.
• Aphasia, anomia may develop forcing the patient to leave work.
• The depression apparent in the earlier stages of the disorder may give way to
an agitated, restless state.
• Apraxias and visuospatial disorientation ensue, causing the patient to
become lost easily.
• Primitive reflexes are commonly found.
• A frontal lobe gait disorder may become apparent, with short, slow, shuffling
steps, flexed posture, wide base, and difficulty in initiating walking.
• Late stages: Psychiatric symptoms, including psychosis with paranoia,
hallucinations, or delusions, may be prominent.
• Seizures occur in some cases.
• Examination may show extrapyramidal rigidity and bradykinesia.
• Mutism, incontinence, and a bedridden state are terminal manifestations.
• Death typically occurs from 5 to 10 years after the onset of symptoms.
Pick’s Disease
• Pick’s disease is one of a group of idiopathic neurodegenerative disorders that
produces a syndrome sometimes referred to as frontotemporal dementia.
• These disorders may be distinguished from AD by their earlier onset, more
prominent behavioral than cognitive dysfunction at presentation, and
preferential atrophy of the frontal and anterior temporal lobes on CT or MRI
scans.
• However, definitive diagnosis is usually not possible during life, and relies
instead on histopathological features.

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• These include the distinctively circumscribed pattern of lobar atrophy, the
presence of Pick cells and Pick inclusion bodies, and the ABSENCE of amyloid
plaque and neurofibrillary tangles characteristic of AD.
• Familial occurrence of Pick’s disease and of other frontotemporal dementias has
been documented.
• There is no treatment.
Creutzfeldt-Jakob Disease
• Creutzfeldt-Jakob Disease is a fatal disorder of the CNS and is characterized by
rapidly progressive demential and variable focal involvement of the cerebral
cortex, basal ganglia, cerebellum, brainstem, and spinal cord.
• A proteinaceous infectious particle (prion) has been proposed as the etiologic
agent.
• Prions have been implicated in three other rare disorders:
– kuru, a dementing disease of tribe in New Guinea
– Gerstmann-Straussler syndrome, a familial disorder characterized by
dementia and ataxia
– fatal familial insomnia, which produces disturbances of sleep and of
autonomic, motor, and endocrine function
Creutzfeldt-Jakob Disease :Clinical Findings
• Dementia is present in virtually all cases and may begin as a mild global
cognitive impairment or a focal cortical disorder such as aphasia, apraxia, or
agnosia.
• Progression to akinetic mutism or coma typically ensues over a period of
months.
• Psychiatric symptoms including anxiety, euphoria, depression, labile affect,
delusions, hallucinations, and changes in personality or behavior may be
prominent.
• Aside from cognitive abnormalities, the most frequent clinical manifestations
are myoclonus (often induced by a startle), extrapyramidal signs (rigidity,
bradykinesia, tremor, dystonia, chorea, or athetosis), cerebellar signs, and
extrapyramidal signs.
• Visual field defects, cranial nerve palsies, and seizures occur less often.
• A clinically and pathologically distinct new variant of Creutzfeldt-Jakob
disease has been described and is thought to result from the transmission of
bovine spongiform encephalopathy.
Dementia With Lewy Bodies
• Up to one-fourth of elderly demented patients who are autopsied have round,
eosinophilic, intracytoplasmic neuronal inclusions (Lewy Bodies) in the
cerebral cortex and brainstem.
• Dementia with Lewy bodies is found in patients with and without
histopathological features of AD, and is probably a heterogenous disorder.
• In contrast to AD, it is characterized clinically by cognitive decline without
prominent early memory impairment.
• Other distinctive features include fluctuating cognitive ability, well-formed
visual hallucinations, and signs of parkinsonism, especially rigidity and
bradykinesia.

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• These patients may respond well to anticholinesterase drugs such as tacrine or
donepezil, but are especially sensitive to extrapyramidal side effects of
antipsychotic drugs.
AIDS
• Dementia is the most common direct neurologic complication of AIDS,
occurring in up to 70% of patients.
• While especially common in severely immunosuppressed patients late in the
course of the disease, it can also be an early or presenting manifestation.
• Right, cerebrocortical atrophy with ventricular dilation, diffuse involvement of
subcortical white matter.
AIDS Dementia Complex
• AIDS dementia complex results from direct invasion of the brain by a
retrovirus, human immunodeficiency virus-1 (HIV-1).
• The virus and viral DNA and RNA can be isolated from the brain and CSF of
affected patients, and antibodies against HIV-1 are produced within the CNS.
• The virus appears to reach the CNS early in the course of systemic HIV-1
infection.
• Neurologic involvement at this stage may be asymptomatic, or it can produce
transient symptomatic HIV-1 meningitis.
• The infections then seems to be contained until progressive
immunosuppression impairs normal host defense mechanisms, leading to
increased HIV-1 production in the brain.
• Clinical Findings: The onset of AIDS dementia complex is usually insidious
and is associated with cognitive and behavioral symptoms, such as
forgetfulness, apathy, social withdrawal, and motor symptoms, including
impaired balance, leg weakness, and deterioration of handwriting.
• Early stages may also show cerebellar ataxia, pyramidal signs such as
hyperreflexia and extensor plantar responses, weakness in one or both legs,
postural tremor, and dysarthria.
• As the disease progresses, hypertonia, fecal and urinary incontinence,
primitive reflexes, myoclonus, seizures, delusions and visual hallucinations.
Neurosyphilis
• Dementia from neurosyphilis is now rare, but the recent resurgence of syphilis
suggest that it may become more common.
• Syphilis is caused by Treponema pallidum transmitted by sexual contact, which
results in infection in about one-third of encounters with infected individuals.
• Primary syphilis is characterized by local skin lesions (chancres) that usually
appear within 1 month of exposure.
• There are no neurologic symptoms.
• Hematogenous spread of T pallidum produces symptoms and signs of
secondary syphilis within one to six months.
• These include fever, skin, rash, alopecia, anogenital skin lesions, and
ulceration of mucous membranes.
• Neurologic symptoms are still uncommon at this stage.
• Meningeal syphilis, the earliest form of symptomatic neurosyphilis, is most
often seen 2-12 months after primary infection.

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• Clinical features include headache, stiff neck, nausea and vomiting, and
cranial nerve (II, VII or VIII) involvement.
Progressive Multifocal Leukoencephalopathy
• Progressive multifocal leukoencephalopathy results from infection with a
papovavirus called JC virus.
• While antibodies to this virus are present in most of the adult population,
symptomatic infection is rare.
• The disease is most common in patients with AIDS, lymphoma or leukemia,
carcinoma, sarcoidosis, tuberculosis, or pharmacologic immunosuppression
following organ transplantation.
• It is rare in patients with normal immune function.
• The virus infects oligodendrocytes, leading to diffuse and patchy
demyelination that most prominently affects white matter of the cerebral
hemispheres but also involves the brain stem and cerebellum.
• Gray matter involvement and inflammatory changes are minimal.
• The disorder is a subacute infection that runs a progressive course, usually
leading to death in 3-6 months.
• Fever and systemic manifestations are absent.
• The clinical picture is dominated by cognitive disturbances, usually dementia,
and focal cortical dysfunction.
• Hemiparesis, visual deficits, aphasia, dysarthria, sensory impairment, and
dysphagia are also common.
• Ataxia is seen less frequently, headache is uncommon and seizures do not occur.
Treatment and Prognosis
• The disorder has been almost uniformly fatal, and treatment with such antiviral
agents as cytosine arabinoside, adenine arabinoside, or amantadine has generally
been unsuccessful.
Metabolic Disorders
• Several complications of alcoholism are known to cause dementia.
• These include acquired hepatocerebral degeneration as a result of alcoholic
liver disease, chronic subdural hematoma from head trauma, and certain rare
disorders resulting from nutritional deficiency.
• Pellagra: caused by deficiency of nicotinic acid (niacin), affects neurons in the
cerebral cortex, basal ganglia, brainstem, cerebellum, and anterior horns of
the spinal cord.
• Systemic involvement is manifested by diarrhea, glossitis, anemia, and
erythematous skin lesions.
• Neurologic involvement may produce dementia:
• psychosis
• confusional states
• pyramidal, extrapyramidal, and cerebellar signs
• polyneuropathy
• optic neuropathy
• Treatment is with nicotinamide, but the neurologic deficits may persist despite
treatment.

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• Marchiafava Bignami Syndrome: characterized by necrosis of the corpus
callosum and subcortical white matter and occurs most often in malnourished
alcoholics.
• The course can be acute, subacute or chronic.
• Clinical features include dementia, spasticity, dysarthria, gait disorder, and
coma.
• The diagnosis can sometimes be made by CT or MRI.
• NO specific treatment is available beside cessation of drinking and nutrition
supplementation.
• Outcome is variable; patients may die, survive with dementia or have a
complete recovery.
• Hypothyroidism (myxedema) causes acute confusional states, can also
produce a reversible dementia or chronic organic psychosis.
• The dementia is a global disorder characterized by mental slowness, memory
loss, and irritability.
• Focal cortical deficits do not occur.
• Psychiatric problems include depression, paranoia, visual and auditory
hallucinations, mania, and suicidal behavior.
• Patients with myxedema may complain of headache, hearing loss, tinnitus,
vertigo, weakness, or paresthesia.
Hypothyroidism (myxedema)
• Diagnosis of myxedema is based upon the laboratory finding of decreased blood
levels of T4 and T3 usually associated with increased TSH.
• Treatment consists of levothyroxine and corticosteroids.
• Cognitive dysfunction is usually reversible with treatment.
Metabolic Disorders
• Vitamin B12 deficiency is a rare cause of reversible dementia and organic
psychosis.
• The dementia consists of global cognitive dysfunction with mental slowness,
impaired concentration, and memory disturbance.
• Aphasia and other focal cortical disorders do not occur.
• Psychiatric manifestations are often prominent and include depression, mania,
and paranoid psychosis with visual and auditory hallucinations.
Trauma
• A syndrome of delayed and progressive post-traumatic dementia following
repeated head injury (dementia pugilistica) has been described in boxers.
• It may begin—and typically continues to progress—years after the episodes
of trauma have ceased.
• Dementia is characterized by cheerful or labile affect, mental slowness,
memory deficit, and irritability.
• Associated neurologic abnormalities include tremor, rigidity, bradykinesia,
dysarthria, cerebellar ataxia, pyramidal signs, and seizures.
• Neuroradiologic investigations may show cortical atrophy and cavum septi
pellucidi.
Amnestic Syndromes

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• A disorder of memory (amnestic syndrome) may occur as one feature of an acute
confusional state or dementia or as an isolated abnormality.
• Memory is a complex function that can be viewed as phases of acquisition,
consolidation and retrieval of which the hippocampus plays a major role.
• Bilateral damage to the hippocampus and surrounding structures results in
impairment of short-term memory.
• This is manifested in clinical terms as not being able to form new memories.
• Long-term memories, which involves retrieval of previously learned
information, is relatively preserved.
• Some patients with amnestic syndromes may attempt to fill in gaps in memory
with false recollections (confabulation), which can take the form of elaborate
contrivances or of genuine memories misplaced in time.
Acute Amnesia
• Head Trauma
• Hypoxia or ischemia
• Bilateral posterior cerebral artery occlusion
• Transient global amnesia
• Alcoholic blackouts
• Wernicke’s encephalopathy
• Dissociative (Psychogenic) amnesia: Amnesia may be manifestation of a
dissociative disorder or of malingering.
• In such patients a prior psychiatric history, additional psychiatric symptoms,
or a precipitating emotional stress can often be identified.
• Dissociative amnesia is characterized by an isolated or a disproportionate loss
of traumatic or stressful personal memories.
• Dissociative amnesia is usually localized in time to the immediate aftermath of
a traumatic experience or selective for some but not other events during such a
period.
• In some cases, the patient may be unable to remember even his own name—
an exceedingly rare finding in organic amnesia.
• Despite such disorientation to person, orientation to place and time may be
preserved.
• In addition, recent memories may be less affected than remote memories—the
reverse of the pattern is seen in amnesia caused by organic disease.
• Examination under hypnosis or after administration of amobarbital sodium
may be helpful in establishing that amnesia is of psychogenic origin.

LECTURE 36: Visual System


The visual system is served by the optic nerve (CN II) which is a special somatic
afferent (SSA) nerve.
The Retina
• The retina is the innermost layer of the eye.
• It is derived from the optic vesicle of the diencephalon and contains efferent
fibers that give rise to the optic nerve, which is actually a fiber tract of the
diencephalon.
• The retina is sensitive to wavelengths from 400nm to 700nm.

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Structures Associated with the Retina
• The optic disc is located 3.5mm nasal to the fovea centralis.
• It contains unmyelinated axons from the ganglion cell layer of the retina.
• The optic disk is the BLIND SPOT because it contains NO rods or cones.
• It contains a central cup, a peripheral disk margin, and retinal vessels.
• The macula lutea is a yellow-pigmented area that surrounds the fovea centralis.
• The fovea centralis is located within the macula lutea, close to the optic disk.
• It contains only cones and is the site of HIGHEST visual acuity.
• Avascular, the fovea receives its nutrients by diffusion via the choriocapillaris.
• It subserves COLOR or day (photopic) vision.
• The retina is supplied by the choriocapillaris of the choroid layer and the
central retinal artery, a branch of the ophthalmic artery.
• Occlusion of the central retinal artery results in blindness.
Cells of the Retina
Cells of the retina constitute a chain of three neurons that project visual impulses via
the optic nerve and the lateral geniculate body (LGB) to the visual cortex.
• Rods and cones are the first-order receptor cells that respond directly to light
stimulation.
• They generate only graded potentials and utilize glutamate as a
neurotransmitter.
– Rods (100 million) contain rhodopsin (visual purple) and are sensitive to
low-intensity light thus help allow night vision (scotopic).
– Cones (7 million) contain the photopigment iodopsin and operate only at
high illumination levels.
• Cones are concentrated in the fovea and are responsible for day
(photopic) vision, color vision and high visual acuity.
Optic Disk
Fovea
Cells of the Retina
• Bipolar neurons are second-order neurons that relay stimuli from the rods and
cones to the ganglion cells.
• They generate only graded potentials and utilize glutamate as a neurotransmitter.
• Few cones synapse on a single bipolar cell, which synapses on a single ganglion
cell.
• This arrangement is the basis for the high acuity and low sensitivity of
the cones.
• In the fovea, where acuity is highest, the ratio of cones to bipolar cells is
1:1.
• Many rods synapse on a single bipolar cell.
• As a result, there is less acuity in the rods than in the cones.
• There is also greater sensitivity in the rods because light striking any one
of the rods will activate the bipolar cell.
• Ganglion cells are third-order neurons that form the optic nerve (CN II); they
are the output cells of the retina.
• They are retinal cells with voltage-gated sodium channels that generate action
potentials.

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• Ganglion cells project directly to the hypothalamus, superior colliculus,
pretectal nucleus, and LGB.
• They use glutamate for their neurotransmitter.
• Horizontal cells are interneurons that interconnect photoreceptors and
bipolar cells.
• They inhibit neighboring photoreceptors (lateral inhibition), generate only graded
potentials, and utilize GABA as a neurotransmitter.
• They play a role in the differentiation of colors.
• Amacrine cells are small cells that have no axons and few dendrites.
• They receive input from bipolar cells and project inhibitory signals to ganglion
cells.
• Amacrine cells mediate lateral interactions at the bipolar-ganglion cell
synapse.
• They use GABA, glycine, dopamine, and acetylcholine (ACh) as
neurotransmitters.
Muller cells are radial glial cells that have a support function similar to astrocytes and
extend from the inner limiting layer to the outer limiting layer.
Phototransduction
• In rods and cones, the ligand of the receptor (opsin), is a vitamin A derivative
(11-cis retinal) that enables the photopigments to absorb visible light.
• Slight differences among the opsins of rods and each of the three types of cones
results in differences in the wavelengths absorbed preferentially by each
pigment.
• Decreased levels of cGMP causes closure of Na+ channels, decreased inward
Na+ current, and hyperpolarization of the receptor cell membrane.
• When the receptor cell is hyperpolarized, there is decreased release of either an
excitatory or an inhibitory neurotransmitter.
• If the neurotransmitter is excitatory, the response of the bipolar or horizontal
cell to light is hyperpolarization.
• If the neurotransmitter is inhibitory, then the response of the bipolar or
horizontal cell to light is depolarization.
• Inhibition of Inhibition=Excitation
• Cones have smaller outer segments, less visual pigment, and smaller, briefer
single-photon responses than rods.
• All of this makes cones less sensitive (but faster) than rods and they require
moonlight or greater levels of illumination to function effectively.
• Therefore, we use:
• rods to see by starlight (scotopic vision)
• both rods and cones in moonlight (mesopic vision)
• only cones for anything brighter than moonlight (photopic vision)
Meridional Divisions of the Retina
• The visual field is the environment seen by one eye (monocular field) or by
both eyes (binocular field).
• The vertical meridian divides the retina into nasal and temporal hemiretinae.
• The horizontal meridian divides the retina into upper and lower hemiretinae
(upper and lower quadrants).

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• The temporal hemiretina receives image input from the nasal visual field.
• It has ganglion cells that project to the ipsilateral LGB (which has 6
layers), layers 2,3, and 5.
• The nasal hemiretina receives image input from the temporal visual field.
• It has ganglion cells that project to the contralateral LGB, layers 1, 4, and
6.
Lateral Geniculate Body
• The LGB has six layers which the optic tract fibers terminate in a precise
retinotopic pattern.
• Each layer receives input from only one eye: layer 1 (most inferior), 4 and 6
(most superior) from the contralateral eye and layers 2,3, and 5 from the
ipsilateral eye.
Meridional Divisions of the Retina
• The upper retinal quadrants receive image input from the lower visual fields.
– It has ganglion cells that project via the LGB to the upper areas of the
calcarine fissure.
• Lower retinal quadrants receive image input from the upper visual fields.
– It has ganglion cells that project via the LGB to the lower banks of the
calcarine fissure.
Concentric Divisions
• Macular area is a small area surrounding the fovea that serves central vision
(high visual acuity) which contains cones and predominantly projects to the
posterior part of the visual cortex.
• Paramacular area is a large area surrounding the macular area that contains
predominantly rods. It projects to the visual cortex anterior to the macular
area.
• Monocular area represents the peripheral monocular field and projects to the
visual cortex anterior to the paramacular area.
Image Projection
• All information from the temporal side of the vertical line passing through a
given fovea enters the ipsilateral optic tract.
• All information from the nasal side crosses in the chiasm and enters the
contralateral optic tract.
• The result is that each optic tract “looks” at the contralateral visual field.
Visual Pathway
• The visual pathway transmits visual impulses from the retina to the LGB, and
from the LGB to the primary visual cortex (area 17) of the occipital lobe.
• This pathway consist of:
– Ganglion cells with constitute the ganglion cell layer of the retina with
axons that eventually form the optic nerve (CN II).
– They project from the nasal hemiretina to the contralateral LGB and
from the temporal hemiretina to the ipsilateral LGB.
Visual Pathway: Optic Nerve
• The optic nerve is a myelinated tract of the CNS and is really not a true nerve.

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• It is invested by the pia-arachnoid and dura mater and receives its blood supply
from the central retinal artery, pial arteries, posterior ciliary arteries, and the
arterial circle of Willis.
• It is surrounded by the subarachnoid space and is incapable of regeneration.
Visual Pathway: Optic Chiasm
• Optic chiasm is part of the diencephalon and lies dorsal to the hypophysis.
• It contains decussating fibers from the two nasal hemiretinae and non-crossing
fibers from the two temporal hemiretinae.
• It receives its blood supply from the anterior cerebral and internal carotid
arteries.
• Midsagittal transection or pressure results in bitemporal hemianopia
(pituitary tumor).
• Bilateral lateral compression results in binasal hemianopia (calcified internal
carotid arteries).
Visual Pathway: Optic Tract
• The optic tract contains fibers from the ipsilateral temporal hemiretina and
the contralateral nasal hemiretina.
• It contains pupillary reflex fibers and projects to the LGB and, via the
brachium of the superior colliculus, to the pretectal nuclei and superior
colliculus.
• The optic tract receives its blood supply from the posterior communicating
artery and the anterior choroidal artery.
• Transection results in contralateral homonymous hemianopia and in
transsynaptic degeneration of the ipsilateral LGB.
Visual Pathway: Lateral Geniculate Body
• The LGB is a thalamic relay nucleus that subserves vision.
• It receives fibers from the ipsilateral temporal hemiretina, which terminate on
layers 2,3, and 5.
• It receives fibers from the contralateral nasal hemiretina, which terminate in
layers 1, 4, and 6.
• The LGB projects via the geniculocalcarine tract, the visual radiation to the
primary visual cortex (area 17) (the stripe of Gennari marks the calcarine
cortex).
• The visual cortex is served by branches of the posterior cerebral artery and the
anterior choroidal artery.
• Destruction results in a contralateral homonymous hemianopia.
Visual Pathway: Geniculocalcarine tract (optic radiation)
• The optic radiation extends from the LGB to the calcarine sulcus, the visual
cortex (area 17).
• It receives its blood supply by branches of the middle cerebral artery, anterior
choroidal artery, and calcarine artery (a branch of the posterior cerebral
artery).
• Transection results in contralateral homonymous hemianopia.
• It contains two divisions: an upper and lower division (Meyer loop).
Visual Pathway: Visual (striate) cortex (area 17)

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• The visual or striate cortex is located on the banks of the calcarine sulcus and
receives retinal input via the ipsilateral LGB.
• The calcarine artery, a branch of the posterior cerebral artery supplies the
striate cortex.
Clinical Notes
Refractive Errors
• Emmetropia: normal; light focuses on the retina.
• Hypertropia: farsightedness; light focuses behind the retina and is corrected with
a convex lens.
• Myopia: nearsighted; light focuses in front of the retina and is corrected with a
biconcave lens.
• Astigmatism: curvature of the lens is not uniform and is corrected with a
cylindric lens.
• Presbyopia: is a result of loss of the accommodation power of the lens that
occurs with aging.
• The near point (closest-point on which one can focus by accommodation
of the lens) moves farther from the eye and is corrected with a convex
lens.
Accommodation
• Accommodation happens when contraction of the circular ciliary muscle
slackens the tension on the elastic fibers holding the lens, and the lens, which
has an intrinsic capacity to become rounder, assumes a more biconvex shape.
Refractive Errors
• Scotomas: abnormal blind spots in the visual fields. There are numerous types:
– Central scotomas
– Centrocecal scotomas
– Paracentral scotomas
– Ring scotomas
– Scintillating scotomas
Clinical Correlations
• Anisocoria (unequal pupils) is a condition in which the two pupils are not equal
and is present in 10% of the population.
• It is seen in Horner’s Syndrome and third nerve palsies.
• Argyll Robertson pupil (pupillary light-near dissociation) is the absence of a
miotic reaction to light, both direct and consensual, with preservation of miotic
reaction to near stimulus (accommodation convergence).
• This condition may be present in tertiary syphilis, diabetes mellitus, and lupus
erythematosus.
• A fixed and dilated pupil, ptosis, and a “down and out” eye due to pressure on
the ipsilateral oculomotor nerve.
• Contralateral homonymous hemianopia, due to compression of the ipsilateral
posterior cerebral artery, which serves the visual cortex.
• Papilledema (choked disk) is a noninflammatory congestion of the optic disk
caused by increased intracranial pressure.
• It is most commonly caused by brain tumors, subdural hematoma, and
hydrocephalus.

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• Papilledema usually does not alter visual acuity or result in visual field defects.
• It is usually asymmetric and will be greater on the side of the supratentorial
lesion.
• Ptosis is a drooping eyelid seen in may syndromes.
• Oculomotor ptosis is due to paralysis of the levator palpebrae (e.g.
transtentorial herniation).
• Oculosympathetic ptosis is due to paralysis of the Muller muscle as seen in
Horner syndrome.
• This is very light ptosis or pseudoptosis (e.g. Pancoast tumor—produces
Horner’s syndrome).
• Myasthenic ptosis is seen in myasthenia gravis.
• It usually increases with increasing fatigue and immediately improves
after an injection of a cholinesterase inhibitor (edrophonium).
• It is usually bilateral and asymmetric.

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