NEUROSCIENCE

LECTURE
SUPPLEMENT
Nachum Dafny, Ph.D., Professor
Department of Neurobiology and Anatomy
University of Texas Medical School at Houston

D. Homeostasis and Higher Brain Functions

 TABLE OF CONTENTS

Page

Hypothalamus: Structural Organization ..................................................................1

Hypothalamic Control of Pituitary Hormone .......................................................12

Central Control of the Autonomic Nervous System and Thermoregulation .........24

Central Control of Feeding Behavior.....................................................................34

The Limbic System: Anatomy, Pathways and Function of the Hippocampus ......41

The Limbic System: Anatomy, Pathways and Function of the Amygdala............54

Learning and Memory............................................................................................63

Sleep and Arousal ..................................................................................................70

i
 HOMEOSTASIS AND THE HYPOTHALAMUS:
STRUCTURAL ORGANIZATION

Patrick M. Dougherty, Ph.D.

.

I. Definitions.
Homeostasis is the process by which a steady state of equilibrium, or constancy, in the
body with respect to physiological functions and chemical compositions of fluids and tissues is
maintained. Physiological set points refer to the baseline level at which functions such as heart
rate, and at which chemical compositions such as plasma sodium concentration are normally
maintained. These set points are represented in the brain by specific discharge rates in neurons
dedicated to the monitoring and control of specific physiological processes. Thus, there are
groups of neurons dedicated to the control of heart rate, temperature, etc., by their set point
discharge rate. The hypothalamus has the greatest concentration of nuclei at which set points
are encoded, monitored and controlled, and so can be considered as the key brain region for the
control of homeostasis. Specific receptors and sensors throughout the body detect disruptions in
the normal balance of body functions and chemistry that are produced by stress stimuli that can
range from injury or infection to pain and emotional distress. This data is transmitted to the
central nervous system and affects the discharge rate of set point neurons in hypothalamic nuclei.
These changes in discharge rate results in altered hypothalamic efferent outflow and hence
change in the functions of regulatory systems that counteract the stress stimulus and restore
homeostasis. These effects include alterations in the functions of the autonomic nervous,
endocrine, and immune systems as well as alterations in behavior by hypothalamic influences on
limbic brain circuitry. Each of the target systems influenced by the hypothalamus return
feedback controls onto the hypothalamus completing a circuit and so establishing a homeostasis
system.

The H omeostasis System

feedback
Limbic Brain Nuclei

H YPOTH ALAM I C
Stress NUCLEI
Stimuli ANS NES

Peripheral Target
Tissues: feedback
muscles
glands
lymphoid cells

1
 Boundaries of the Hypothalamus
Superior
Hypothalmic Sulcus

Rostral
Anterior Commisure
Lamina Terminalis
Optic Chiasm Posterior (& Inferior)
Mammillary Bodies

Inferior
Median
Infundibulum Eminence Tuber Cinereum

II. Anatomy of the hypothalamus.

The role of the hypothalamus in regulation of homeostasis is essential for survival and
reproduction of the species. The importance of this function is underscored by the structural
organization and connectivity of the hypothalamus as almost every major subdivision of the
neuraxis communicates with the hypothalamus and is subject to its influence.

A. Boundaries. Landmarks that are visible on the ventral and medial (ventricular)
surfaces of the brain define the boundaries of the hypothalamus. The rostral boundary
visible on the ventral surface of the brain is formed by the optic chiasm while the
mammillary bodies define the posterior boundary. Between these structures the oval
prominence from the floor of the third ventricle is the tuber cinereum and
evaginating from this is the median eminence which then tapers into the
infundibular stalk which together form the inferior boundary of the hypothalamus.
On the medial (ventricular) surface of the brain other structures contributing to the
rostral boundary that are visible include the lamina terminalis and the anterior
commisure. Also visible on the medial surface of the brain is the hypothalamic
sulcus, which is the rostral continuation of the sulcus limitans that defines the
superior boundary of the hypothalamus. Finally, the internal capsule that is only
visible on coronal or horizontal sections of the brain forms the lateral boundary.

1. Zones. Immediately bordering the third ventricle, just inside of the ependymal
cell lining, is a thin layer of cells that comprise the periventricular zone. This
zone contains few distinct nuclei, but two that are very prominent are the arcuate
nucleus and the paraventricular nucleus, which are involved in neuroendocrine
and autonomic regulation. Immediately adjacent to this is the medial zone, which
is comprised of several cytoarchitectonically distinct nuclei that are listed below.
Nuclei in the medial zone are especially involved in the regulation of the
autonomic nervous system as well as involved in regulation of the neuroendocrine
system. Finally, the lateral zone, has few nuclei or clear landmarks, but contains
important fiber pathways such as the median forebrain bundle. Demarcated by the
fornix, the lateral zone is involved in regulation of the autonomic nervous system.
2
 Hypothalamic Zones

Periventricular
Fornix
Medial
Lateral

neuroendocrine systems
periventricular

enteric systems
medial

cardiovascular systems
lateral

2. Regions. Each of the zones described above are further subdivided into regions
based on rostrocaudal landmarks. The anterior region runs from the lamina
terminalis to the caudal aspect of the optic chiasm. The portion of the anterior
region that is rostral to the optic chiasm is often also referred to as the preoptic
region, however this distinction is now less emphasized. The next region that is
identified when proceeding caudally is the tuberal region. The margins of this
region include the areas that are above and including the tuber cinereum. Finally,
the posterior region is defined by the area above and including the mammillary
bodies.

3
 Regions of the Hypothalamus
Anterior Tuberal

Anterior Commisure
Posterior
Lamina Terminalis

Optic Chiasm

Infundibulum
Tuber
Cinereum
Median
Eminence Mammillary Bodies

3. Nuclei. There are eleven major nuclei in the hypothalamus. The functions of
many of these will be covered in further detail in later sections. However, a brief
note on the organization of these can be useful. The nuclei can be grouped based
on their locations in the hypothalamic zones and regions. Starting medially, the
paraventricular nucleus is located in the periventricular zone and runs rostro-
caudally through the anterior into the tuberal region. The arcuate nucleus also
has a portion located in the periventricular zone though it also extends laterally
into the medial zone. This nucleus sits in the floor of the tuberal region of the
hypothalamus. Both of these nuclei, along with the supraoptic nucleus, located
just above the optic chiasm in the anterior region of the medial zone extending
laterally into the lateral zone, have key roles in neuroendocrine regulation. The
paraventricular nucleus also has an important role in regulation of the
autonomic nervous system. Additional nuclei found in the anterior region of the
medial zone include the suprachiasmatic nucleus involved in circadian timing,
the anterior nucleus involved in control of the autonomic nervous system, and
the preoptic nucleus which also extends into the lateral zone and involved in
control of the autonomic nervous system. Additonal nuclei in the tuberal region of
the medial zone include the dorsomedial and ventromedial nuclei, which are
involved in control of behavior and of appetite, body weight and insulin secretion,
respectively. Nuclei of the posterior region of the medial zone include the
posterior nucleus, which is another autonomic nervous system control center,
and the mammillary nuclei, which are involved in control of emotional
expression and memory. Finally, the lateral tuberal complex in the tuberal
region of the lateral zone is involved in control of appetite.

4
 Nuclei of the Hypothalamus
Dorsomedial
Ventromedial
Arcuate

Anterior

Paraventricular

Preoptic

Suprachiasmatic Posterior
Supraoptic Mammillary

Nucleus Zone(s) Region(s)

Paraventricular Periventricular Anterior,Tuberal
Preoptic Medial, Lateral Anterior
Anterior Medial Anterior
Suprachiasmatic Medial Anterior
Supraoptic Medial, Lateral Anterior
Dorsomedial Medial Tuberal
Ventromedial Medial Tuberal
Arcuate Periventricular, Medial Tuberal
Posterior Medial Posterior
Mammillary Medial Posterior
Lateral Complex Lateral Tuberal

B. Circuitry of the Hypothalamus. The hypothalamus has the most complex circuitry
of any brain region. Like other brain areas there are neural interconnections. But
unlike other brain areas, there are also extensive non-neural communication
pathways between the hypothalamus and other brain regions and the peripheral world.

1. Neural Connections. The most noteworthy (and complex) feature of the neural
connections of the hypothalamus is that except for a few exceptions, they are
extensively bi-directional.

a. Limbic Circuits. These pathways are essential for the normal expression and
control of emotions, learning and reproductive behavior. The bi-directional
(afferent and efferent) pathways include the medial forebrain bundle, the
fornix, the stria terminalis and the ventral amygdalofugal pathway. The
medial forebrain bundle interconnects basal forebrain structures including
the septal nuclei and ventral striatum with hypothalamus and structures in the
5
 brainstem tegmentum including the locus ceruleus, the parabrachial nucleus,
dorsal motor nucleus of the vagus . The fornix interconnects the hippocampal
formation to the septal, preoptic and medial mammillary nuclei. The stria
terminalis interconnects the amygdala to the septal region and the
hypothalamus especially, the preoptic and ventromedial regions. Finally, the
ventral amygdalofugal pathway interconnects the amygdala, especially the
central amygdaloid nucleus with the septal region and the preoptic areas of
the hypothalamus. In addition to these bi-directional pathways, there are also
two uni-directional efferent limbic pathways from the hypothalamus. The
mammillo-thalamic tract projects from the mammillary

cortex

medial forebrain bundle

basal forebrain
amyg. hipp.

ventral
stria Ant.
amygdalofugal septum fornix Thal.
pathway terminalis n.

eye
Hypothalamus
mammill. mamillo-thalamic
retino-hypothalamic n. tract
tract
midbrain mammilo-tegmental
dorsal longitudinal tract
fasciculus
hypothalamic-spinal
spino-hypothalamic tract
tract spinal
cord

nuclei to the anterior nucleus of the thalamus. The anterior nucleus of the
thalamus in turn projects to the cingulate cortex, which completes the circuit
of Papez by projecting back onto the subiculum of the hippocampus. The
circuit of Papez was the first circuit proposed to mediate emotions and still is
considered one of the chief circuits of the limbic system. The mammillo-
tegmental tract projects from the mammillary nuclei to the brainstem
tegmentum and as far caudal as the lateral gray of the spinal cord.
b. Sensory and Autonomic Circuits. These pathways provide visceral and
somatosensory input to the hypothalamus and output of the hypothalamus to
control the autonomic nervous system. These pathways are especially
important for the control of feeding, insulin release and reproduction. The bi-
directional pathways in this circuitry include the medial forebrain bundle
noted as part of limbic circuitry above, as well as the dorsal longitudinal
fasciculus. Whereas the medial forebrain bundle runs laterally through the
brainstem and hypothalamus, the dorsal longitudinal fasciculus runs
6
 medially through the periventricular and periaqueductal gray matter. Both
pathways bring visceral and somatic input to the hypothalamus from the
nucleus of the solitary tract, the parabrachial nuclei, the reticular formation
and the periaqueductal gray. The medial forebrain bundle also brings
monoaminergic fibers containing noradrenaline and serotonin into the
hypothalamus from various brainstem nuclei including the raphe nuclei that
have key roles in modulating neuroendocrine functions. More rostral
projections of these monoaminergic fibers as well as peptide-containing
efferent fibers that originate in the hypothalamus and join the medial
forebrain bundle as it ascends into the orbital cortex, insula and frontal
cortex are involved in the control of motivation. Descending efferent
projections of the hypothalamus through these pathways terminate on
parasympathetic nuclei of the brainstem such as the dorsal motor nucleus of
the vagus. Uni-directional afferent input to the hypothalamus is derived from
the spino-hypothalamic tract and the retino-hypothalamic tract. The
spino-hypothalamic tract is a component of the anterolateral system of
somatosensory fibers that also includes the spinothalamic tract and provides
input concerning pain as well as input necessary for orgasm. The retino-
hypothalamic tract provides input to the suprachiasmatic nucleus that is used
to entrain circadian rhythms to the light-dark cycle. Finally, uni-directional
efferent pathways from the hypothalamus include the hypothalamo-spinal
tract, which projects onto brainstem and finally spinal preganglionic
sympathetic and parasympathetic neurons in the spinal intermediolateral cell
column, and a histamine projection to thalamus and cortex from the inferior
lateral tuberal region that regulates the sleep-wake cycle.

2. Neuro-Humoral Connections. Unlike any other brain structure the

hypothalamus both sends and receives information by way of the blood stream.
There are two pathways that comprise the neuro-humoral connections of the
hypothalamus.

a. The Pituitary. These pathways include the hypophyseal-portal system of

blood vessels that surround the median eminence, the infundibulum and
pituitary gland. The details of this system in neuroendocrine function will
comprise the third lecture of this section.

7
 Subfornical
Organ

corpus callosum Pineal

Gland
column of fornix

anterior
commisure
Hypothalamus
lamina terminalis
cerebellum

optic chiasm parabrachial

nucleus
pituitary

ventrolateral
Organum medulla

Vasculosum Median
Eminence

Area
Postrema

b. Circumventricular Organs. There are several sites at which the blood brain
barrier is highly permeable and at which specific transporters are present that
allow passage of chemosensory stimuli from the blood into the brain. For
example, the organum vasculosum of the lamina terminalis is the site at
which pyrogens such as interleukin-1 and tumor necrosis factor bind to
receptors that transport these molecules into the CNS and initiate the central
synthesis of prostaglandins. These in turn act on the anterior nucleus to initiate
a change in body temperature set-point resulting in fever. Passage of
hormones through both the organum vasculosum and the median eminence
is essential for normal feedback on the hypothalamus for neuroendocrine
control. The area postrema is the location of the chemotoxic trigger zone at
which emesis is induced by various toxins in the blood stream and that affect
the hypothalamus to induce taste aversion. Passage of peptides through the
subfornical organ are thought to participate in mechanisms of learning, while
passage of signals through the pineal body affects circadian and circannual
timing patterns.

III. Functions of the Hypothalamus

It has been highlighted several times in this section that the overarching function of the
hypothalamus is the integration of body functions for the maintenance of homeostasis. The
multiplicity of functions that are entailed in this level of integration should be intuitively
obvious. The table below lists many of these functions and the nuclear groups that are most
closely associated their execution.

8
 Nucleus Zone(s) Region(s) Functions
Paraventricular Periventricular Anterior, Fluid balance, Milk let-down, parturition,
Tuberal autonomic & anterior pituitary control
Preoptic Medial, Lateral Anterior Thermoregulation, Sexual Behavior
Anterior Medial Anterior Thermoregulation, Sexual Behavior
Suprachiasmatic Medial Anterior Biological Rhythms
Supraoptic Medial, Lateral Anterior Fluid balance, Milk let-down, Parturition
Dorsomedial Medial Tuberal Emotion (rage)
Ventromedial Medial Tuberal Appetite, Body Weight, Insulin regulation
Arcuate Periventricular, Medial Tuberal Control of Anterior Pituitary, Feeding
Posterior Medial Posterior Thermoregulation
Mammillary Medial Posterior Emotion and Short-Term Memory
Lateral Complex Lateral Tuberal Appetite and Body Weight Control

A. Thermoregulation, Neuroendocrine control, Feeding and Satiety. The details

concerning thermoregulation, neuroendocrine function, and control of feeding will be
the subject of later lectures.
B. Biological Timing and Rhythms. Circadian timing refers to the daily fluctuations
that occur in hormone levels, body temperature, sleep-wake cycle, etc.; while
circannual timing refers to fluctuations in function that occur on a yearly cycle. The
chief hypothalamic nucleus involved in this process is the suprachiasmatic nucleus
(SCN), which can be considered as the body’s master clock. The neurons in the SCN
have an intrinsic rhythm of activity that in the absence of light will re-cycle at 25 hour
intervals. Input to the SCN from the retinohypothalamic tract resets and entrains the
activity of SCN neurons to the daily 24 hour light-dark cycle. The SCN has
projections into multiple hypothalamic nuclei that control the specific functions that
show daily or annual rhythms. Thus, the SCN is considered as a master pacemaker
that regulates the functions of multiple intra- and extra-hypothalamic slave
oscillators. One extraordinary example of an extra-hypothalamic slave oscillator is
the induction of fetal circadian timing from the mother. A specific, and perhaps more
concrete example of this circuitry is illustrated by the regulation of melatonin
secretion. Activation of the SCN by light results in increased input to the
paraventricular nucleus, which in turn activates sympathetic pre-ganglionic neurons
in the T1-T2 spinal intermediolateral cell column. These neurons activate the superior
cervical ganglion which sends noradrenergic innervation into the pineal gland that
inhibits the release of melatonin. With the onset of darkness, this inhibition is
removed, and so melatonin secretion increases through a disinhibition process.

9
 Paraventricular Nucleus

corpus callosum Pineal

Gland
column of fornix

anterior
commisure

lamina terminalis
cerebellum

optic chiasm
pituitary

Superior Cervical
Suprachiasmatic Ganglion
Nucleus

Intermediolateral
Cell Column
(T1-T2)

There are two major classes of disorders in circadian timing, phase shifting and
entrainment failure, both of which manifest themselves as sleep disorders. The most
common phase shift disorder is the rapid time-zone change syndrome, or jet lag,
characterized by daytime sleepiness and nighttime insomnia. A second type of phase
shift disorder is delayed sleep phase syndrome commonly seen in adolescents and
possibly linked to an endocrine-mediated desensitization of SCN pacemakers to
phase-advancing stimuli. Finally, advanced sleep phase syndrome, characterized by
onset of sleep in the early evening followed by very early pre-dawn awakening is
commonly observed in the elderly. Entrainment failure is often, though not always,
observed in the blind. It is important to remember that the retino-hypothalamic tract
has nothing to do with vision and so can be preserved in the blind, and may also be
absent in those with vision.

It has become increasingly evident that circadian timing can have tremendous impact
on the susceptibility to disease as well as conversely, to the optimal timing of curative
therapy. Chronomobidity refer to the observation that certain disorders
characteristically show peak prevalence at particular times of the day, while
Chronotherapeutics is the application of therapies at the time of day when their
effects can be expected to have the greatest impact. The best current example of
effective chronotherapeutics is that treatment of seasonal affective disorder (a form of
entrainment failure) is successfully treated with bright light therapy only when
applied during the morning hours.

10
 Midnight

Rheumatoid Arthritis

Noon

IV. Summary

A. The hypothalamus is the key brain site for integration of multiple biologic systems to
maintain homeostasis. The three major systems controlled by the hypothalamus for
maintenance of homeostasis are the autonomic nervous system, the neuroendocrine system,
and the limbic system (behavior).

B. The broad scope of brain regions affected by the hypothalamus is reflected by a very
widespread extent of connectivity of the hypothalamus to other brain areas and by unique
neuro-humoral communication pathways.

C. One key function of the hypothalamus is regulation of body functions in concert to the daily
light:dark cycle.

11
 HOMEOSTASIS AND THE HYPOTHALAMUS II:
HYPOTHALAMIC CONTROL OF PITUITARY HORMONE

I. The Neuroendocrine System represents the second, and last, major efferent system of the
hypothalamus that we will consider in detail in this section. The third efferent system, the
limbic system, will be covered in the following section of the course. As many of you know
the information transfer in the hypothalamic-neuroendocrine pathways are unique in that they
are largely blood bourne as opposed to neurally mediated. Traditionally, the neuroendocrine
system has been considered in two parts, that part dealing with the posterior pituitary, or
neurohypophysis; and that part dealing with the anterior pituitary, or adenohypohysis.
However, it is increasingly clear that the immune system also has such an important effect on
neuroendocrine regulation that it must now also be considered as a special “diffuse”
neuroendocrine component.

Paraventricular nucleus

Supraoptic
nucleus
Hypothalamo-
neurohypophyseal
tract

Neurohypophysis
Inferior hypophyseal
Adenohypophysis artery

vein

A. The Posterior Pituitary. The posterior pituitary is often termed the neurohypophysis
because the hormones of this part of the pituitary are released directly from the axonal
endings of their source neurons into the circulation. The hypothalamic nuclei in which the
cell bodies of these neurons reside are the supraoptic and the paraventricular nuclei.
As we discussed in the previous lecture, both nuclei are composed of multiple cell types,
but it is only the large magnacellular neurons that produce the hormones and that send
axons into the neurohypohysis. The pathway from the hypothalamus to the posterior
pituitary is called the hypothalamo-neurohypophyseal tract. It is along this tract that
the hormones oxytocin and vasopressin (also called antidiuretic hormone or ADH) are
cleaved from their prohormones and prepared for release in vesicles along with their co-
peptides neurophysin I (oxytocin) and neurophysin II (vasopressin). Although the two
nonapeptides only differ by two amino acids, a given neuron produces only one or the
other type of hormone at a time, but not both simultaneously. Release of hormones into
the circulation of the posterior pituitary occurs following various neural stimuli and so

12
the functions of this portion of the neuroendocrine system is characterized by reflexes
with neural input and hormonal output.
1. Oxytocin has no diurnal rhythm but is released in three reflexes following the
influence of several different types of stimuli.
a. In the milk let-down reflex the tactile stimuli applied to the breast by the suckling
infant are transmitted to the hypothalamus by the spino-hypothalamic tract
directly to the preoptic and paraventricular nuclei to excite the magnacellular
neurons and so provoke the release of hormone into the circulation. Oxytocin
travels through the bloodstream acts on the mammary glands to cause milk release
so that about 13 seconds later milk enters the ducts of the gland. Other non-tactile
stimuli can also provoke this reflex including the sound of the baby crying, visual
cues, anxiety, and other stimuli that increase hypothalamic sympathetic tone.
b. During parturition oxytocin induces powerful contractions of the uterine
myometrium. Parturition itself is not induced by oxytocin, but the strength and
frequency of the contractions of labor are enhanced by oxytocin. Pressure on the
cervix or uterine wall are transmitted to the hypothalamus by the spino-
hypothalamic tract inducing hormone release as above which enters the blood
acting to enhance contractions and so closing a positive feedback loop. Once the
baby is born the cervical pressure is released and contractions cease. Synthetic
oxytocin (Pitocin) is often given to increase uterine tone and control uterine
bleeding following birth and after some gynecological procedures.

Spinohypothalamic
Tract

sperm transport
Oxytocin
milk let-down

uterine contractions

c. Oxytocin also produces contractions of the uterine myometrium and smooth

muscles of the male and female reproductive tract that are important for sperm
transport. The stimuli in this reflex are inputs from CNS sympathetic pathways
activated with sexual activity.

13
 Subfornical Organ
(Angiotensin II)
Organum
Vasculosum
(osmolality)

Medial Forebrain
Bundle (BP,O2)

Vasopressin permeability of collecting duct

2. Vasopressin acts on V2 receptors on the contraluminal surface of the distal tubular

epithelium primarily in the collecting duct of the kidney to increase permeability and
allow reabsorption of water and electrolytes into the circulation. Vasopressin has a
diurnal peak late at night and early in the morning and a trough in the mid-afternoon.
Sensors for plasma osmolality control the evoked secretion of vasopressin by
magnacellular neurons in the paraventricular and supraoptic nuclei of the
hypothalamus. The magnacellular neurons have intrinsic osmoreceptors in their
plasma membrane and also receive afferent inputs from osmo-sensitive neurons in the
organum vasculosum of the lamina terminalis. Sensors in the subfornical organ for
angiotensin II also stimulate the release of vasopressin. Angiotensin II in the blood is
elevated following the release of renin from the kidney in response to a decrease in
blood pressure. Finally, the carotid and aortic arch bodies that signal the
hypothalamus via the vagus and glossopharyngeal nerves via relay in the solitary
nucleus also detect a decrease in blood oxygen or pressure and promote the release of
vasopressin.
1. Disorders of the Posterior Pituitary
a. Oxytocin: No disorders have been acknowledged.
b. Diabetes Insipidus results due to insufficient vasopressin secretion in response to
normal physiologic stimuli (central or neurogenic diabetes insipidus) or due to
failure of the kidney to respond to vasopressin (nephrogenic diabetes insipidus).
Neoplastic or infiltrative lesions, pituitary or hypothalamic surgery, severe head
injuries, and idiopathic causes in that order most frequently cause central diabetes
insipidus. The second two may remit spontaneously due to revascularization of
the hypothalamo-pituitary stalk. The symptoms include large amounts of dilute
urine, dehydration and thirst. Treatment is by hormone replacement.
c. Syndrome of Inappropriate AVP Secretion (SIADH) is associated with some
central nervous system disorders including trauma, encephalitis, cerebrovascular
accident and acute psychosis. Some drugs, including vincristine some general
anesthetics and antidepressants release or potentiate the effects of vasopressin.
Elevated vasopressin also occurs in some tumors following ectopic synthesis and
release. Clinical signs include hyponatremia, edema, hypovolemic features,
hyperosmolality of the urine, and hyperlipidema. Treatment requires fluid
restriction and then identification and treatment of the underlying cause.
A. The Anterior Pituitary is an endocrine gland controlled by the hypothalamus in several
fundamentally different fashions than is the posterior pituitary. None of the six major
14
 hormones released by the adenohypohysis are of hypothalamic origin, rather all are
synthesized in cells embryonically derived from Rathke’s pouch in the anterior pituitary
itself and released directly into the blood stream. Releasing- and release-inhibiting
hormones

Ultrashort Loop
Feedback Paraventricular nucleus
-
Indirect Long Loop
-
Feedback
- Arcuate
nucleus
Supraoptic
Short Loop nucleus
Feedback
Releasing
hormone Tubero-infundibular
tract
+
- Superior hypophyseal
artery Neurohypophysis
Direct Long Loop Hypophyseal-portal
Circulating vein
Feedback hypophyseal
hormone
Adenohypophysis
+
Circulating
hormone
Target gland vein

that are synthesized in the arcuate, paraventricular, periventricular and supraoptic

nuclei of the hypothalamus control anterior pituitary hormone secretion. Parvocellular
neurons in these nuclei send their axons into the tubero-infundibular tract and
terminate on a capillary bed of the superior hypophyseal arteries located around the
base of the median eminence. A given parvocellular neuron may release one or more
releasing factor into these capillaries that coalesce into 6 to 10 small straight veins that
form the hypophysial-portal blood circulation which descends along the infundibular
stalk and forms a second capillary plexus around the anterior pituitary. The releasing-
hormones gain access to the five distinct types of target cells in the anterior pituitary from
this plexus and stimulate anterior pituitary hormone release back into the capillary bed
that then drains into the systemic circulation and transports the hormones to peripheral
target tissues. The target tissues are stimulated to produce final mediator hormones that
induce the physiological changes in peripheral tissues typical of each hormone. Control
of secretion of the releasing factors, pituitary hormones and peripheral endocrine
hormones is tightly inter-related in a set of feedback loops. The ultra-short feedback
loop is mediated by the hypothalamic releasing factors limiting their own release by a
type of autocrine effect on targets in the hypothalamus. Inhibition of releasing-factor
secretion by pituitary hormones comprises short loop feedback. Finally, peripheral
hormone inhibition of pituitary secretion comprises the direct long-loop feedback and
inhibition on hypothalamic secretion of the releasing factors comprises the indirect long-
loop feedback.
1. Growth hormone (GH) is secreted from somatotrophs, which comprise about half of
the cells in the anterior pituitary. GH release is characteristically pulsatile being very
low most of the day except following meals, exercise, during slow wave sleep, and at
other individualized intervals. GH is necessary for normal linear growth and greatly
influences intermediary metabolism by way of its induction of somatomedians
(insulin-like growth factors, IGF) from target tissues most notably including the liver,
15
 chondrocytes, kidney, muscle, pituitary and the gastrointestinal tract. The
hypothalamic regulation of GH secretion is illustrative of the mechanisms that govern
all hormones of the anterior pituitary. Release is controlled by Growth hormone
releasing hormone (GHRH) a 39 amino acid peptide that is primarily synthesized in
the arcuate nucleus.

Arcuate N Periventricular N.
_
α-Ad
DA + + NE
5-HT } GHRH 2hrs SOM DA
Enk + cAMP
_ _ +
+

+ _
GH
Gs Gi
Gq

IGF

GHRH release from the arcuate nucleus is stimulated by inputs from other brain
regions using the neurotransmitters norepinephrine, dopamine, serotonin,
acetylcholine and the enkephalins. Release of GHRH is inhibited by somatostatin and
very importantly, by the actions of GH and IGF. The regulation of GHRH release by
somatostatin is an example of ultra-short loop feedback, regulation of release by
GH is an example of short-loop feedback, and regulation by IGF is an example of
indirect long loop feedback.
2. Prolactin is necessary for lactation and is secreted by pituitary lactotrophs, which
constitute 15 to 20 percent of the cells in the normal pituitary. Control of prolactin
secretion by the hypothalamus is unique to that of the other anterior pituitary
hormones in that under normal circumstances it is restrained and not elicited.
Dopamine released from the arcuate and paraventricular nuclei acts on D2
receptors to increase adenylate cyclase in lactotrophs and inhibit prolactin release.
Increases in plasma prolactin induces increased levels of dopamine in the arcuate and
paraventricular nuclei and so establishes short-loop feedback.
3. Leutinizing hormone and follicle-stimulating hormone control the gonads in men
and women. These hormones are secreted by the gonadotrophs, which comprise about
10 percent of the adenohypophysis. Leutinizing hormone-releasing hormone
(LHRH) is the hypothalamic factor that controls release of the gonadotrophs and
primarily is released itself from the arcuate nucleus. Feedback regulation of LHRH
is provided by low levels of estrogen in females and by testosterone in males.
4. Thyroid-stimulating hormone (TSH) is secreted by about 5 percent of the cells in
the pituitary called thyrotrophs and regulates thyroid function. Thyrotropin-
releasing hormone (TRH) is found in the highest concentrations in the medial
division of the paraventricular nucleus. The thyroid hormones thyroxine (T4) and
triiodothyronine (T3) inhibit TSH production and release at the level of the pituitary
(short loop) and inhibit the release of TRH at the level of the hypothalamus (long
indirect loop).

16
5. Adrenocorticotropin (ACTH) controls glucocorticoid function of the adrenal cortex.
ACTH is produced by the corticotrophs that comprise the remaining 15 percent of
pituitary cells as part of the larger pro-opiomelanocortin gene product from which γ-
melanocyte stimulating hormone and β-endorphin are also derived. ACTH is released
in pulses with an overall circadian rhythm peak at around 4AM and a trough in the
early evening. Corticotropin releasing-factor (CRH) is the primary but not the only
hypothalamic factor that regulates ACTH release. CRH is primarily found in the
paraventricular nucleus. The release of both ACTH and CRH are inhibited by the
hormone cortisol secreted from the adrenal, and the release of both are strongly
stimulated by stress.
6. Disorders of every hormone of the anterior pituitary have been identified and are
characterized by either a hypo-secretion or over-secretion following various lesions,
trauma, or tumors.
a. Acromegaly and Gigantism results from excess GH in adults and in children,
respectively. More than a cosmetic disease, these conditions are associated with
multiple system problems such as headaches, poor vision, sinus congestion,
congestive heart failure, impotence, kidney stones, paresthesias, weakness, and
arthritis and is associated with a shortened life span.
b. Dwarfism results from insufficient GH in children, while decreased GH in adults
is usually cryptic. However, GH supplements are finding utility in restoring vigor
in aged individuals.
c. Hyperprolactinemia has many causes, is evidenced by hypogonadism and/or
galactorrhea, and associated with pituitary adenomas (the most common type of
functional pituitary adenoma), hypothalamic or renal disease.
d. Prolactin deficiency is evidenced by an inability to lactate and often the first sign
panhypopituitaryism resulting from pituitary infarction in the post-partum period
(Sheehan’s Syndrome)
e. Hypogonadotropic Hypogonadism occurs as a central, congenital or inherited
disorder (Kallmann’s Syndrome) and an acquired, secondary disorder. In
Kallmann’s Syndrome the LHRH-producing cells of the hypothalamus fail to
migrate during development from the olfactory placode into the brain. Acquired
deficits occur as a result of hyperprolactinemia (adenoma), anorexia, starvation,
and stress.
f. Hypergonadotropism can occur with pituitary tumors as well as from ectopic
hormone-producing tumors of the lung, liver and germinal cell lines.
g. Hypothyroidism can result due to failure of the thyroid gland (primary) or
following pituitary or hypothalamic disease (secondary). The primary form of the
disease will result in hypertrophy of the thyrotrophs that can result in pituitary
enlargement resulting in visual field deficits.
h. Pituitary (TSH-induced) Hyperthyroidism is usually not a cause of
hyperthyroidism but may occur in two conditions. First, pituitary macroadenomas
are associated with overproduction of the alpha subunit of TSH. Second, pituitary
resistance to thyroid hormone can occur.
i. Cushing’s disease is characterized by central distribution of adipose, muscle
weakness, purplish striae, hypertension, osteoporosis, fatigue and psychiatric
changes. Primary Cushing’s disease These usually are the result of
microadenomas of the pituitary in over 90 percent of cases and result due to
macroadenomas in most of the remaining cases. Ectopic ACTH production is not
17
 uncommon with some fast-growing tumors such as oat cell carcinoma of the lung,
but in these conditions the physical signs of hypercortisolemia are less
pronounced. Rather, hypokalemia, muscle weakness, weight loss and
hyperpigmentation characterize patients. Ectopic ACTH produced by slower
growing tumors show more characteristics of typical Cushing’s disease.
Overproduction of CRF is a rare cause of Cushing’s disease.
j. ACTH deficiency is also called secondary adrenal insufficiency. It may
reversibly occur following prolonged glucocorticoid administration.

Ectopic CRF
Cushing’s
Pituitary
Syndrome
Pituitary
ACTH Cushing’s
Syndrome

Tumor

corticosteroids

Adrenal
Cushing’s
Target Tissues
Syndrome

C. The Hypothalamic-Immune System-NeuroEndocrine Axis. Important bi-directional

interactions between the immune system and the nervous and neuroendocrine systems
have become defined over the past twenty years. These interactions account for
modification of immune system function by nervous system activity and contrawise,
modification of behavior, metabolism and neuroendocrine function by activity within the
immune system compartment. The cascade of behavioral responses induced by activation
of the immune system is termed the acute phase response, while the influence of brain
activity on immunity has been termed psychoneuroimmunology.
1. The acute phase response is a constellation of behavioral and physiological
changes that occur following invasion of the body by pathogens or tissue injury that
we know as “feeling sick”, and thus also called sickness behavior. One component of
the acute phase response we have already discussed is fever. Other components

18
 Pituitary

vagus ACTH TSH LH, FSH

adrenals thyroid gonads

autonomics

corticosteroids T3,T4 gonadal

hormones

Neuropeptide
Receptors
VIP
SP
Enk TRH
β-End ACTH Releasing Factor
CRH Receptors
NE Lymphocyte
Neurotransmitter Ach GH
Receptors 5HT GHRH

GH Prl β-End Enk ACTH TSH

Neuropeptides
Cytokines Released
Interleukins, Interferons
TNF

Infection
Inflammation
Injury

include an increase in slow wave sleep, anorexia, affective and cognitive impairment,
decreased social and sexual behavior and lowered pain threshold. Additionally, there
are changes in blood chemistry including an increase in C-reactive protein,
haptoglobin, serum amyloid A, α2-macroglobulin, fibrinogen, plasma zinc and
copper, and a decrease in plasma iron. These proteins are synthesized and released
from the liver following neural input that arises in the hypothalamus. These changes
are geared to reallocate energy resources to the generation of fever and the
proliferation of immune cells and to induce as hostile an environment to the invading
pathogens as possible. There are four primary cytokine mediators of this response.
a. Interleukin-1β (IL-1β) is the chief mediator of the acute phase response
following infection. There are two additional members of the IL-1 family, IL-1α
and IL-1 receptor antagonist, but neither of these have any effect in producing the
acute phase response. IL-1β exerts its effects within the CNS by induction of the
enzyme cyclo-oxygenase type 2 (COX2) in endothelial cells of the vasculature at
the circumventricular organs, especially the organum vasculosum of the lamina
terminals. Induction of this enzyme results in the generation of prostaglandin E2
(PGE2) that passes through the fenestrated blood brain barrier and binds to the
type 4 prostanoid receptor (EP4). Receptor binding raises cyclic adenosine
monophosphate in neurons of the hypothalamus and brainstem, most notably the
preoptic-anterior paraventricular, and A2 nuclei, which induces fever, activates
the neuroendocrine axis and stimulates hepatic acute phase protein synthesis and

19
 IL-1β
circulation
IL-1R1
endothelial cell complex

+
+ MAP kinases
COX-2
- & NK-κB pathways

PGE2

EP4 neurons in PVN, A2, POAH

G
G
s
+
AC

cAMP FEVER
(POAH)
+ corticosteroids
PKA

+
gene expression ACTH

+ +
Acute Phase + CRF
Proteins IL-6-R (PVN)
(PVN, A2)

release. An alternate mechanism that may contribute to other aspects of sickness

behavior is the binding of IL-1β to the receptors on the subdiaphragmatic vagus.
Projections from the nucleus tractus solitarius to the hypothalamus, hippocampus,
amygdala and other limbic sites are proposed to induce somnolence, anorexia,
irritability and cognitive impairment. This pathway and the

central release of PGE2 has also

been suggested to induce the
mirror-like CNS generation of
cytokines that is observed with
activation of the immune
system. The CNS sources of
cytokines, such as IL-1β,
interferons, and TNF are from
activated astrocytes, lie in the
figure at right, as well as from
microglia and neurons
b. Interleukin-6 does not induce
the acute phase response when
injected alone, yet nevertheless
is the most potent agent for
prolonged induction of acute
phase proteins when injected to
the brain of animals already
primed by interleukin-1. Most
20
 likely these effects are because
IL-6 receptor (IL-6R) is
expressed at low levels in non-
primed animals, but the receptor
is up-regulated during induction
of sickness responses. Thus, it
has been proposed

that IL-6 functions to sustain the acute phase response that is triggered by IL-1β.
Activation of the neuroendocrine axis by IL-1β and IL-6 results in elevated
plasma cortisol that in turn suppresses COX2 and IL-6R expression. This
feedback is essential for termination of the acute phase response as the illness
resolves.
c. The interferons (type I) and tumor necrosis factor. These agents are much less
potent than those above, yet play especially prevalent roles in the sickness
responses with viral and neoplastic illnesses.
d. Other hormones produced by lymphoid cells include a whole constellation we
have already discussed including GH, Prolactin, ACTH, TSH, β-endorphin
and enkephalins that may also be involved in the signal pathways between the
immune system and the CNS.
2. Psychoneuroimmunology refers to the pathways that underlie brain-induced
modifications of immune system function. These pathways include the
neuroendocrine system as well as inputs to all lymphoid tissues from the sympathetic
and parasympathetic nervous systems. Immunological responses can be conditioned
like any other biological response and so, components of many common diseases
ranging from asthma to cancer have been correlated to various behavioral traits.
a. Stress. Demographic studies of merchant marine from World War I detected high
early mortality rates from a variety of causes. This suggested the idea that chronic
stress is an immune suppressant. Cortisol was subsequently shown to be a
powerful direct inhibitor of all lymphoid process and so became a widely used
anti-inflammatory drug. Later stressful stimuli adequate to induce CRF release
from the hypothalamus were experimentally shown to result in immune
suppression. However, as research has progressed it has become clear that stress
per se is not always counter productive to immunity. Low levels of stress act to
redistribute lymphoid cells from storage compartments such as the spleen into the
circulation. Similarly, low levels of cortisol, such as those normally provoked by
infection, act to focus the immune response by creation of a type of lateral
inhibition so that only those cell lines with the most focussed epitopes and so
most strongly activated to proliferate continue to expand. Thus, the stress
response can be subdivided into eustress, which is beneficial to immunity, and
distress, which is immunosuppressive.

21
 EUSTRESS
-maintains homeostasis
-leukocyte redeployment promotes innate immunity
-increased cell-mediated immunity
-increased humoral immunity
-increased resistence to cancer and infection

DISTRESS
-disrupts homeostasis
-suppresses leukocyte trafficking and innate immunity
-decreased cell-mediated and humoral immunity
-increased incidence of cancer and infection

} recruitment baseline

stress
} redistribution

recovery

0-10 min 1-2 hr TIME 1-4 hr

EPI,NE CORT HORMONES EPI,NE,CORT

b. Circadian Susceptibility to Disease is a direct consequence of the nervous

system’s impact on immunological functions. The levels of hormones and tone in
the autonomic nervous system fluctuate through the course of the day.
Immunological function tends to be most suppressed early in the morning when
the body is at its lowest level of sympathetic tone and highest level of
adrenocorticotropic activity. In converse, immunological function is at its peak in
the evening as sympathetic tone peaks. Thus, as you progress in your career you
will frequently note that patients almost always feel their best in the early
morning hours and feel their worst in the evening. This same phenomenon also
underlies the fact that physical performance is best for most athletes in the
evening hours.
D. Summary
Secretion of the posterior pituitary hormones is directly from magnacellular neurons of
the paraventricular and supraoptic nuclei into the circulation. These neurons project
axons into the posterior pituitary via the

22
 Midnight

Rheumatoid Arthritis

Noon

hypothalamo-neurohypophyseal tract and terminate on a capillary bed of the inferior

hypophyseal artery. Control of release in this system is under neural control and so
this represents a reflex system with neural input and hormonal output.
2. Secretion of anterior pituitary hormones is driven by the influence of releasing- or
release-inhibiting hormones (factors) that are synthesized in parvocellular neurons of
the supraoptic, paraventricular, arcuate and periventricular hypothalamic nuclei.
These neurons project axons in the tubero-infundibular tract onto a capillary bed of
the superior hypophyseal artery at the base of the median eminence. These capillaries
coalesce into the hypophyseal portal veins, which descend to the anterior pituitary
and form a second capillary bed where the anterior pituitary hormones are released.
The anterior pituitary hormones diffuse to peripheral targets to provoke release of
endocrine hormones that induced tissue effects. Control of release in this system is
via feedback of releasing-hormones, anterior pituitary hormones, and peripheral
endocrine hormones onto hypothalamic and pituitary cells in a series of feedback
loops. This system thus represents a hormone-and neural-evoked and hormone-output
reflex.
3. The immune system provokes neural and neuroendocrine responses in an acute phase
“sickness” response to illness or injury. The immune system is also influenced by
neural activity.

23
 CENTRAL CONTROL OF THE AUTONOMIC NERVOUS SYSTEM
AND THERMOREGULATION

I. The Principles of the Central Regulation of the Autonomic Nervous System

A. Defining the Central Autonomic Network. Because many students have been led
to believe that the autonomic nervous system is relatively primitive, most have
concluded that normal regulation of this system occurs at ganglionic, or at best, spinal
levels. Thus, they are often quite surprised to discover that dysfunction of the brain is
typically accompanied by autonomic dysfunction that can be life-threatening. For
example, patients with spinal transection can have severe hypertensive crises
provoked by a full bladder, impacted colon, or even stroking of the skin. This is not to
say that the spinal cord and autonomic ganglia do not play important roles in
autonomic regulation. But, that the organization of autonomic output takes place at
supraspinal levels.
There is an extensive interconnection between sites receiving visceral inputs and
that control autonomic efferent outputs, between sites for the control of sympathetic
versus parasympathetic nervous system output, and between sites for autonomic
control and somatic, endocrine and limbic circuitry. Collectively, this set of
interconnections is termed the central autonomic network.
cranial nerve
visceral efferents + cranial nerve
visceral and
Brain somatic
afferents
+

spinal sympathetic &

parasympathetic
+/- -
efferents premotor and + dorsal horn
+ spinal visceral
preganglionic
neurons interneurons and somatic
afferents

Spinal Cord

B. Structure of the Autonomic Network. The central autonomic network is composed

of both hypothalamic and extra-hypothalamic nuclei. Some of these sites regulate
sympathetic outflow while others regulate parasympathetic outflow. This structure
was first revealed in lesion studies that revealed multisynaptic connections
descending from the hypothalamus and midbrain to preganglionic neurons in the
brainstem and spinal cord. Similarly, connections from various limbic brain
structures, most especially the amygdala, through the hypothalamus have been
demonstrated. The net result of this network in full operation is the induction of
autonomic responses to visceral and somatic stress stimuli, such as elevated heart rate
and blood pressure with the onset of pain. Alternatively, chronic hypertension in type
“A” or stressed individuals represents increased central autonomic outflow in
response to increased limbic system input. Hierarchy in the autonomic network
results in the loops from the brainstem to spinal cord being responsible for rapid
short-term regulation of the autonomic nervous system, hypothalamic-brainstem-
spinal cord pathways serving longer-term, metabolic and reproductive regulation, and
24
finally limbic system-hypothalamic-brainstem-spinal cord loops serving anticipatory
autonomic regulation.

1. Hypothalamic Structures. The single most important hypothalamic nucleus of

the central autonomic network is the paraventricular nucleus (PVN). There are two
broad morphological classes of neurons in the PVN that fall into three functional
categories. The magnacellular (big) neurons contain vasopressin and oxytocin and
project their axons into the posterior pituitary where these hormones are released
directly into the blood stream. The smaller parvocellular neurons in the PVN also
include a neuroendocrine-related subset that project to the median eminence where
they secrete releasing hormones into the hypophyseal portal blood stream for control
of anterior pituitary hormone secretion. More on these two functional groups will be
covered in the next section. The third functional group of neurons in PVN is the
group we are interested in regarding central autonomic control. There are three types
of pre-autonomic parvocellular neurons (Types A, B and C) separable based on
anatomic and physiologic criteria, as well as based on subnuclear location within the
PVN. Pre-autonomic PVN neurons project directly onto preganglionic autonomic
neurons in the dorsal motor nucleus of the vagus, the autonomic relay nuclei of the
brainstem (A5, rostral ventral lateral medulla) and even directly to the
intermediolateral spinal columns. These projections descend ipsilaterally

25
 CENTRAL AUTONOMIC NETWORK

anterior amygdala, hippocampus & septal n. posterior

hypothalamus cingulate, orbitofrontal, insular,& rhinal Cx hypothalamus

lateral mammillary
hypothalamus nucleus
Paraventricular Nucleus

rostral
dorsal motor ventral
nucleus of lateral
the vagus medulla (A5)

nucleus of raphe nuclei trigeminal

the soliatry parabrachial n. pars
tract central gray caudalis

spinal spinal
parasympathetic IML IML
outflow to column column sympathetic
tissues outflow to
tissues
through the brainstem and spinal cord with four points of decussation
(suprammammillary, pontine tegmentum, commisural part of the nucleus of the
solitary tract (the major one), lamina X of the spinal cord) so that ultimately
innervation is bilateral but with an ipsilateral dominance. Thus, the PVN unlike any
other brain site has direct influence over both sympathetic and parasympathetic
outflow. Furthermore, the PVN receives direct sympathetic and parasympathetic
afferent inputs from trigeminal pars caudalis (sympathetic) and the nucleus of the
solitary tract (parasympathetic). The PVN therefore is the only brain site in a closed
efferent-afferent reflex loop with both the sympathetic and parasympathetic nervous
systems. Other hypothalamic nuclei in the central autonomic network include the
dorsomedial nucleus, the lateral hypothalamic area, the posterior hypothalamic
nucleus and the mammillary nucleus. These nuclei send and receive projections
from the PVN, the dorsal motor nucleus of the vagus, the central gray matter, the
parabrachial nucleus, the nucleus of the solitary tract, the lateral and ventral medulla
and the intermediolateral spinal columns. The lateral hypothalamus is especially
involved in cardiovascular control as well as in control of feeding, satiety and insulin
release.

2. Extra-hypothalamic Structures. Numerous brain structures were itemized above

as innervation targets of the hypothalamic structures of the central autonomic
network. These extra-hypothalamic sites can be roughly divided into those associated
with control of the two components of the autonomic nervous system. The sites
associated with control of sympathetic outflow include the norepinephrine-containing
neurons of the dorsal mesencephalon (locus ceruleus) and the rostral and caudal
ventrolateral medulla (the A5 and A1 regions) and the serotonin-containing neurons
of the pontine and medullary raphe nuclei. The extra-hypothalamic sites associated
with control of parasympathetic outflow include the central nucleus of the
amygdala, the dorsal motor nucleus of the vagus, the nucleus ambiguus, the
raphe nuclei, the periaqueductal gray, and the parabrachial nucleus. Finally,
limbic cortices, including the cingulate, orbitofrontal, insular and rhinal cortices;
and the hippocampus influence both sets of autonomic outflow.

26
A. Circuitry for Hypothalamic Control of the Autonomic Nervous System. The
hypothalamus is interconnected with the remainder of the central autonomic network
by way of three major pathways: the dorsal longitudinal fasciculus, the medial
forebrain bundle, and the mammillotegmental tract.

1. The principal pathway of the hypothalamus in the central autonomic network is

the dorsal longitudinal fasciculus (DLF). The DLF originates in the region of
the paraventricular nucleus and descends along the most medial aspect of the third
ventricle through the periaqueductal gray and mesecephalic reticular formation.

MFB

Septal DLF
Nuclei

Hypothalamus

Mammillary Body

Amygdala
Mesencephalic
reticular formation
Pontine reticular Mammillotegmental
Tract Dorsal motor
formation
Raphe Nuceli nucleus of the
vagus
Nucleus
ambiguus to autonomic nuclei
of the spinal cord

The DLF continues caudally in the midline near the floor of the fourth ventricle
until the closure of the open medulla where it becomes internalized near the
central canal remnant. This position leaves the DLF in ideal position to innervate
the periaqueductal gray, the parabrachial nucleus, the mesencephalic raphe
nuclei, and the locus ceruleus rostrally and the dorsal motor nucleus of the
vagus, the nucleus ambiguus and the medullary raphe more caudally. The
centralized location of the DLF as it continues into the lower medulla and then the
spinal cord renders it in perfect location to innervate the parasympathetic and
sympathetic neurons of the intermediolateral spinal cord. As detailed above the
DLF projections are bilateral, though with an ipsilateral dominance, due to several
points of decussation. Afferent inputs from the periaqueductal gray, parabrachial
nucleus, and the locus ceruleus ascend through the DLF to the hypothalamus.

2. The medial forebrain bundle (MFB) is the primary route for input to the
hypothalamus from the septal nuclei and basal forebrain limbic structures. Inputs
from the amygdala and hippocampus, though first arriving to the hypothalamus by
way of the stria terminalis, ventral amygdalo-fugal pathway, and fornix,
ultimately join with the MFB and thereby gain access to the paraventricular
nucleus. The MFB also has fibers from the paraventricular nucleus that descend to
27
 innervate essentially the same nuclei as that by the DLF. Visceral afferents from
the nucleus of the solitary tract ascend from the brainstem into the hypothalamus
by way of the MFB. The MFB, like the DLF has several points of decussation so
that there is input to bilateral structures but with an ipsilateral dominance.

3. The mammillotegmental tract is less prominent than either the DLF or MFB
nevertheless, this pathway that originates in the mammillary nucleus sends
projections into the mesencephalic and pontine reticular formations that in turn
influence the activity of the brainstem autonomic nuclei listed above.
4. Somatic afferents ascend to the hypothalamus by way of the spino-hypothalamic
tract.

B. Disorders of Central Autonomic Control.

1. Autonomic Dyreflexia is a condition observed in about 85 percent of patients

following spinal cord injury above C6. Exaggerated autonomic reflexes,
especially sudden dramatic increases in blood pressure are provoked by
inappropriate stimuli, such as pressure on the bladder.
2. Riley-Day Syndrome (familial dysautonomia) is an autosomal recessive disorder
in Askenazic Jews associated with decreased tearing and sensitivity to pain and
absent fungiform papillae on the tongue. Episodic abdominal crises and fever are
very common as is orthostatic hypotension.
3. Shy-Drager Syndrome is a progressive degenerative condition of unknown
origin affecting cells of the central autonomic network in the brainstem,
intermediolateral cell column, locus ceruleus, dorsal motor nucleus of the vagus,
and other nuclei including the substantia nigra caudate nucleus, and cerebellum.
The presence of Lewy bodies in many of these areas suggests this syndrome may
be related to Parkinson’s disease, in which there is also often a high degree of
autonomic dysfunction. The hallmark sign is profound orthostatic hypotension
without a compensatory increase in heart rate.
4. Sudden Infant Death Syndrome is thought to be a developmental defect in the
central autonomic network of the brainstem involved with respiratory drive. An
abrupt increase in facial skin temperature related to the onset of periods of apnea
suggest there may be a broader developmental defect of central autonomic
control.
5. Horner’s Syndrome typically results following damage to the dorsolateral pons
or medulla and is characterized by a profound disturbance in sympathetic nervous
system function. A common cause of this type of lesion is thrombosis of the
posterior inferior cerebellar artery or following damage to the white matter of the
cervical spinal cord where the hypothalamic-spinal tract descends. The most
common signs in Horner’s syndrome are ipsilateral miosis, ptosis, anhidrosis and
erythemea.

II. The Central Autonomic Network and Control of Body Temperature. As noted above the
central autonomic network consists of three hierarchically ordered circuits or loops. The
mechanisms underlying the short-term brainstem-spinal loops are covered in physiology, and
the mechanisms underlying the limbic brain-hypothalamic-brainstem-spinal cord loops
mediating anticipatory and stress responses are the subject for discussion in the lectures you
will have on the limbic system. Thus, we will focus here on the mechanisms of the
intermediate length hypothalamic-brainstem-spinal cord loops mediating longer-term
28
autonomic reflexes. First we will consider the mechanisms of thermoregulation in detail and
in a lecture tomorrow we will discuss the mechanisms regulating the control of feeding.
A. The Hypothalamic Basis of Temperature Set-Point. Regulation of core
temperature is essential because most of the metabolic processes necessary for life are
strongly temperature-dependent. The normal body temperature set-point is primarily
determined by the activity of neurons in the medial preoptic and anterior
hypothalamic nuclei as well as by neurons in the adjoining medial septal nuclei.
Collectively this region is often termed the preoptic-anterior hypothalamus
(POAH). The second region that also plays a critical, though subservient role to the
POAH, in temperature regulation is the posterior hypothalamus.

1. Temperature-Sensitive Neurons. It was previously mentioned that the

hypothalamus is one of the few brain areas where CNS neurons reside that are
themselves directly sensitive to physical or chemical variables such as
temperature, plasma osmolality, plasma glucose, and various hormones. The
POAH has three types of neurons involved in determining the temperature set-
point, Warm-sensitive neurons, Cold-sensitive neurons, and Temperature-
insensitive neurons, that are defined by changes in discharge rate following local
warming or cooling of the POAH. Warm-sensitive neurons comprise about 30%
of the neuronal pool in the POAH. These neurons have a firing rate versus
temperature as shown in the diagram on the previous page. Change in temperature
below 37 degrees has little effect on discharge rate. However, as temperature rises
above 37 degrees the discharge rate of these neurons increases dramatically.
Activation of warm-sensitive neurons results in an activation of neurons in the
paraventricular nucleus (PVN) and lateral hypothalamus that result in heightened
parasympathetic outflow to promote the dissipation of heat. Cold-sensitive
neurons which are only about 5% of the cell population in the POAH, but more
prevalent in the posterior hypothalamic nucleus, have discharge properties
opposite that of
warm-sensitive neurons. The cold-sensitive neurons show low rates of discharge at
temperatures above 37 degrees, but increase firing rate steeply as temperature is
Cutaneous & Spinal
Warm Receptors
37oC Highest Skin Temperature

+ 5 spikes.s-1/oC

Pyrogens W Lowest Skin Temperature

TNF, IFN, IL-1,PGE2 _ Temperature

To PVN & lateral hypothalamus

increased parasympathetic outflow
W
To PVN & Posterior Hypothalamus
Increased Sympathetic Outflow
37oC
Cutaneous & Spinal _
Cool Receptors
+ C
+
Temperature
I o
37 C

29

Temperature
 lowered below 37 degrees. Increased discharges in cold-sensitive neurons results in
activation of neurons in the PVN and the posterior hypothalamus that increase
sympathetic outflow to promote the generation and conservation of heat. The relative
concentration of warm-sensitive neurons in the POAH that promote heat loss and of
cold-sensitive neurons in the posterior hypothalamus that promote heat generation has
resulted in the POAH often being termed as the heat dissipation center and the
posterior hypothalamus being labeled as the heat generation/conservation center.
The final group of neurons found in the POAH and posterior hypothalamus is the
temperature-insensitive neurons. These are by-far the most numerous of the neurons
in these nuclei, comprising greater than 60 percent of those in the POAH. Although
by definition not sensitive to changes in temperature these neurons play a crucial role
in heat generation/conservation as discussed below.
1. Neural Mechanisms of Temperature Set-Point. The master circuit in regulation
of body temperature is heat dissipation. The warm-sensitive neurons of the POAH
have intrinsic membrane receptors that are sensitive to changes in brain and blood
temperature above 37 degrees. These are non-specific cation channels that very
likely are related to the vanilloid (capsaicin-sensitive) family of thermoreceptors.
Warm-sensitive neurons also receive excitatory inputs from cutaneous and spinal
thermoreceptors. As illustrated above, inputs from cutaneous receptors induce a
leftward bias in the firing rates of hypothalamic warm-sensitive neurons, so that
baseline discharge rate is greatly elevated. Interestingly, though the firing rate of
these cells continues to grade with body temperature, the slope of this increase is
reduced. Thus, the drive to dissipate heat is actively driven by inputs from thermal
receptors. It is not clear that such is the case for heat generation and conservation.
Cool-sensitive neurons do not appear to have intrinsic temperature-sensitive
receptors. Rather, the increase in discharge observed in cool-sensitive cells with
cooling results from the decreases in discharge of the warm-sensitive neurons and
subsequent disinhibition so that the cool-sensitive neurons are now driven by
tonic inputs from the thermal-insensitive neurons. Thus, the temperature set-point
is principally a function of activity in warm-sensitive neurons of the POAH. The
short-term effects of output from both warm- and cool-sensitive neurons on body
temperature occur as a result of changes in autonomic tone to cutaneous arterioles
and so the amount of cutaneous blood flow. Changes in sympathetic outflow to
sweat glands and adipose tissue provide additional targets used for heat
dissipation and generation. Longer-term effects of these groups of neurons in
response to sustained changes in environmental temperature include the induction
of behavioral and neuroendocrine responses to changes in environmental
temperature.
B. Disorders of Thermoregulation.
1. Fever
“Humanity has but three great enemies: fever, famine, and war,and of these by far the
greatest, by far the most terrible, is fever.” William Osler.
The statement above highlights well the fact that fever has been a scourge battled by
physicians since antiquity. However, recently fever has become recognized as in fact only
one in a constellation of physiological adaptations that take place during infection
referred to as the “sickness-” or “acute phase response”. The sickness response includes
behavioral, cognitive, metabolic, and neuroendocrine adaptations that are all geared to
make the body less hospitable to pathogens and most primed for optimizing
immunological defenses. Thus, fever is initiated because most bacteria proliferate poorly
at temperatures above 39 degrees, whereas the function of lymphoid cells is optimal at
30
this temperature. Fever is initiated during infection following the activation of
macrophages and the subsequent synthesis and release of endogenous pyrogenic
substances including interleukin-1 (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-
6), and the interferons (IFN). These pyrogens enter the blood stream and exert their
effects in the CNS at the organum vasculosum of the lamina terminalis (OVLT). As
discussed in the previous section, the OVLT is one of several sites in the CNS where the
blood brain barrier is relatively permeable and so allows the brain to “taste” the internal
milieu of the body. The endothelial cells of the OVLT have receptors for the endogenous
pyrogens that when activated cause both the synthesis and release into the CNS of
prostanoids, in particular, prostaglandin E2 (PGE2) as well as the synthesis and release
within the CNS of IL-1, IL-6, TNF, and IFN. PGE2 gains access to the warm-sensitive
cells of the POAH immediately adjacent to the OVLT where it binds to surface receptors
and induces increases in cellular levels of cyclic AMP. The increased cAMP activates the
protein kinase A system resulting in reduced excitability of the warm-sensitive neurons
and lowering of their discharge rate. This allows the discharge rate of the cool-sensitive
neurons to increase thus, establishing a new, higher temperature set-point. The use of
antipyretics such as aspirin and indomethacin counteracts fever by interrupting the
synthesis of PGE2 through antagonism of the cyclooxygenase enzyme system in the
endothelium of the OVLT.
2. Heat Exhaustion. Prolonged exposure or over-exertion in very warm
environments can result in an excessive loss of fluids and electrolytes resulting in

Release of Pro-Inflammatory
Cytokines: IL-1, TNF, IFN, IL-6

Infection

Proliferation of immune cells is optmized

while bacterial growth is slowed. Infection
resolves. Increased PGE2 suppresses
warm cells which disinhibits cool
cells. Thermal set-point is raised.
Elevated set-point causes
shivering and warmth-seeking
behavior unitl core achieves new
set point. chill flush
40
set-point
temperature
39

38 core
temperature
37

Hours
fever fever
onset breaks

muscle cramps, dizziness, vomiting and fainting. In extreme conditions a degree

of hypotension can develop. However, heat exhaustion is distinguished from heat
stroke in that the body temperature set-point remains well regulated and the
mechanisms mediating heat dissipation are intact. Thus, the skin is cool and moist
and body temperature is normal or slightly below normal. Rest and replacement
of fluids and electrolytes quickly remedy this condition.
3. Heat Stroke. If heat exhaustion is not remedied it can progress to heat stroke.
Extreme hypotension will result in a drop in cutaneous blood flow and decrease in
perspiration. Core temperature will subsequently rise. If this rise is too severe the
brain’s normal functioning can be interrupted and control of the temperature set-
31
 point fails. This results in further deterioration of the heat dissipation mechanisms
and allows core temperature to rise further so that tissue damage ensues which
can lead to coma and then death. The heat stroke patient is in a medical
emergency and requires urgent lowering of core temperature, fluid and electrolyte
replacement. Hepatic damage is common in this condition and jaundice may
develop 1 to 2 days after admission. Acute oliguric renal failure may occur. The
development of coma and disseminated intravascular coagulation are very poor
prognostoic factors.
4. Malignant Hyperthermia is a group of inherited disorders characterized by
sudden and extreme increases in core temperature following exposure to gaseous
anesthetics including halothane, methoxyflurane, cyclopropane, or ethyl ether; or
following exposure to muscle relaxants, particularly succinylcholine. These
agents provoke an excessive release of calcium from the muscle sarcoplasmic
reticulum resulting in activation of myosin ATPase and so excess heat generation.
One form of the disease is inherited in an autosomal dominant fashion while a
second is inherited in a recessive manner in boys and less often in girls that also
have a number of other congenital abnormalities that comprise King’s syndrome.
Malignant hyperthermia also sometimes occurs with other myopathies such as
myotonia congenita and Duchenne’s muscular dystrophy. Some patients show an
elevated creatinin phosphokinase, but most are normal between attacks. Biopsied
muscle will show abnormal contraction on exposure to caffeine or gas anesthetic,
but this is obviously a clumsy manner to screen for the condition. Careful history
of surgical complications in relatives and identification of other contributing
conditions is the best way to detect and prevent malignant hyperthermia.
Occurrence is a medical emergency and requires immediate institution of the
treatment protocol prescribed by the American Society of Anesthesiologists. The
surgery and gas anesthetic is stopped, all tubing from the anesthetic devices are
changed, and external cooling is initiated. One hundred percent oxygen, 1-2mg/kg
sodium bicarbonate, and 1mg/kg dantrolene sodium are given. Drugs for cardiac
arrhythmias are given as needed.
5. Hypothermia is defined as a core temperature of 35 degrees or lower and
represents a potential medical emergency. Accidental hypothermia is common in
winter following prolonged exposure, not necessarily to excessively low
temperatures, and may accompany sepsis, hypothyroidism, pituitary or adrenal
insufficiency, hypoglycemia, myocardial infarction and the ingestion of drugs-
particularly alcohol. However, hypothermia can also occur in certain medical
conditions without exposure, including congestive heart failure, uremina, drug
overdose, acute respiratory failure, and hypoglycemia. Most of these patients are
elderly. Patients presenting with a core temperature of less than 26.7 degrees are
usually unconscious, miotic, bradypnenic, bradycardic, and hypotensive with
generalized edema. At core temperatures below 25 degrees patients are in coma,
areflexic and may appear in rigor mortis. However, no one is dead until they are
warm and dead! Treatment requires establishing an airway and providing oxygen.
Blood volume can be expanded with warmed glucose while the blood gases and
cardiac rhythm are carefully monitored. External warming is applied to the thorax
only so that the limbs remain vasoconstricted to prevent a precipitous drop in
blood pressure.

32
III. Summary

Heat Exhaustion

heat

cutaneous excess
vasodilation sweating

hypovolemia cold stress

metabolic disease
drugs, burns
cardiac blood age
output pressure

CNS impairment

insufficient inadequate
heat loss set-point
regulation

core core
temperature temperature

tissue
damage

coma

death
Heat Shock
Hypothermia

A. Several forebrain, diencephalic and brainstem structures are interconnected to organize the
output of the autonomic nervous system. Collectively, this is referred to as the central
autonomic network and is further organized into a hierarchy of functional loops.

B. The hypothalamus is the key brain site for central control of the autonomic nervous system,
and the paraventricular nucleus is the key hypothalamic site for this control. The major
pathway from the hypothalamus for autonomic control is the dorsal longitudinal fasciculus.

C. Regulation of body temperature is one example of hypothalamic control of brainstem and

spinal autonomic nuclei related to longer-term autonomic reflexes. Thermoregulation is
principally a function of warm-sensitive neurons of the preoptic-anterior hypothalamus that
directly control the dissipation of heat.

D. Fever is the most common disorder of thermoregulation. Fever is following the release of
endogenous pyrogens that elevate the level of prostaglandin E2 in the preoptic-anterior
hypothalamus, which causes a decrease in activity of warm-sensitive neurons and subsequent
disinhibition of cool-sensitive neurons.

33
 CENTRAL CONTROL OF FEEDING BEHAVIOR

I. Theories of Caloric Homeostasis.

Feeding by its nature is intermittent, yet glucose

CNS
oxidizes mainly
the need for energy in tissues is constant. glucose
TISSUES
ketones
Thus, mechanisms have evolved for the LIVER
oxidize glucose or
lipids

ebb and flow of nutrients after feeding and oxidizes lipids

stores carbohydrates
during the post-absorptive period; and the
ADIPOSE
maintenance of near-normal function Insulin stores lipid

during fasting. The remarkable stability of Pancreas

body weight in persons with access to
adequate food supplies is testament to the GI
Tract
precision by which metabolic needs are
monitored and maintained. Aberrations in
these controls can produce serious and
even life-threatening conditions. Two
major hypotheses have been put forward
to account for the process by which the
usual balance in caloric intake is
established.

Brain A. The Depletion-repletion

Hypothesis is essentially based on
Food Food
the idea of a caloric set-point. In its
Amount
Available
Types
Available simplest version individuals match
energy expenditure and energy
Food
Intake intake without reference to the level
Energy
Need
Nitrogen
Need
of fat storage. In more complicated
Caloric GI Tract Nitrogen models fat (energy) depots, and
presumably other nutrient depots,
Short-Term Content Content Short-Term
Energy Nitrogen
Storage Storage
Excretion
send signals to the brain about their
Long-Term
Energy
Long-Term
Nitrogen
current status. These inputs are
Storage Storage
compared to desired set points and
food intake and energy expenditure
are modified to effect adjustments
to the levels of stores. The best
evidence for this view is from small
mammals.
A. Glucose-responsive neurons that increase firing rate with glucose levels and
glucose-sensitive neurons that are stimulated as glucose levels fall have been
identified. Further, small mammals will habitually return to a body mass that is
appropriate for their age, stage of development and/or environment after a forced
perturbation. Thus, rats exposed to a period of food restriction or imposed
overfeeding (gavage) express a compensatory hyper- or hyophagia on return to ad

34
 libitum feeding. The current studies on leptin has heightened interest in this
potential mechanism.

B. The Primed Response Hypothesis essentially boils down to the idea that animals
will eat whenever an opportunity presents itself unless it is specifically inhibited.
Evidence in support of this idea comes from studies looking at the relationship
between caloric content in meals and feeding intervals. There is not a correlation
between the amount eaten in a meal and the interval to the previous meal. Rather,
the larger a given meal, the longer it will be to the next. This suggests that eating
is inhibited by satiety signals generated in response to a meal.
II. Mechanisms of Satiety. There are really two main issues in the concept of satiety.
The first concerns the mechanisms that contribute to the termination of feeding at
a given meal, while the second concerns the mechanisms that govern intracranial
intervals. These mechanisms overlap to a degree.
A. Neural Signals are essentially dependent on the vagus and involve both afferent
and efferent components. The afferent signals in the vagus conveyed to the brain
that function to limit meal size include information from stretch receptors in the
stomach wall, and sensors in the portal blood vessels for cholycystokinin (CCK),
glucose, osmolality and pH. All these stimuli limit meal size. You might recall
from lectures on sensory systems that vagal afferents synapse in the nucleus of the
solitary tract. In addition, the vagus sends afferents to the area postrema. These
sites send projections to the paraventricular nucleus to inhibit feeding. The vagus
also functions in an afferent capacity in that input from the vagus to the pancreas
mediates the cephalic phase of insulin release. The sight and smell of food
initiates activity in limbic cortex that in turn activates the central autonomic
network. Outflow to the dorsal motor nucleus of the vagus and finally to the
pancreas results in the first surge of insulin in the blood that accompanies a meal.
Two additional increases in plasma insulin later occur as food enters the gut (the
gastrointestinal phase) and then as nutrients enter the intestines (the substrate
phase). In fact, these stimuli also result in satiety as insulin not only promotes
energy storage but also acts as a humoral signal back to the brain for satiety.

B. Humoral Signals for satiety are an Anorexia Constant Feeding

extremely hot topic of research due to the

vast potential weight-control market. The
main factors in the blood that affect the
CNS to limit/promote feeding are insulin,
leptin, glucose, and CCK. Insulin, leptin
and glucose gain access to the CNS at the
circumventricular organs of the median
eminence and the area postrema and act on
specific receptors in neurons of the nuclear
cell groups adjoining these areas. Insulin
and leptin have received considerable recent
interest as the mediators of satiety signals
related to the caloric content of a meal and

35
 in relation to maintenance of a body weight
set point, respectively.

Chief among the CNS sites of action for

these compounds as discussed below is
the arcuate nucleus. CCK exerts its chief
effects on satiety in the periphery by an
action on the vagus to potentiate the
responses to glucose, pH, and osmolality
in the portal blood. As noted below CCK
is also a transmitter substance in the
CNS satiety network. However, this
CCK is induced from neurons in the
hypothalamus and does not originate in
the periphery.

36
II. The CNS Satiety Network
PVN
The Dual Center Hypothesis
evolved about fifty years ago when
it was demonstrated that bilateral
lesions placed in the region of the
DMH
ventromedial hypothalamus (VMH)
produced a condition of voracious Ach
appetite and resulting marked LHA
hyperphagia. These animals would
VMH
ultimately become remarkably
obese. On the other hand, bilateral
POMC/CART
lesions of the ventrolateral
NPY/AGRP

hypothalamus (VLH) produced an Arcuate N.

anorexic condition that resulted in
animals failing to feed and 5HT

ultimately wasting. The assumption R

a
behind this set of experiments was p
that there are specific feeding and h
e N
satiety centers. The conclusion in T
this set of experiments was that the S
feeding center was the VLH and the A
P
satiety center was the VMH.
Although this dual center hypothesis
Vagus
has proven useful, the CNS satiety (distension, CCK-a, portal
network has proven to be more glucose)
complex. More recent repeats of the
older lesion studies showed that in
fact animals with VMH lesions
would not eat continually until they
exploded, nor would the animals
with VLH lesions necessarily starve
to death. Rather, the VMH lesioned
animals would eat excessively until
they reached some new higher body
weight at which point they would
then reduce their food consumption
to maintain this new set point.

Likewise, once the VLH lesioned animals had dropped to some new level, they would
again eat normally to maintain the new lower body weight set-point. What these
studies indicate is that satiety and feeding is a balancing process between two major
groups of neurochemical pathways that ultimately govern the relative tone between
the sympathetic and parasympathetic components of the central autonomic network.
The main entry points for information to this network are both neural and humoral.
The neural inputs are from the vagus nerve via synapses in the nucleus of the solitary
tract and the area postrema as well as inputs from the raphe nuclei. These inputs

37
ascend in the medial forebrain bundle to the paraventricular and the lateral
hypothalamic area (LHA). The humoral inputs pass the circumventricular organs and
affect the area postrema and the arcuate nucleus. The arcuate nucleus projects into the
LHA and the ventromedial nucleus as well as to the paraventricular and dorsomedial
(DM) nucleus. The paraventricular nucleus returns inputs to the arcuate nucleus as
wellas to the VMH and LHA. There are no direct interconnections between the VMH
and LHA, rather these are processed through the DM.

B. Neurochemistry. Several peptides are involved in hypothalamic regulation of

feeding and body mass. These can be sorted based on their behavioral effects
into anabolic/orexigenic peptides that promote feeding and increase of body
mass or as catabolic/anorexigenic peptides. Each set of peptides includes
what appears to be a key signal molecule that promotes either feeding or
satiety as well as an antagonist of the opposing stimulus.
1. Anabolic/orexigenic peptides include neuropeptide Y (NPY), agouti-
related protein (AGRP), melanin-concentrating hormone (MCH), orexin,
and galanin. NPY is the key feeding-promoting neuropeptide and NPY-
receptor subtype 5 is the key site of action. NPY increases in the arcuate
nucleus within 6 hours of food deprivation. Of note the neurons that
express NPY in rodents also express receptors for leptin and insulin and so
are yoked to plasma-derived feeding signals. AGRP is an antagonist for
the anorexigenic peptides as it blokcs the MC3 and 4 receptors for γ- and
α-melanocyte-stimulating hormones, respectively.

Weight Loss
Weight Gain

Plasma Leptin & Insulin

Plasma Leptin & Insulin

arcuate neurons arcuate neurons

OB-Rb OB-Rb OB-Rb OB-Rb

POMC & CART NPY & AGRP POMC & CART NPY & AGRP

NPY AGRP CART γMSH αMSH

_ + _ _ _ +
+ +
NPY-R5 NPY-R5 MC3-R MC4-R
LHA PVN (parasymp) Arcuate? PVN (symp),VMH

Food Intake Feeding Efficiency Food Intake

38
 2. Catabolic/anorexigenic peptides include α-melanocyte stimulating
hormone (α-MSH), cocaine- and amphetamine-regulated transcript
(CART), glucagon-like peptides 1 and 2 (GLP-1, GLP-2) and prolactin-
releasing peptide (PrlRP). These peptides fall with food deprivation and
conversely rise with forced overfeeding. For example, corticotropin-
releasing factor (CRF) increases in the paraventricular nucleus (PVN) and
pro-opiomelanocortin (POMC) increases in the arcuate nucleus with
overfeeding. The key anorexigenic signals are α- and less so γ-MSH
acting at the MC4 and MC3 receptors, respectively. The antagonist in this
group for the orexigenic peptide NPY is CART.
III. Disorders of Feeding and Satiety
A. Obesity is characterized by an excess of adipose tissue, however, the exact
definition of “excess” is somewhat enigmatic. The simplest way to define
“excess” is that amount of adipose tissue that creates a health risk. The best index
at present is that this represents an amount of adipose tissue that puts an
individual 20% or greater above their ideal body weight. Using these criteria
somewhere between 20 and 40 percent of adults are obese with these rates over-
representative by minorities and the poor. Excess intake of calories is the usual
major contributor to obesity. Basal metabolic rate in a 70kg man is about 1500
calories/day, so anything above this in a sedentary, healthy individual will result
in weight gain. Another mechanism besides excess caloric intake that may
contribute to obesity is the lipoprotein lipase hypothesis in which an excess of
adipose tissue lipoprotein lipase preferentially stores lipid calories as adipose
tissue. Obesity has several important metabolic sequela that can contribute to
additional medical problems.
a. Hyperinsulinemia with hyper- or euglycemia. Insulin resistance may
develop due to an abnormal beta cell product, circulating antibodies or
tissue insulin insensitivity. Insulin insensitivity results due to a
combination of receptor and post-receptor defects in insulin action.
b. Hyperlipoproteinemia. Obesity is characterized by elevated VLDL and
elevated serum triglyceride and an increase in serum free fatty acid
turnover.
c. Hypertension, Hypoventilation (Pickwickian Syndrome) are often
observed in the obese patient. Other endocrine disorders may also develop.
A. Froehlich’s Syndrome is characterized by obesity, hypogonaotropic
hypogonadism and other variable features including diabetes insipidus, visual
impairment and mental retardation. It is thought to result due to a
hypothalamic lesion.
B. Anorexia Nervosa is a disorder almost exclusively seen in young, white
women of middle-class background, with a prevalence of as high as 1 per 100
being reported. Subclinical prevalence may be as high as 5 percent. Diagnosis
is made on a clinical basis as there is no diagnostic test. Patients observed to
be below about 80% of ideal body weight are suspect when no other medical
(psychological) causes can be identified. A disordered attitude toward eating,
food or weight that overrides hunger, ritualized exercise, amenorrhea,
bradycardia, hypotension, and hypothermia complete the usual clinical

39
 picture. Patients with anorexia are vulnerable to sudden death from ventricular
tachyarrhythmias. There is no specific treatment.
C. Bulimia is often considered a disorder related to anorexia nervosa. The
disorder is characterized by the episodic ingestion of large amounts of food in
a compulsive fashion (“ox-hunger”) coupled with the awareness that the
eating pattern is abnormal, that it cannot be stopped, and depression at
completion of the act. There is usually a morbid fear of becoming fat,
although body weight is usually in the normal range. Induced vomiting that
eventually becomes reflexive usually follows episodes of binge eating.
Patients frequently have additional behavioral/psychiatric abnormalities.

IV. Summary
A. Caloric homeostasis is maintained by a body weight set point. This set point is
at least in part maintained by a set of signals from peripheral energy stores
into the brain that stimulate feeding to maintain adequate stores of nutrients.
Feeding also appears to largely occur as a primed response whenever food is
available and that continues until inhibitory satiety signals are received in the
brain that are derived from a meal.
B. Satiety in a given meal and that determines the time to the next meal is
determined by neural and humoral signals. The neural signals come from the
vagus and include information concerning the size (stretch of stomach) and
caloric/nutrient content (portal glucose, plasma insulin, leptin).
C. The CNS satiety network is in fact a subdivision of the central autonomic
network. Thus, it includes the brainstem afferent and efferent relays for the
vagus as well as the brainstem sympathetic relays such as nuclear group A2
and the raphe system. The arcuate nucleus and less so the area postrema are
key sites for registration of humoral inputs to this network. Integrated activity
between the ventromedial, dorsomedial and lateral hypothalamic areas
ultimately is integrated at the paraventricular nucleus that determines a net
balance between the feeding promoting central parasympathetic circuitry and
the satiety-promoting central sympathetic circuitry.

40
 THE LIMBIC SYSTEM

Anthony Wright, Ph.D.

I. Introduction

Limbic System: Limbic is a Latin term which means border. Like the familiar word “limbo”, it
means an intermediate or transitional state, which is a border. In this case, the border is between
the neocortex and the subcortical structures (diencephalon). The limbic system includes the
hippocampal formation, amygdala, septal nuclei, cingulate cortex, entorhinal cortex, perirhinal
cortex, and parahippocampal cortex. These last three cortical areas comprise different portions
of the temporal lobe. (Some experts would also include parts of the hypothalamus, thalamus,
midbrain reticular formation, and olfactory areas in the limbic system.)

II. Hippocampus

The term hippocampal formation typically refers to the dentate gyrus, the hippocampus proper
(i.e., cornu ammonis), and the subicular cortex. A hippocampal formation is located in the
temporal lobe of each cerebral cortex, medial to the inferior horn of the lateral ventricle.

Hippocampus means seahorse in Greek. Each hippocampus looks like a seahorse due to the way
it is folded during development.

41
The hippocampus is also called cornu ammonis. Ammon was an Egyptian god, near whose
temple ammonia or the salt of Ammon was prepared. The hippocampus is also called Ammon’s
Horn because the two hippocampi bend around in the form of the horns of a ram.

Schematic drawing showing the major and surrounding structures of the limbic system.

42
 A. Overall Structure of the Hippocampus, Fornix, and Anterior Commissure

Structure of the hippocampus, uncus, crua, fornix, anterior commissure, precommissural fornix,
postcommissural fornix, and columns. (“Reprinted from The Human Brain, by John Nolte, 2002,
p. 573, with permission from Elsevier Science”)
The fornix is a “C “shaped tract (in sagittal section). The fornix begins as the bundle of fibers
called the alveus. The alveus is white matter consisting of mylinated afferents and efferents. As
the fibers of the alveus travel posteriorly, they aggregate medially to form the fimbria of the
fornix. Fimbria means fringe and in this case it is the fringe of the hippocampus. The fimbria
looks like a thick rubber band. The fimbria of each hippocampus thickens as it moves
posteriorly and eventually splits off from the hippocampus forming the crua or “legs”
(singular—crus) of each hippocampus. The two crua come together and form the hippocampal
commissure. The hippocampal commissure provides one of two major paths whereby the
hippocampi communicate with each other.

After the hippocampal commissure the single fiber bundle is properly referred to as the fornix.
The fornix continues in an arc to the anterior commissure.
The anterior commissure is important as a landmark because this is where the fornix splits into
three parts and goes to different structures:

1. The split just before the anterior commissure is called the precommissural fornix and this
branch goes to the area of the septal nuclei called the substantia innominata, to the
striatum, and to the cingulate cortex.
2. Some fibers from the fornix also pass through the anterior commissure to the
contralateral hippocampus. This is the second of the two major paths by which the
hippocampi communicate with each other.
3. The split after the anterior commissure is called the postcommissural fornix and this
branch goes to the mammillary bodies of the hypothalamus and the anterior nuclei of the
thalamus.

43
 B. Output Pathways of the Hippocampus

Outputs or efferents from the hippocampus pass directly from the subiculum to the entorhinal
cortex and amygdala or through the fornix to a variety of anterior structures. (“Reprinted with
modifications from The Human Brain, by John Nolte, 2002, p. 575, with permission from
Elsevier Science”)

It is important to remember that afferents and efferents of the hippocampus are bundled together
in the same paths. Thus, by knowing the output paths, for example, you will also know the input
paths, or vice versa. There are basically two major input/output routes: 1. Entorhinal cortex; 2.
Fornix.

The precommissural branch of the fornix connects to the area of the septal nuclei called the
substantia innominata. The name means “substance with no name.” But since it has a name
substantia innominata, it is a self-contradiction or oxymoron (like the term “cruel kindness”).
The substantia innominata is just beneath the globus pallidus and superior to the amygdala. The
substantia innominata is also called the nucleus basalis or the nucleus basalis of Meynert. This
name means base nucleus of Meynert. About 90% of the neurons in the nucleus basalis are
cholinergic neurons and have widespread projections to the cerebral cortex and back to the
hippocampus. The nucleus basalis may be the major source of cholinergic innervation of the
entire cerebral cortex, analogous to the raphe nuclei and locus ceruleus for serotonergic and
noradrenergic innervation, respectively. The nucleus basalis is additionally important because,
along with the areas of the hippocampus, these cholinergic neurons have distinct degenerative
changes with Alzheimer’s disease. No one knows what causes neural degeneration in
Alzheimer’s disease, but anatomically the disease is characterized by plaques and tangles. The
neurofibrillary tangles are cytoskeletal filaments, and the senile plaques are extracellular deposits
of B(eta)-amyloid protein

44
Other fibers of the precommisural fornix project to the lateral preoptic nuclei, ventral striatum,
orbital cortex and anterior cingulate cortex.

The postcommissural branch of the fornix connects to the anterior nucleus of the thalamus and
the mammillary bodies of the hypothalamus. The mammillary bodies are destroyed in
Korsakoff’s syndrome as the result of alcoholism and thiamine deficiency. Patients with
Korsakoff’s syndrome have profound difficulty forming new memories. Because the
mammillothalamic tract also goes to the anterior thalamic nucleus, the hippocampus can affect
the thalamus indirectly as well as directly.

The anterior thalamic nuclei in turn connect to the cingulate cortex. The cingulate cortex
projects back to the entorhinal cortex of parahippocampal gyrus, completing a “great” loop
called the Papez circuit. The Papez circuit like many other areas of the limbic system is involved
in learning and memory, emotion, and social behavior, and was originally (by James Papez) to
provide the anatomical substrate of emotional experience. The amygdala is now known to be
centrally involved in emotional experience. Its connections to the original Papez circuit are
shown in the next figure and the amygdala and emotion are discussed more thoroughly in the
next section.

The original circuit proposed by Papez is shown by thick lines and more recent connections are
shown by thin lines. Note the reciprocal connections between the hippocampal formation
and the association cortex, and the inclusion of the amygdala and prefrontal cortex

The hippocampus has direct connections to the entorhinal cortex (via the subiculum) and the
amygdala. These structures connect to many other areas of the brain. The entorhinal cortex

45
projects to the cingulate cortex. Therefore, the hippocampus can affect the cingulate cortex
through the anterior thalamic nucleus or the entorhinal cortex. The cingulate cortex, in turn,
projects to the temporal lobe cortex, orbital cortex, and olfactory bulb. Thus, all of these areas
can be influenced by the hippocampus.

HIPPOCAMPUS: FORNIX AND

ANTERIOR COMMISSURE
‹ SUBICULUM (Fibers Originate)
‹ FORNIX
– Alvius
– Fimbria
– Crus (Crua)
– Hippocampal Commissure
→Contralateral Hippocampus
‹ PRECOMMISSURAL FORNIX
→Substantia Innominata of Septal Nuclei
Nucleus Basalis of Meynert -- Cholinergic Neurons and Alzheimer’s
‹ ANTERIOR COMMISSURE
→Contralateral Hippocampus
‹ POSTCOMMISSURAL FORNIX
→Mammillary Bodies of Hypothalamus
→Anterior Nuclei of Thalamus
→Cingulate Gyrus
→Entorhinal Cortex
→Hippocampus -- PAPEZ CIRCUIT

C. Input Pathways of the Hippocampus

The medial section showing the right hemisphere. The line shows location of a cut through
the left hemisphere. A blowup of the cut surface through the hippocampus shows the relationship
of the hippocampal formation to the entorhinal and parahippocampal cortecies. Output
and input pathways through the hippocampus.

46
Inputs or afferents to the hippocampus. Major inputs come from the entorhinal cortex, which in
turn communicate inputs from the cingulate, temporal, orbital, and olfactory cortices and
amygdala to the hippocampus. (“Reprinted with modifications from The Human Brain, by John
Nolte, 2002, p. 575, with permission from Elsevier Science”)
The input paths are just the reverse of the output paths. The entorhinal cortex is a major source
of inputs to the hippocampus. In addition, the cingulate cortex, temporal lobe cortex, amygdala,
orbital cortex, and olfactory bulb all have inputs to the hippocampus via the entorhinal cortex.

The hippocampus receives inputs via the precommissural branch of the fornix from the nucleus
basalis of meynert, which is a portion of the substantia innominata and which in turn is a
portionof the septal nuclei. Also the hippocampus receives inputs via the postcommissural
branch of the fornix inputs from the mammillary bodies of the hypothalamus.

HIPPOCAMPAL AFFERENTS
‹ Entorhinal Cortex
– Receives Inputs from:
Neocortex
Cingulate Cortex
Temporal Lobe Cortex
Orbital Cortex
Olfactory Bulb
‹ Fornix
– Inputs return from Septal area and Hypothalamus
‹ Amygdala
‹ Contralateral Hippocampus

47
D. Structures and Processes within the Hippocampus

Structure of the hippocampus

The hippocampus proper and the dentate gyrus processes information that passes through the
hippocampus. These two structures, the hippocampus proper and the dentate gyrus, form two
interlocking “Cs.” The term dentate gyrus comes from the beaded or toothed appearance of this
structure resulting from the many small blood vessels from subarachnoid space that penetrate the
dentate gyrus. The hippocampus and dentate gyrus are actually cortex, but it is 3-layered cortex
rather than 6-layered cortex as in the neocortex. Because of the smaller number of layers and
their location between the neocortex and diencephalon, these cortices have been called
paleocortex, which means old cortex or archicortex which means ancient cortex. These terms are
misleading because they give the false impression that these cortices are antiquated remnants
left over as the brain evolved and became more complex. They are brain regions that have
actually continued to develop structurally and functionally throughout phylogeny.

The hippocampus and dentate gyrus, like the neocortex, have a superficial molecular layer and a
deep polymorphic layer, but because these structures are “inside-out” cortex, the molecular layer
is on the inside and the polymorphic layer on the outside. The middle layer of the hippocampus
proper is a pyramidal cell layer. The middle layer of the dentate gyrus is a granular layer. The
molecular layer of the hippocampus proper faces the dentate gyrus. The area of the hippocampus
proper that is capped by the dentate gyrus is referred to as CA3 (CA for cornu ammonis).

The polymorphic layer is the alveus and is equivalent to the white matter of the neocortex. The
subiculum is the transition layer from the hippocampus to the parahippocampal gyrus and
changes gradually from three to six layers.

48
The hippocampus coordinates information from a variety of sources. A major flow of
information through the hippocampus is a one-way circuit. Some inputs to the hippocampus
(perforant pathway) from the entorhinal cortex pass through to the dentate gyrus. From the
dentate gyrus connections are made to CA3 of the hippocampus proper via mossy fibers and to
CA1 via Schaffer collaterals. From these two CA fields information then passes through the
subiculum entering the alveus, fimbria, and fornix and then to other areas of the brain.

Slice through the hippocampal formation showing the location of CA1 and CA3
cells and the Dentate gyrus.

Information flows into and through the hippocampus by three principal pathways: 1. the
perforant pathway from the entorhinal cortex to granule cells of the dentate gyrus; 2. the mossy
fiber pathway from the granule cell of the dentate gyrus to the pyramidal cells of the CA3 region
of the hippocampus; and 3. the Schaffer collateral pathway from the CA3 region of the
hippocampus to the CA1 region of the hippocampus.

49
 Another view of the three-cell circuit of the hippocampal formation.

E. Mechanisms of Hippocampal function

1. Temporal Lobe Epilepsy

Identification of an epileptic seizure can be made through EEG (Electroencephalogram)

recordings. The EEG records from hundreds of thousands of neurons from scalp electrodes. A
few electrodes are placed on the scalp. Voltage differences are recorded relative to an reference
electrode some distance from the site.

The pyramidal cells of the middle layer of the hippocampus proper are the major input of the
EEG recording. The pyramidal cells have specialized structures for input called dendritic spines,
little spines that are attached to the dendritic shafts. The pyramidal cells are glutamate excitatory
neurons and are the major neurons that project to the cerebral cortex and are the major driving
force of temporal lobe epilepsy.

50
Schematic diagram of a CA1 hippocampal pyramidal neuron showing dendritic regions receiving
specific inputs from other neurons

Special Properties of Hippocampal Pyramidal Cells:

1. The dendrites are parallel to one another resulting in summation of extracellular current
flow and hyper-excitability seen in epilepsy.
2. The pyramidal dendrites are perpendicular to the cortical surface resulting in different
layers of cortex impinging at different points along the dendritic tree.
3. The pyramidal dendrites contain dendritic spines that amplify currents (inputs) so that
distant synaptic sites can more easily generate action potentials.
4. The pyramidal cells (dendrites) receive inputs from basket cells that regulate excitability
of the pyramidal cells through recurrent inhibition.

51
 Schematic diagram of the relationship between a pyramidal neuron, a basket cell,
and the resulting recurrent inhibition.

Pyramidal cells would be in a continuous bursting firing mode if there were no basket cells. The
diagram shows a cartoon pyramidal cell, axon, excitatory collateral to basket cell, basket cell,
and inhibitory connection to pyramidal cell. This simple circuit is what is called recurrent
inhibition. This is a general feature of nervous system. Collateral to special cell—the basket
cell. The pyramidal cell excites the basket cell. Excitation of the basket cell in turn produces
negative feedback or inhibition of the pyramidal cell. That is, action of the pyramidal cell acts
through the basket cell to regulate its own activity. The neurotransmitter of the basket cell is
GABA or gamma-aminobutyric acid, typical of most inhibitory neurons.

Epilepsy is a synchronous discharge of pyramidal cells. This synchronous discharge produces

stereotyped and involuntary jerking movements, loss of awareness, and in the most extreme case
convulsions and loss of consciousness. Next to stroke, epilepsy is the most common
neurological disease. Possibly as mush as 1% of the population is affected at one time or the
other.

Focal or partial epilepsy is restricted to a particular brain region. But an epileptic attack can
begin as a focal but spread to other cortex and become a generalized seizure.

For an epileptic seizure hundreds of thousands of neurons must be firing in synchrony. The way
this happens is a breakdown in postsynaptic inhibition. The importance of inhibition and the role
of the basket cell can be demonstrated by disabling the connection between the basket cell and
the pyramidal cell.

Picrotoxin, a GABA antagonist, will disable this junction and results in a cascade of excitation
and the synchronous activity of an epileptic seizure.
Also, examination of sections through the hippocampus in patients with temporal lobe epilepsy
has shown a loss of cells in the plexus surrounding pyramidal cells. This is where the basket

52
cells are located. Thus, there is a loss of the inhibitory input that is normally found there. The
brake on the system, that is control of the burst firing of pyramidal cells, has been removed when
the basket cells have been removed.
2. Long-term Potentiation
Long-term potentiation was discovered by efforts to determine how the hippocampus might
determine memory. Patient H.M. had just recently demonstrated that the hippocampus was
critical in lying down new memories. Researchers found that neural activity can modify synaptic
strength in certain areas of the hippocampus. This modified synaptic strength (LTP) may be a
storage mechanism for memory.

Long-term potentiation (LTP) as recorded in the Schaffer collateral pathway from the CA3
region to the CA1 region of the hippocampus. A single train of 100 impulses in one second to the
Schaffer collateral pathway increases the strength of the synaptic connection between CA3 and
CA1 neurons for more than one hour.

LTP in the Schaffer collateral pathway is different from LTP in the mossy fiber pathway. LTP in
the Schaffer collateral pathway depends upon a postsynaptic event—NMDA glutamate receptor

53
must be activated by the displacement of Mg2+ for LTP to occur. To initiate LTP in the Schaffer
collateral an especially strong signal is required—stronger than in the mossy fiber pathway.
Researchers have speculated that this stronger signal is like a the unconditioned stimulus (UCS)
that follows the conditioned stimulus (CS) in classical conditioning or like the reward that
follows the response in instrumental conditioning. Thus, they speculate that this LTP may be
associative LTP—possibly the type of LTP that forms the basis for learning and memory.

III. ANATOMY, PATHWAYS AND FUNCTION OF THE AMYGDALA

A. General Considerations
Amygdala is integrative center for emotions, emotional behavior, and motivation.
If the brain is turned upside down the end of the structure continuous with the hippocampus is
called the uncus. If you peal away uncus you will expose the amygdala which abuts the anterior
of the hippocampus.
Just like with the hippocampus major pathways communicate bidirectionally and contain both
efferent and afferent fibers.

B. Inputs to the Amygdala

Inputs or afferents to the amygdala via the stria terminalis, ventral amygdalofugal pathway,
olfactory stria, and directly from temporal lobe structures.

As was the case with the hippocampus, fibers carrying inputs to the amygdala are in virtually all
cases combined with fibers carrying outputs from the amygdala.
The amygdala receives inputs from all senses as well as visceral inputs. Since the amygdala is
very important in emotional learning it is not surprising that visceral inputs are a major input

54
source. Visceral inputs come from the hypothalamus, septal area, orbital cortex, and
parabrachial nucleus. Olfactory sensory information comes from the olfactory bulb. Auditory,
visual and somatosensory information comes from the temporal and anterior cingulate cortices.

C. Major Output Pathways of the Amygdala

1. Ventral amygdalofugal pathway

2. Stria terminalis
3. Directly to the hippocampus
4. Directly to the entorhinal cortex

Outputs or efferents from the amygdala via the stria terminalis, ventral amygdalofugal
pathway, and direct pathways

Ventral Amygdalofugal Pathway. The term “fugal” comes from the word fuge—to drive away—
as in fugitive. This pathway continues to the anterior olfactory nucleus, anterior perforated
substance, piriform cortex, orbitofrontal cortex, anterior cingulate cortex, and ventral striatum
including the nucleus accumbens septi. The ventral striatum in turn projects to the ventral
pallidum of the globus pallidus. These ventral striatum projections are links in a basal ganglia
circuit that are important in stimulus-response associative learning. In addition, the amygdala
has connections to the hypothalamus and septal nucleus through the ventral amygdalofugal
pathway, but its major connections to these structures are through the stria terminalis.

The ventral amygdalofugal pathway is important because it is a link whereby motivation and
drives, through the limbic system, can influence responses. It is also a link whereby responses

55
are learned. In this case this is the link whereby associative learning takes place. That is where
responses are associated with appetitive and aversive consequences that is rewards and
punishers.
The ventral amygdalofugal pathway also goes on to prefrontal cortex.
The ventral amygdalofugal pathway also makes links with septal nuclei and hypothalamus. This
is loop where the ventral amygdalofugal pathway meets the stria terminals, the other major
pathway.

Stria Terminalis

Stria is a Latin word that means line, groove, or band. Related to the word “Striated”.

Three simplifications:
1. The stria terminalis is similar in form, function, and location as the fornix for the
hippocampal pathway. Thus: The stria terminalis is to the amygdala as the fornix is to
the hippocampus.
2. The stria terminalis connects only to subcortical structures. (Connection to cortical
structures is through the ventral amygdalofugal pathway.)
3. The stria terminalis overlaps with the ventral amygdalofugal pathway in that it also
connects to the septal nuclei and hypothalamus and thus forms a loop.

Further similarities to the fornix:

Like the fornix, the stria terminalis has precommissural and postcommissural branches in
relation to the anterior commissure. The precommissural branch goes to the septal area. This is
exactly what the fornix does. The postcommissural branch goes to the hypothalamus. This is
exactly what the fornix does. Where as the postcommissural branch of the fornix projects to
mammillary bodies of the hypothalamus, the postcommissural branch of the stria terminalis
projects to the lateral nucleus and ventral-medial nucleus of the hypothalamus.
As in the fornix, some fibers enter anterior commissure cross to the contralateral side. They
enter the contralateral stria terminalis and project down to the contralateral amygdala. Just as in
the case of the two hippocampi communicating with each other through the anterior commissure,
the two amygdala communicate with each other through the anterior commissure.
The stria terminalis also projects to the habenuli, which is part of the epithalamus.

56
 AMYGDALA MAJOR PATHWAYS
‹ VENTRAL AMYGDALOFUGAL PATHWAY
→Nucleus Accumbens Septi (Ventral Striatum)
→Globus Pallidus (Ventral Pallidum)
→Basal Ganglia
→Dorsomedial Thalamus
→Prefrontal Cortex
→Anterior Olfactory Nucleus
→Orbital Cingulate Cortex
→Septal Area
→Hypothalamus
‹ STRIA TERMINALIS
→Septal Area
→Hypothalamus
→Habenula
→Contralateral Amygdala
‹ DIRECT CONNECTIONS FROM AMYGDALA
→Hippocampus
→Entorhinal Cortex

The central nucleus of the amygdala produces autonomic components of emotion (e.g., changes
in heart rate, blood pressure, and respiration) primarily through output pathways to the lateral
hypothalamus and brain stem.
The central nucleus of the amygdala also produces conscious perception of emotion primarily
through the ventral amygdalofugal output pathway to the anterior cingulate cortex and
orbitofrontal cortex.

D. More on Function of the Amygdala

Stimulation of the amygdala causes intense emotion such as aggression or fear.

Irritative lesions of temporal lobe epilepsy have the effect of stimulating the amygdala. In its
extreme form irritative lesions of temporal lobe epilepsy can cause a panic attack. Panic attacks
are brief spontaneously recurrent episodes of terror that generate a sense of impending disaster
without a clearly identifiable cause. PET scans have shown an increase in blood flow to the
parahippocampal gyri, beginning with the right parahippocampal gyrus. Similar but attenuated
blood flow increases occurs during anxiety attacks.
Destructive lesions such as ablation of the amygdala cause an effect opposite to the irritative
lesions of temporal lobe epilepsy. Destructive lesions of the amygdala cause tameness in
animals, and a placid calmness in humans characterized as a flatness of affect. Lesions of the
amygdala can occur as a result of Urbach-Wiethe disease where calcium is deposited in the
amygdala. If this disease occurs early in life then these patients with bilateral amygdala lesions
cannot discriminate emotion in facial expressions, but their ability to identify faces remains. The
anatomical area for face recognition and memory is in the multimodal association area of the

57
inferotemporal cortex. This is a good example of how emotion in one area (amygdala) is linked
with perception in another area (inferotemporal cortex) to create an intense emotionally charged
memory.

fMRI results showing amygdala activity in normals viewing facial expressions from happy
to fearful.

Flatness of affect is one of the symptoms of the previously mentioned Kluver-Bucy syndrome
where the entire temporal lobes of monkeys were removed. Actually,just lesions of the
amygdala were shown to be primarily responsible for flatness of affect. This work eventually led
to the psychosurgical technique of prefrontal lobotomies. Remember the movie with Jack
Nicholson, “One Flew Over the Cuckoo’s Nest.” The prefrontal cortex inputs into the amygdala.
By severing this input a flatness of affect is produced which was thought to be desirable in
schizophrenic patients who were aggressively violent or emotionally agitated.

The amygdala combines many different sensory inputs. Like the hippocampus it combines
external and internal stimuli. Every sensory modality has input. These are integrated with
somatosensory and visceral inputs—this is where you get your “gut reaction”. The link between
prefrontal cortex, septal area, hypothalamus, and amygdala likely gives us our gut feelings, those
subjective feelings, about what is good and what is bad.
It is also where memory and emotions are combined. When the reward is particularly sweet, that
behavior and association may last a lifetime. Likewise, the trauma and humiliation of
punishment may be remembered for a long time too.

58
Fear Conditioning: An Example of the Role of the Amygdala in Learning

Another example of emotion being linked to some perceptual experience is fear conditioning. In
this example the sensory experience is auditory rather than visual as in the emotion of faces.
Much of what we know about the amygdala and its role in emotional learning and memory
comes from fear conditioning, mostly but not exclusively conducted with animals. This is an
example of classical conditioning or Pavlovian conditioning. In the classic experiments
conducted by Pavlov just after the turn of the century, a neutral stimulus—a bell—was sounded
and after a brief interval food powder—the unconditioned stimulus—was placed in the dog’s
mouth. After a few such pairings the dog would salivate to the sound of the bell. The crucial
aspect of classical conditioning is that it is a pairing between two stimuli. No response is
required to get the reward. In fear conditioning, an organism hears a noise or sees a visual
stimulus. A few seconds, later it receives a mild shock. The reactions involve freezing, elevated
blood pressure and heart rate, and it gets twitchy—startles easily.

59
 Pathways of fear conditioning and emotional information.

Pathways from the thalamus to the amygdala are particularly important in emotional learning.
Output pathways from the central nucleus of the amygdala makes extensive connections with the
brain stem for emotional responses and extensive connections with cortical areas through the
nucleus basalis. Cholinergic projections from the nucleus basalis to the cortex are thought to
arouse the cortex.

The following diagram provides additional information on outputs controlled by the amygdala
during fear conditioning.

60
 Control and expression of different emotional responses by the amygdala.

Some pathways of fear conditioning have been discovered and this is a hot research topic in
neuroscience. If the auditory cortex pathway is lesioned, for example, basic fear conditioning is
unaltered, but discrimination is altered. In the discrimination procedure one sound is paired with
shock and another sound is not paired with shock. The animals had to rely solely on the thalamus
and amygdala for learning and they could not learn the discrimination; apparently the two stimuli
were indistinguishable.

So, the cortex is not needed for simple fear conditioning; instead it allows us to recognize an
object by sight or sound— to interpret the environment.

Thus, pathways from the sensory thalamus provide only a crude perception of the world, but
because they involve only one neural link they are fast pathways. Why might FAST be
important? We need a quick reaction to potential danger. The thalamus—amygdala pathway
provides us with this and may also prepare the amygdala to receive more highly processed
information from the cortex.

On the other hand, pathways from the cortex offer detailed and accurate representations of the
environment. Because these pathways have multiple neural links they are slow by comparison.
If for example we see a slender curled shape behind a tree its much better to jump back and later
recognize its a garden hose than to fail to quickly jump back if it were a snake. There is plenty
of time later to reflect that it was foolish to be startled in our own secure garden where there are
no snakes.

61
Fear producing visual stimuli are quickly processed by the thalamus and this information is
passed to the amygdala (red) producing a quick response (green) to danger. The thalamus also
passes the information to the cortex so that more careful (and slower) judgments can be made
about the real potential danger (from LeDoux).

The amygdala is involved in pleasureful emotional learning as well as fearful emotional learning.
Consider instrumental learning. Unlike classical conditioning where two stimuli are paired, in
instrumental conditioning responses are followed by reward and stimulus-response associations
are learned. There are thus three events: a stimulus, a response, and a reward. It has become
clear that all three pairwise combinations are learned in instrumental conditioning. Where the
amygdala comes in is that lesions of the basolateral nuclei of the amygdala disrupt the
association the stimulus and rewarding attributes of the food.

This amygdala memory system serves as an example of memory systems generally. The
establishment of memories is a function of the entire network, not any single component
The amygdala is involved in a kind of primitive emotional memory, one that is likely preserved
by evolution. According to the diagram of memory systems (e.g., Nolte, p.577), declarative
memory is mediated by the hippocampus and the cortex. But like the cortex, lesions of the
hippocampus have little effect on fear conditioning except in discriminating environmental
stimuli.

A study of patients with damage to the amygdala, hippocampus, or both clearly demonstrates the
distinctive roles of these two structures in memory. These patients were shown slides of green,
blue, yellow, or red colors. After some colors, a loud and frightening horn blast was sounded.
Autonomic responses were recorded (via GSR recordings) to determine learning. Amygdala
patients did not become conditioned to colors followed by the loud horn. But when asked how
many colors were presented and which were followed by the horn, their recall was correct. That
is, they had explicit memory about the events. On the other hand, hippocampal patients showed
learning and conditioning to the colors followed by the horn, but could not recall which they
were. That is, they had implicit memory about the events. Patients with both types of lesions
showed no conditioning and had no explicit memory about which colors were followed by the
horn. In the next lecture Dr. Crow will say more about explicit memory and the hippocampus.

62
 LEARNING AND MEMORY

Terry Crow, Ph.D.

Our nervous systems have the capacity for relatively long-term changes in function brought
about as a result of experience. Such changes are broadly defined as learning, or learned
modifications of behavior. One of the last frontiers of biological research is the identification
and understanding of the basic mechanisms of learning. The concepts of learning and memory
are related where memory generally refers to the persistence of learning that can be expressed at
a later time. There are many different systems or models of memory that have been proposed;
however, there are certain basic requirements for any memory system that must be met to be
effective. Information must be received by the nervous system and stored. Finally, when
needed, the information must be retrieved from storage. Retrieval refers to the utilization of
information previously stored in memory. The central nervous system does a remarkable job of
handling the requirements for such an information system. Studies of animal models of memory
and human memory systems have revealed that memory consists of several stages or processes
that have different temporal characteristics, anatomical substrates, and different mechanisms.
The major categories or stages of memory are indicated in Figure 1. The multi-stage memory
system consists of immediate memory, short-term memory, intermediate memory, and long-term
memory. Immediate memory is the ability to hold ongoing experiences for milliseconds to a few
seconds. Short-term memory is the ability to hold information for seconds to minutes.
Intermediate memory can hold information from minutes to hours depending upon the memory
63
task. The last stage or category is long-term memory which involves the retention of information
in a relatively permanent form of storage for days, weeks, or even over a lifetime. Immediate
memory may involve all sensory modalities, but has a limited capacity for storing information
and a high forgetting rate. Short-term memory also has limited capacity and rapid forgetting
rate, as does intermediate-term memory. Long-term memory is proposed to have unlimited
capacity and a relatively low rate of forgetting. A special type of short and intermediate-term
memory is called working memory, which refers to the capacity to hold information in order to
conduct sequential actions. Working memory involves multiple sensory modalities.

64
Studies of memory have identified two qualitatively different systems of information storage
referred to as declarative memory and procedural memory. Both of these systems are shown in
Figure 2. Memory can be classified as "knowing that" (declarative) and knowing how"
(procedural). Declaration memory refers to conscious recollections of facts and events, or
material that is available to consciousness and can be expressed by language. Nondeclaration
memory refers to our collection of abilities and skills, and is typically not available to
consciousness. Current evidence that will be discussed later in the lecture suggests that the
formation of declaration memory depends upon the integrity of limbic structures. Procedural
memory, including priming effects, the acquisition of motor skills, the acquisition of simple
associative learning, and the acquisition of nonassociative learning such as sensitization and
habituation. Priming refers to the influence of information on performance even when the
information is not recognized.

If information entering memory is not transferred into a more enduring form, it is forgotten.
Figure 3 shows the results of an experiment demonstrating that short-term memory can decay
fairly rapidly. When rehearsal of the information is prevented, then little is remembered after
approximately 10 seconds. The available evidence from studies of humans and animal models of
memory indicates that memory processes are time dependent in addition to the involvement of
memory in different phases.
65
Memories appear to be somewhat labile shortly after input into the nervous system and are thus
in a state where they are susceptible to interference. Figure 4 provides evidence that memories
require time to "consolidate". The figure shows a typical retrograde amnesia gradient obtained
from studies of memory disruption. As the interval between the time of training and
administration of the amnestic treatment (electroconvulsive shock) increases, the degree of
retention increases. Additional clinical evidence that supports the time dependency of memory
comes from studies of head injuries. Patients who suffer head injuries may have a permanent
loss of memory for experiences that occurred seconds, hours or sometimes days prior to the
injury. The length of the period for the memory impairment, termed retrograde amnesia, varies
with the severity of the injury.

Retrograde amnesia tends to be temporally graded such that the severity of amnesia is inversely
proportional to the age of the memory at the time of the treatment or injury. Figure 5 shows the
results of a test of memory administered to psychiatric patients who were receiving a series of
bilateral electroconvulsive therapy treatments (ECT). The memory test was given before the first
treatment and one hour after the fifth treatment. After five ECT sessions, patients exhibited a
selective impairment for material learned one to three years before the treatment. Paradoxically,
material in memory becomes resistant to disruption and also becomes gradually more difficult to
recall.

66
Figure 6 shows the different anatomical areas of the nervous system that have been implicated in
contributing to the formation of declarative and procedural memory. Normal declarative
memory formation requires structures in the medial-temporal region and diencephalon. Clinical
evidence suggests that structures involved in anterograde amnesia involving conscious memory
formation are the hippocampal formation, medial temporal lobe, and midline diencephalic areas.
In addition, studies of the neuropathology of Korsakoff's disease indicates that the mammillary
bodies, dorsal medial nucleus of the thalamus, and parts of the fornix may be involved in
memory disorders associated with the disease. Examples of procedural learning involve various
components of the motor system and structures associated with the limbic system for emotional
learning.

Perhaps the most extensively studied case of a human memory disorder is that of patient HM.
This patient was treated for intractable temporal lobe epilepsy. The surgical procedure involved
a bilateral removal of the temporal region including the anterior two-thirds of the hippocampus,
parahippocampal gyrus, uncus, and amygdala as indicated in the drawings shown in Figure 7.
Following the surgery HM exhibited a marked impairment in the ability to learn. The unique
characteristic of HM's disorder was an impairment in memory for events that occurred after the
treatment. This impairment is called anterograde amnesia.

67
The test of memory shown in Figure 8 emphasizes the distinction between normal short-term
memory and problems with long-term memory formation in H.M.’s deficit. Normal subjects can
extend their digit spans, typically requiring less than 15 trials to reach 20 digits. H.M. began
with a span of 6, and was unable to extend this, even after 25 trials.

Another example of anterograde amnesia associated with damage to limbic structures is shown
in Figure 9. Patient RB had an ischemic episode during cardiac bypass surgery. Following
recovery from surgery, RB exhibited memory deficits. RB had difficulty in transferring
information in short-term memory into long-term memory. A postmortem of RB revealed that
the cell bodies were absent in area CA1 of the hippocampus as diagrammed between the arrows
in Figure 9.

68
Amnestics may have difficulty in processing new information in short-term memory into a more
enduring form (long-term memory). Alternatively, amnestics may have difficulties in retrieving
information at the time of recall. The performance of amnestics is generally enhanced by
providing cues at the time of retesting, however prompting does not exert a unique effect on the
memory of amnestic patients as shown in Figure 10. Amnestic patients have available much
more information than they can produce by free recall, just as normals have more information in
storage. This type of amnesia appears to reflect the reduced capacity to store information in an
enduring form (long-term memory).

Figure 11 shows serial position curves for amnestic patients and control subjects. The serial
position effect refers to the ability to recall more words from the start and end of a list of items
than from the middle. The better recall of words from the beginning of the list (primacy effect)
is proposed to be due to greater rehearsal given to these words and to their relative protection
from interference. The better recall of words at the end of the list (recency effect) is due to the
fact that the words can be recalled from short-term memory. All subjects were read 10-word
lists and then requested to recall the items in any order. The percentage of items recalled plotted
as a function of position in the list is shown in the figure. Amnestic patients show the normal
recency effect but an impaired primacy effect. (Adapted from Baddeley and Warrington, 1970)

69
 SLEEP AND AROUSAL

Brainstem structures play a critical role in the sleep-waking cycle. An ascending brainstem
projection regulates the level of forebrain wakefulness. The ascending reticular activating system
(ARAS) maintains a state of wakefulness by its indirect projections to the cerebral cortex. The
output of the ARAS is to the diencephalon, where it divides into two branches. One branch
(thalamocortical system) projects to the midline, reticular nucleus, and intralaminar nuclei of the
thalamus, and these thalamic structures project to various areas of cerebral cortex. A second
projection extends into the posterior hypothalamus and forebrain. The projections of the
posterior hypothalamus are also to forebrain structures. Most of the ascending projections are
from the tegmental nuclei of the brainstem and are located in the central tegmental tract. The
brainstem aminergic nuclei project to cortex and hypothalamus. The diagram in Figure 1 depicts
the general area of the central core between the caudal midbrain and rostral pons containing the
tegmental nuclei of the brainstem making up the ARAS. The ascending arousal system sends
projections from brainstem and tuberomammillary nuclei of the hypothalamus throughout the
forebrain. Transection of the midbrain at a level between the superior and inferior colliculi
produces a forebrain that displays a continuous EEG pattern of high-voltage, slow-wave activity
typical of sleep. Transection at a level between the caudal medulla and spinal cord results in a
forebrain that exhibits normal cycles of sleep and waking. Originally it was believed that the
forebrain slept permanently because there was insufficient sensory input to arouse it. However,
more recently it was demonstrated that lateral tegmental lesions which severed classical
ascending sensory pathways did not alter sleep and wakefulness. Midline lesions that cut the
rostral projections of the ARAS produced a EEG pattern that resembled sleep.

70
Recent evidence using modern anatomical tracing methods has shown that the main origin of the
thalamic projection from the caudal midbrain and rostral pons is from the pedunculopontine
(PPT) and laterodorsal tegmental (LDT) nuclei; collectively tegmental nuclei. The cholinergic
neurons in these tegmental nuclei (PPT-LDT) project in a topographic fashion to intralaminar
thalamus, midline nuclei, and the reticular nucleus of the thalamus. The activity of PPT-LDT
neurons varies with different states of consciousness. During wakefulness, many PPT-LDT
neurons fire at a higher frequency. However, during sleep, few PPT-LDT neurons are active.
Neurons in the tuberomammillary nucleus, raphé, and locus coeruleus also project to cortex and
modulate the activity of forebrain neurons. Neurons in all three groups of nuclei are active during
wakefulness, and show reduced activity during non-REM sleep and little or no activity during
REM sleep. Neurons of the tuberomammillary nucleus contain histamine, neurons of the raphé
contain 5-HT, and neurons of the locus coeruleus contain noradrenaline. The descending
projections from the GABAergic ventrolateral preoptic nucleus are inhibitory (See Fig. 8).

The primary determinant in identifying stages of sleep is the electroencephalogram (EEG). The
EEG is a gross potential record of the fluctuations of the electrical activity of the brain recorded
from the surface of the scalp. Gross potentials recorded from the scalp result from extracellular
current flow associated with summated postsynaptic potentials in synchronously activated
vertically oriented pyramidal cells. Action potentials contribute little to the EEG except when
there is synchronous activity in large groups of neurons. The frequencies of potentials recorded
from the surface of the scalp vary from 1 to 30 Hz with amplitudes that range from 20 to 100 μV.
The frequencies vary although a few dominant frequencies are typically observed as listed
below.

alpha 8-13 Hz
beta 13-30 Hz
delta 0.5-4 Hz
theta 4-7 Hz

The awake state is typically characterized by either alpha or beta patterns.

71
 Using the EEG as an indicator, a number of stages in the pattern occur during sleep.
Examples of this pattern are shown in the recordings in Figure 3. Stages 1 through 4 of slow
wave sleep are characterized by progressively slower-frequency and higher-voltage activity. As
a person initially cycles into sleep, the EEG progresses gradually over a 30-45 minutes period
through stages 1-4 of slow wave sleep, and then emerges in reverse order over a similar time
span. Slow wave sleep is characterized by, relaxed muscles and a decline in heart rate and blood
pressure. Respiration declines and becomes even and the arousal threshold varies inversely with
EEG frequency. About 90 minutes after the onset of sleep there are a number of changes that
occur in tonic physiological measures. The EEG becomes desynchronized exhibiting low-
voltage, fast activity. Head, neck and general skeletal muscles are actively inhibited and EMG
measures are dramatically reduced. There is a concomitant loss of muscle tonus except for eye
and middle ear muscles. The rapid eye movements (REM) are the most prominent phasic event
that occurs during this period. The REMs appear to be driven by phasic bursts of activity which
can be recorded in the pons, oculomotor nuclei, lateral geniculate nuclei and visual cortices.

The phasic ocular movements are probably triggered by what are called "monophasic sharp
waves". The waves are also called PGO spikes since they are recorded from the pons, geniculate
bodies, and occipital cortices. In addition to the changes in tonic and phasic electrophysiological
measures, dreaming is associated with this sleep stage. This unique stage of dream related sleep
has been called "paradoxical" because of the presence of a "waking" EEG. Normal subjects
alternate between periods of REM and NREM sleep with REM stages recurring at approximately
90 minute intervals. Increasing REM length is associated with successive sleep cycles, as shown
in Figure 4. REM sleep occupies approximately 20-25% of the sleep period of young adults.

72
The stages of sleep form a cyclical patterns as shown in Figure 4. A. EEG recordings during
different stages of wakefulness and sleep. Each line represents 30 sec. The top recording of
low-voltage, fast activity is that of an awake brain; the next four represent successively deeper
stages of non-REM slow-wave sleep. Note that the stage 2 sample contains several characteristic
bursts of waxing and warning waves (sleep spindles) of 1-2 sec duration. Stage 1 REM sleep can
be distinguished from stage 1 non-REM sleep only by additional electrooculographic and
electromyographic criteria. B. A typical night’s pattern of sleep staging in a young adult. The
time spent in REM sleep is represented by a black bar. The first REM period is usually short (5-
10 min), but it tends to lengthen in successive cycles. Conversely, stages 3 and 4, which together
are often referred to as “delta sleep,” dominate the non-REM periods in the first third of the
night, but are often completely absent during the later, early morning cycles. The amount of
stage 2 non-REM sleep increases progressively until it completely occupies the non-REM
periods toward the end of the night. Note that in this example, because the morning awakening
interrupted the last REM period, the likelihood of a dream recall is good. If, instead, the REM
period had been completed and the sleeper had been awakened by an alarm clock from the next
stage 2 non-REM sleep, the chance of a dream recall would have been greatly reduced.

73
Positron emission tomography (PET) measuring regional cerebral blood flow during REM sleep,
shows activation of extrastriate visual cortices, attenuation of activity in primary visual cortex,
activation of limbic and paralimbic regions, and a reduction of activity in frontal association
areas. Figure 5 shows that activity is dramatically reduced during REM sleep in dorsolateral
prefrontal cortex and posterior cingulate cortex. However, activity in the anterior cingulated
cortex, amygdala, parahippocampal gyrus and pontine tegmentum is substantially increased
during REM sleep. The increase in limbic system activity, coupled with the decrease in the
influence of the frontal cortex during REM sleep may explain some of the characteristics of
dreams such as emotionality and often inappropriate social content.

74
Figure 6 shows that rapid eye movement (REM) sleep is associated with a membrane potential
depolarization in pontine reticular formation neurons. Continuous record of waking, non-REM
sleep, REM sleep, and return to waking in the cat. Waking is indicated by electromyographic
(EMG) activity, low-voltage fast-electroencephalographic (EEG) eye movements (EOG); and
non-REM sleep shows high-voltage slow-EEG waves. The transition to REM sleep is heralded
by the onset of spiky waves in the lateral geniculate nucleus EEG recording (PGO waves), and
with the occurrence of REM sleep, there is muscle atonia, low-voltage fast-EEG, PGO waves,
and rapid eye movements. The bottom trace is of the membrane potential (MP) of an
intracellularly recorded pontine reticular formation neuron with the action potentials filtered out;
in this example, the membrane potential depolarization begins before and remains throughout
REM sleep.

75
During the past 20 years, research has tried to localize the REM-generating mechanisms more
precisely within the pons. According to a model shown in Fig. 7, two classes of neurons (or
systems) are involved in the control of the REM-non-REM cycle.
(1) An aminergic system (“REM-off” cells) is located in the dorsal raphé nuclei
(serotonergic), the locus coeruleus (noradrenergic), and the nucleus peribrachialis lateralis
(noradrenergic). Cells in this system show their highest discharge rates during wakefulness, a
progressive decline during non-REM sleep, and very low or no discharge during REM sleep.
Neuronal firing in this brainstem system is inhibitory to postsynaptic neurons in the brainstem.
(2) A second cholinergic system that is not part of the pons-midbrain cholinergic system
(tegmental nuclei) may contribute to REM sleep. This cholinergic reticular system (“REM-on”
cells) is primarily located in the mesencephalic, medullary, and pontine gigantocellular
tegmental fields (FTG). When an animal is not moving, unit activity in these cells is opposite to
the “REM-off” aminergic system; lowest in waking, increased during non-REM, and highest
during REM sleep. Cells in this system appear to be cholinergic, and excitatory. The model
postulates that these two opposing systems continuously interact to produce the alternation
between non-REM and REM sleep (Adapted from Hobson, 1974).

76
As shown in Figure 8, the tegmental cholinergic and aminergic networks responsible for the
awake state are periodically inhibited by GABAergic neurons in the ventrolateral preoptic
nucleus (VLPO) of the hypothalamus. Activation of VLPO neurons are proposed to contribute
to the onset of sleep, and lesions of VLPO neurons produce insomnia. Both aminergic and
tegmental cholinergic systems are active during the waking state and suppress REM sleep.
Decreased activity of the aminergic and tegmental cholinergic systems results in the onset of
non-REM sleep. In REM sleep the second cholinergic system (FTG cells) (See Fig. 7) exhibits
increased activity similar to the awake state as summarized in Table 1.

A summary of activity in brainstem and diencephalic structures contributing to sleep and

wakefulness is shown in Table 1. Neurons in the tegmental nuclei, locus coeruleus,
tuberomammillary nuclei and raphé nuclei are active during wakefulness. The same nuclei show
decreased activity during non-REM sleep. Neurons in the tuberomammillary nuclei, locus
coeruleus and raphé are inactive during REM sleep.

77
Figure 9 shows REM sleep as a percentage of total sleep time in infants born 10 and 5 weeks
prematurely, at full-term birth, and in children and adults at the indicated years of age. Notice
the dramatic decline of REM sleep during early life and the long plateau during maturity, with a
decline observed only in the seventh decade.

78
As shown in Figure 10 the duration of stage 4 sleep changes with age. The graph shows stage 4
(i.e., delta) sleep in minutes as a function of age. There is little delta wave activity at birth,
presumably reflecting cortical immaturity. Delta wave activity peaks between 3 and 5 years of
age and declines exponentially thereafter.

The results of sleep deprivation studies have shown that there is marked lengthening and
increased frequency of REM periods during recovery. This phenomenon is called "REM
rebound" or "REM compensation". With more prolonged deprivation there is a larger and longer
REM rebound. These results are shown in Figure 11 adapted from a study by Dement.

79
 SUMMARY OF SLEEP DISORDERS

Insomnia
Insomnia is the chronic inability to obtain the necessary amount on quality of sleep to
maintain adequate daytime behavior. Insomnia encompasses many disorders, many of which are
poorly understood. The two most common causes of insomnia are disruption of normal
circadian rhythms and the inevitable consequence of aging. In addition, emotional disturbance
such as depression may affect sleep. Many hypnotic drugs used to treat insomnia may also lose
effectiveness within two weeks. In addition, most patients show rebound insomnia when
withdrawn from hypnotics. Many hypnotics, especially barbiturates, severely suppress REM
sleep and drug withdrawal is associated with REM rebound.

Somnambulism
Somnambulism or sleepwalking is associated with the non-REM phase of sleep. It
occurs most frequently in stages 3 and 4 of sleep. Somnambulism is more common in children
than adults, and its decline with age parallels the normal decrease in the proportion of sleep time
in stage 4 non-REM sleep. An example of EEG activity associated with an episode of
sleepwalking is shown in Fig. 12.

Electrooculogram (EOG), electromyogram (EMG), and EEG records of a sleepwalking incident

observed under laboratory conditions. A high-voltage, slow-wave EEG pattern commences as
the sleepwalker sits up in bed, and non-REM sleep patterns are maintained throughout the
episode. (Adapted from Jacobson et al., 1965).
80
Sleep Apnea
Sleep apnea is a disturbance of sleep characterized by the frequent periodic cessation of
respiration. It is unlikely that sleep apnea represents a unitary disorder. In some cases, the shift
from wakefulness to sleep is associated with a suppression of activity in the medullary
respiratory center.

Narcolepsy
Narcolepsy is an irresistible sleep attack lasting 5-30 min during the day, which may
occur without waking and at behaviorally inappropriate moments. Narcoleptics often exhibit an
abrupt loss of muscle tone, cataplexy, and visual and auditory hallucinations at the beginning of
sleep. These symptoms may reflect the intrusion of the normally inhibited properties of REM
sleep into the waking state. Narcoleptic patients can enter directly into REM sleep as shown in
Fig. 13.

Sleep onset in the normal person is typified by a gradual change from a waking EEG dominated
by alpha activity (10 Hz) to mixed lower frequency patterns coupled with the development of
slow, rolling eye movements in the electrooculogram (EOG) and little change in the
electromyographic (EMG) recording of muscle tonus. In the narcoleptic as shown in B, sleep
onset is actually preceded by several seconds of markedly reduced EMG activity (indicated by
brackets on EMG trace) and then accompanied by conjugate (both traces) rapid eye movements.
Sleep-onset REM usually lasts 10-20 min, after which, if the narcoleptic remains asleep, there
follows a typical progression through stages 1 to 4 of non-REM sleep. (Adapted from Dement,
Guilleminault, and Zarcone, 1975).

81
Orexins are neuropeptides homologous to secretin that are found in neurons of the lateral
hypothalamus. As shown in Figure 14, orexin neurons innervate all of the components of the
ascending arousal system and cortex. Thus, orexin might help maintain wakefulness by
increasing the activity of the ascending arousal system. Studies of orexin knockout mice have
suggested that loss of orexin signaling via the type 2 receptor is sufficient to produce symptoms
of narcolepsy. The loss of excitatory input to nuclei that inhibit REM sleep would allow for
earlier and more frequent transitions to the REM state.

82