Homeostasis And Higher Brain Functions

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 Limbic Brain Nuclei

Stress Stimuli

feedback

H YPOTH ALAM I C NUCLEI ANS

NES

Peripheral Target Tissues:

feedback

muscles glands lymphoid cells

1

Boundaries of the Hypothalamus Superior Hypothalmic Sulcus

Rostral Anterior Commisure Lamina Terminalis

Posterior (& Inferior)

Optic Chiasm

Mammillary Bodies

Inferior Infundibulum

Median 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 Medial

Fornix

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

Posterior

Anterior Commisure

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 rostrocaudally 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 Mammillary

Supraoptic

Nucleus Paraventricular Preoptic Anterior Suprachiasmatic Supraoptic Dorsomedial Ventromedial Arcuate Posterior Mammillary Lateral Complex

Zone(s) Periventricular Medial, Lateral Medial Medial Medial, Lateral Medial Medial Periventricular, Medial Medial Medial Lateral

Region(s) Anterior,Tuberal Anterior Anterior Anterior Anterior Tuberal Tuberal Tuberal Posterior Posterior 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.

ventral amygdalofugal pathway

hipp.

stria terminalis

Ant. Thal. n.

fornix

septum

eye

Hypothalamus mammill. n.

retino-hypothalamic tract midbrain

dorsal longitudinal fasciculus spino-hypothalamic tract

mamillo-thalamic tract

mammilo-tegmental tract hypothalamic-spinal 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 mammillotegmental 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 bidirectional 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 retinohypothalamic 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 Pineal Gland

corpus callosum

column of fornix

anterior commisure

Hypothalamus

lamina terminalis cerebellum

parabrachial nucleus

optic chiasm pituitary

Organum Vasculosum

ventrolateral medulla

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 Paraventricular

Zone(s) Periventricular

Preoptic Anterior Suprachiasmatic Supraoptic Dorsomedial Ventromedial Arcuate Posterior Mammillary Lateral Complex

Medial, Lateral Medial Medial Medial, Lateral Medial Medial Periventricular, Medial Medial Medial Lateral

Region(s) Anterior, Tuberal Anterior Anterior Anterior Anterior Tuberal Tuberal Tuberal Posterior Posterior Tuberal

Functions Fluid balance, Milk let-down, parturition, autonomic & anterior pituitary control Thermoregulation, Sexual Behavior Thermoregulation, Sexual Behavior Biological Rhythms Fluid balance, Milk let-down, Parturition Emotion (rage) Appetite, Body Weight, Insulin regulation Control of Anterior Pituitary, Feeding Thermoregulation Emotion and Short-Term Memory 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

Suprachiasmatic Nucleus

Superior Cervical Ganglion

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 Hypothalamoneurohypophyseal tract

Neurohypophysis Inferior hypophyseal artery

Adenohypophysis 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 copeptides 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 spinohypothalamic 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

Organum Vasculosum (osmolality)

Subfornical Organ (Angiotensin II)

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

-

-

Short Loop Feedback

Arcuate nucleus

Supraoptic nucleus

Releasing hormone

Direct Long Loop Feedback

Tubero-infundibular tract

+

Neurohypophysis

Superior hypophyseal artery Circulating hypophyseal hormone

+ Circulating hormone Target gland

Hypophyseal-portal vein

Adenohypophysis 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 releasinghormones 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 longloop 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

+

α-Ad DA 5-HT } Enk

_

GHRH

_ + Gs Gq

Periventricular N.

_ 2hrs

+

SOM

+

+ NE DA

cAMP

+

_ GH Gi

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. Thyrotropinreleasing 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 γmelanocyte 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 Cushing’s Syndrome

CRF Pituitary

ACTH

Pituitary Cushing’s Syndrome

Tumor

corticosteroids

Adrenal Cushing’s Syndrome

Target Tissues

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 ACTH

vagus

TSH

LH, FSH

thyroid

adrenals

gonads

autonomics

corticosteroids

Neuropeptide Receptors

NE Ach 5HT

gonadal hormones

VIP

Enk β-End Neurotransmitter Receptors

T3,T4

SP

TRH ACTH CRH Lymphocyte

Releasing Factor Receptors

GH GHRH

GH

Cytokines Interleukins, Interferons TNF

Prl β-End Enk ACTH TSH Neuropeptides Released

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 complex

endothelial cell

+ +

COX-2

MAP kinases & NK-κB pathways

-

PGE2 EP4

neurons in PVN, A2, POAH G G s

+ AC

cAMP

FEVER (POAH)

+

corticosteroids

PKA

+

ACTH

gene expression

Acute Phase Proteins (PVN, A2)

+

+

IL-6-R

+

CRF (PVN)

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 nonprimed 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

}

redistribution

stress

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

+

Brain

+ spinal sympathetic & parasympathetic efferents

+/premotor and preganglionic neurons

cranial nerve visceral and somatic afferents

+

dorsal horn interneurons

+

spinal visceral 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-brainstemspinal 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 hypothalamus

amygdala, hippocampus & septal n. cingulate, orbitofrontal, insular,& rhinal Cx

posterior hypothalamus mammillary nucleus

lateral hypothalamus Paraventricular Nucleus

dorsal motor nucleus of the vagus

raphe nuclei parabrachial n. central gray

nucleus of the soliatry tract

parasympathetic outflow to tissues

rostral ventral lateral medulla (A5)

spinal IML column

trigeminal pars caudalis

spinal IML column

sympathetic 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

DLF

Septal Nuclei Hypothalamus Mammillary Body

Amygdala Mesencephalic reticular formation Pontine reticular formation

Mammillotegmental Tract Raphe Nuceli Nucleus ambiguus

Dorsal motor nucleus of the vagus 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 setpoint, Warm-sensitive neurons, Cold-sensitive neurons, and Temperatureinsensitive 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

+ Pyrogens TNF, IFN, IL-1,PGE2

5 spikes.s-1/oC

W

_

Highest Skin Temperature

Lowest Skin Temperature

Temperature

To PVN & lateral hypothalamus increased parasympathetic outflow

W

To PVN & Posterior Hypothalamus Increased Sympathetic Outflow 37oC

_

Cutaneous & Spinal Cool Receptors

+

C +

I

Temperature 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 (IL6), 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

40 39

flush

set-point temperature

core temperature

38 37 fever onset

Hours

fever 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 set31

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 drugsparticularly 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 vasodilation

excess sweating cold stress metabolic disease drugs, burns age

hypovolemia cardiac output

blood pressure

CNS impairment insufficient heat loss

inadequate set-point regulation

core temperature

core temperature tissue damage coma

Heat Shock

death 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 the need for energy in tissues is constant. Thus, mechanisms have evolved for the ebb and flow of nutrients after feeding and during the post-absorptive period; and the maintenance of near-normal function during fasting. The remarkable stability of body weight in persons with access to adequate food supplies is testament to the 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.

CNS

glucose

LIVER

oxidizes mainly glucose

ketones

TISSUES

oxidize glucose or lipids

oxidizes lipids stores carbohydrates

ADIPOSE

Insulin

stores lipid

Pancreas GI Tract

A. The Depletion-repletion Hypothesis is essentially based on the idea of a caloric set-point. In its Food Food Types Amount simplest version individuals match Available Available energy expenditure and energy Food intake without reference to the level Intake Nitrogen Energy of fat storage. In more complicated Need Need GI Tract models fat (energy) depots, and Caloric Nitrogen Content Content Short-Term Short-Term presumably other nutrient depots, Energy Nitrogen Storage Storage Excretion send signals to the brain about their Long-Term Long-Term current status. These inputs are Nitrogen Energy 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 Brain

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 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

Anorexia

Constant Feeding

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 The Dual Center Hypothesis evolved about fifty years ago when it was demonstrated that bilateral lesions placed in the region of the ventromedial hypothalamus (VMH) produced a condition of voracious appetite and resulting marked hyperphagia. These animals would ultimately become remarkably obese. On the other hand, bilateral lesions of the ventrolateral hypothalamus (VLH) produced an anorexic condition that resulted in animals failing to feed and ultimately wasting. The assumption behind this set of experiments was that there are specific feeding and satiety centers. The conclusion in this set of experiments was that the feeding center was the VLH and the satiety center was the VMH. Although this dual center hypothesis has proven useful, the CNS satiety network has proven to be more 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.

PVN

DMH Ach

LHA VMH POMC/CART

NPY/AGRP

Arcuate N. 5HT

R a p h e N T S A P Vagus (distension, CCK-a, portal glucose)

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), agoutirelated protein (AGRP), melanin-concentrating hormone (MCH), orexin, and galanin. NPY is the key feeding-promoting neuropeptide and NPYreceptor 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 POMC & CART

NPY & AGRP

_

+

+

NPY-R5 LHA

_

NPY-R5 PVN (parasymp)

Food Intake

POMC & CART

AGRP

NPY

OB-Rb

OB-Rb

γMSH

CART

_

NPY & AGRP

+ MC3-R

Arcuate?

Feeding Efficiency

αMSH

_

+

MC4-R PVN (symp),VMH

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 prolactinreleasing peptide (PrlRP). These peptides fall with food deprivation and conversely rise with forced overfeeding. For example, corticotropinreleasing 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 overrepresentative 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 beta delta theta

8-13 13-30 0.5-4 4-7

Hz Hz Hz 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 lowvoltage, 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 (510 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