BARR'S The Human Nervous System: An anatomical viewpoint, 9th Edition

PART 2 - Regional Anatomy of the Central Nervous System

Chapter 11

Diencephalon

Important Facts

  • The thalamus, epithalamus, and hypothalamus form the walls and floor of the third ventricle. The thalamus also forms the floor of the lateral ventricle.
  • The reticular nucleus of the thalamus modulates the exchange of signals between other thalamic nuclei and the cerebral cortex.
  • Neurons in the thalamus are reciprocally connected with the cerebral cortex. Most thalamic nuclei also receive subcortical afferents.
  • The ventral group of thalamic nuclei includes the medial and lateral geniculate bodies, which are parts of the auditory and visual systems and the somatosensory ventral posterior nucleus. The ventral lateral and ventral anterior nuclei are parts of pathways to the motor areas of the cerebral cortex.
  • The intralaminar nuclei of the thalamus receive afferents from many sources, including the spinal cord and the brain stem reticular formation. They project to the whole neocortex and to the striatum. Involvement in arousal, awareness, and motor control is suspected as their function.
  • The anterior and lateral dorsal nuclei of the thalamus are parts of the limbic system (which consists of the hippocampus, amygdala, and other parts of the brain connected with these components of the temporal lobe).
  • The mediodorsal thalamic nucleus receives afferents from the amygdala, entorhinal area, spinal cord, and corpus striatum. It projects to the prefrontal cortex. The lateral posterior nucleus and the pulvinar receive input from the visual system and project to the cortex of the parietal and frontal lobes and the cingulate gyrus.
  • The subthalamus contains various bundles of fibers connected with the thalamus, rostral parts of some midbrain nuclei, and the subthalamic nucleus. The subthalamic nucleus is connected with the pallidum; a destructive lesion causes contralateral hemiballismus.
  • The epithalamus consists of the stria medullaris thalami, habenular nuclei, posterior commissure, and pineal gland.
  • The hypothalamus contains several nuclei. Afferents include fibers from the limbic forebrain and the brain stem. Some hypothalamic neurons directly sense changes in hormone concentrations, osmotic pressure, and temperature of the blood.
  • Hypothalamic efferent fibers go to the brain stem and spinal cord for control of autonomic and other involuntary functions.
  • Some hypothalamic neurons secrete hormones, including those of the posterior lobe of the pituitary gland. Releasing hormones enter the hypophysial portal vessels and control the secretion of anterior pituitary hormones.

The diencephalon and telencephalon together constitute the cerebrum, of which the diencephalon forms the central core, and the telencephalon, the cerebral hemispheres. Because it is almost entirely surrounded by the hemispheres, only the ventral surface of the diencephalon is exposed to view, in an area that contains hypothalamic structures (Fig. 11-1). This area is bounded by the optic chiasma and tracts and the region where the internal capsule becomes the basis pedunculi of the midbrain. The diencephalon is divided into symmetrical halves by the slit-like third ventricle. As seen in a median section (Fig. 11-2), the junction of the midbrain and diencephalon is represented by a line that passes through the posterior commissure and is immediately caudal to the mamillary body. The boundary between the diencephalon and the telencephalon is represented by a line that traverses the interventricular foramen (foramen of Monro) and the optic chiasma.

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FIGURE 11-1 Landmarks of the diencephalon on the ventral surface of the brain. Part of the left temporal lobe (right side of picture) has been cut away.

 

FIGURE 11-2 Central region of the brain in median section.

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Gross Features

SURFACES

Each half of the diencephalon has the following landmarks and relations. The medial surface of the diencephalon forms the wall of the third ventricle (see Fig. 11-2). In about 70% of brains, a bridge of gray matter, the interthalamic adhesion or massa intermedia, joins the left and right thalami. A bundle of nerve fibers called the stria medullaris thalami forms a prominent ridge along the junction of the medial and dorsal surfaces. The ependymal lining of third ventricle is reflected from one side to the other along the striae medullares, forming the roof of the third ventricle, from which a small choroid plexus is suspended.

The dorsal surface is largely concealed by the fornix (Fig. 11-3), which is a robust bundle of fibers that originates in the hippocampal formation of the temporal lobe, curves over the thalamus, and ends mainly in the mamillary body. Between the left and right fornices, vascular connective tissue known as the tela choroidea is continuous with the vascular core of the choroid plexuses of the lateral and third ventricles. Lateral to the fornix, the dorsal surface of the thalamus forms the floor of the central part of the lateral ventricle, much of which is concealed by the choroid plexus (see Fig. 11-3).

 

FIGURE 11-3 Dorsal aspect of the diencephalon, exposed by removing the corpus callosum. The fornix and the choroid plexus of the lateral ventricle have been removed on the right side.

Laterally, the diencephalon is bounded by the internal capsule, which is a thick band of fibers connecting the cerebral cortex with the thalamus and other parts of the central nervous system. The ventral surface of the diencephalon presents to the surface of the brain, as previously noted.

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MAJOR COMPONENTS

The diencephalon has four parts on each side: the thalamus, subthalamus, epithalamus, and hypothalamus. The thalamus, by far the largest component, is subdivided into nuclei that have different afferent and efferent connections. Certain thalamic nuclei receive input from the pathways for all the senses except smell; these nuclei project to corresponding sensory areas of the cerebral cortex. Other thalamic nuclei are connected with motor and association areas of the cortex, and yet others participate in memory, sleep, and mental activities. The subthalamus is a complex region ventral to the thalamus; it includes a nucleus with motor functions (the subthalamic nucleus) and tracts from the brain stem, cerebellum, and corpus striatum, which terminate in the thalamus. The epithalamus, situated dorsomedially to the thalamus and adjacent to the roof of the third ventricle, includes the pineal gland as well as nuclei and tracts concerned with autonomic and behavioral responses to emotional changes. The hypothalamus occupies the region between the third ventricle and the subthalamus; it is the part of the forebrain that integrates and controls the activities of the autonomic nervous system and of several endocrine glands. Theneurohypophysis, which includes the posterior lobe of the pituitary gland, is an outgrowth of the hypothalamus. (The anterior lobe of the pituitary gland arises from the embryonic pharynx and is not a part of the brain.)

Thalamus

The thalamus is a roughly egg-shaped structure, about 3 cm anteroposteriorly and 1.5 cm in the other two directions. Its narrower end, the anterior tubercle, forms the posterior wall of the interventricular foramen, and its wide posterior end, the pulvinar, faces the subarachnoid space below the fornix and the splenium of the corpus callosum and above the pineal gland and tectum. Thin laminae of white matter partly outline the thalamus, the stratum zonale on the dorsal surface (see Fig. 11-12), and the external medullary lamina(see Fig. 11-9) laterally. The external medullary lamina is separated from the internal capsule by a thin layer of gray matter that constitutes the reticular nucleus of the thalamus. The internal medullary lamina (Figs. 11-4B and 11-9) divides the thalamus into groups of nuclei.

SCHEME OF THALAMIC ORGANIZATION

Every nucleus of the thalamus except the reticular nucleus sends axons to the cerebral cortex, either to a sharply defined area or diffusely to a large area. Every part of the cortex receives afferent fibers from the thalamus, probably from at least two nuclei. Every thalamocortical projection is faithfully copied by a reciprocal corticothalamic connection. Thalamic nuclei receive other afferent fibers from subcortical regions. Probably only one noncortical structure, the striatum (see Chapter 12), receives afferent fibers from the thalamus.

The thalamocortical and corticothalamic axons give collateral branches to neurons in the reticular nucleus, whose neurons project to and inhibit the other nuclei of the thalamus (Fig. 11-5). Contrary to earlier beliefs, no connections exist between the various nuclei of the main mass of the thalamus, although each individual nucleus contains interneurons. The synapses of the interneurons are inhibitory, and most are dendrodendritic. Other synapses in the thalamus are excitatory, with glutamate as the transmitter, and so are thalamocortical projections (see Fig. 11-5).

RETICULAR NUCLEUS

As noted, the reticular nucleus is a thin sheet of inhibitory (γ-aminobutyrate-ergic) neurons between the external medullary lamina and the internal capsule (see Fig. 11-9). The nucleus receives collateral branches of some of the excitatory corticothalamic and thalamocortical fibers. Some excitatory afferents ascend from the pedunculopontine nucleus, which is a cluster of cholinergic neurons in the rostral pontine reticular formation.

The axons of cells in the reticular nucleus project into the deeper parts of the thalamus to end in the same nuclei that gave rise to afferents to those cells (see Fig. 11-5). All the other thalamic nuclei and all areas of the cerebral cortex are associated with corresponding regions in the reticular nucleus. Certain features of the electroencephalogram

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in normal sleep depend on the activity of neurons in the reticular nucleus of the thalamus, which can suppress the transmission of signals through the thalamic nuclei of the ascending sensory pathways (see Chapter 9).

 

FIGURE 11-4 The thalami, showing positions of the larger nuclei. (A) Lateral view. (B) Dorsal view. (C) Posterior view, with the posterior half of the right thalamus cut away. Nuclei of the ventral group are colored in shades of blue to violet, the lateral group green to yellow, the medial group pink to red, and the midline and intralaminar nuclei bluish green. The internal medullary lamina is white. (From a model made by Dr. D. G. Montemurro.)

Despite its name, the reticular nucleus is not connected with the reticular formation of the brain stem; the alternative name of perithalamus is more appropriate but seldom used. The reticular nucleus, together with a few small

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thalamic nuclei not discussed here, is sometimes called the ventral thalamus. The other thalamic nuclei are then said to constitute the dorsal thalamus.

 

FIGURE 11-5 Scheme of neuronal connections of the thalamus. Excitatory and inhibitory synapses are marked + and -, respectively. The dendrodendritic synapses of the interneurons also inhibit the principal cells.

NUCLEI OF THE DORSAL THALAMUS

The positions of the thalamic nuclei are shown in Figures 11-6, 11-7, 11-8, 11-9, 11-10, 11-11, and 11-12. Their major neural connections are summarized in Table 11-1, which also indicates the functional systems associated with the various nuclei. The cortical areas named in this table are shown in Figure 11-13. (For a complete account, refer to the recommended reading at the end of this chapter.)

Subthalamus

The subthalamus contains sensory fasciculi, fiber bundles from the cerebellum and the globus pallidus, rostral extensions of midbrain nuclei, and the subthalamic nucleus.

The sensory fasciculi are the medial lemniscus, spinothalamic tract, and trigeminothalamic tracts. They are spread out immediately beneath the ventral posterior nucleus of the thalamus, in which the fibers terminate (see Figs. 11-7 and 11-8). Cerebellothalamic fibers from the dentate and interposed nuclei have crossed the midline in the decussation of the superior cerebellar peduncles (see Fig. 7-13). They pass through and around the red nucleus and then form the prerubral area, or field H of Forel (H is from the German Haube; seeFigs. 11-8 and 11-9). The cerebellothalamic fibers end in the posterior division (VLp) of the ventral lateral nucleus of the thalamus. Efferent fibers of the globus pallidus pass through the lenticular fasciculus and the ansa lenticularis (see Figs. 11-9, 11-10, and 12-5) and terminate in the VLa and VA nuclei of the thalamus (see Table 11-1). Beneath the thalamus, the pallidothalamic and cerebellothalamic fibers together constitute the thalamic fasciculus (see Fig. 11-9). A small contingent of axons from the globus pallidus turns caudally and ends in the pedunculopontine nucleus, which is one of the cholinergic nuclei in the reticular formation of the brain stem (see Chapters 9 and 23).

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FIGURE 11-6 Key to levels for Figures 11-7, 11-8, 11-9, 11-10, 11-11, and 11-12. See Figures 11-2 and 11-3 for names of gross anatomical landmarks. (Anterior is to the right.)

 

FIGURE 11-7 Transverse section at the transition between the midbrain and the diencephalon, immediately caudal to the mamillary bodies (Weigert stain for myelin). For abbreviations used in this chapter, see inside front cover of book.

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CLINICAL NOTE

Thalamic Syndrome and Central Neurogenic Pain

The thalamic syndrome (Dejerine-Roussy syndrome) is a disturbance of the somatosensory aspects of thalamic function subsequent to a lesion (usually vascular in origin) that involves the ventral posterior parts of the thalamus. Adjacent structures, including the internal capsule, are also involved in these lesions. The symptoms vary according to the location and extent of the damage. Proprioception and the sensations of touch, pain, and temperature are typically impaired on the opposite side of the body. When a threshold is reached, the sensation is exaggerated, painful, perverted, and exceptionally disagreeable. For example, the prick of a pin may be felt as a severe burning sensation, and even music that is ordinarily pleasing may be disagreeable. Spontaneous pain may develop in some instances, which may become intractable to analgesics. Emotional instability may also be present, with spontaneous or forced laughing and crying. These symptoms are not correlated with destruction of individual thalamic nuclei.

Pain may also result from destructive lesions in parts of the CNS other than the thalamus, including the spinal cord, brain stem, and the cortex and white matter of the parietal lobe. In all these conditions, there is impairment of the perception of real sensory stimuli, attributable to damage to the somatosensory pathways (see Chapter 19). The physiology of pain of central origin is poorly understood, but it has been hypothesized that the condition is caused by abnormal activity in thalamic and cortical neurons that have been deprived of their normal afferents.

OTHER THALAMIC DISORDERS

A rare disease that first affects the thalamus is fatal familial insomnia. This is a prion disease. (Prions are protein molecules, or abnormal variants of normal animal proteins, that behave as infectious agents. Prions are similar to viruses but slower in their actions. Prion molecules may be transferred among individuals by ingestion or transplantation of infected tissue. The gene encoding a prion protein can move vertically from one generation to the next.) The destructive lesions of fatal familial insomnia occur in the mediodorsal nucleus and in the anterior ventral nucleus, a member of the anterior nuclear group. With progression of the disease, dementia and other neurological symptoms develop. Degenerative changes are present in the cerebral cortex and in the inferior olivary nuclei of the medulla. The relationship of the lesions to the neural circuitry involved in sleep is not obvious.

 

FIGURE 11-8 Diencephalon at the level of the mamillary bodies (Weigert stain).

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FIGURE 11-9 Diencephalon at the level of the middle of the tuber cinereum (Weigert stain).

The substantia nigra and red nucleus extend from the midbrain part way into the subthalamus (see Figs. 11-7 and 11-8). The mesencephalic reticular formation also extends into the subthalamus, where it appears as the zona incerta between the lenticular and thalamic fasciculi (see

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Fig. 11-9). The zona incerta is part of a circuit that recognizes thirst and stimulates drinking.

 

FIGURE 11-10 Diencephalon at the level of the optic chiasma (Weigert stain).

 

FIGURE 11-11 Diencephalon rostral to the level of the optic chiasma (Weigert stain).

The biconvex subthalamic nucleus (body of Luys) lies against the medial side of the internal capsule (see Figs. 11-7, 11-8, and 11-9). The subthalamic nucleus has reciprocal connections with the globus pallidus, which are described in more detail in Chapters 12 and 23. These fibers constitute the subthalamic fasciculus, which cuts across the internal capsule.

 

FIGURE 11-12 Rostral end of the diencephalon (Weigert stain).

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TABLE 11-1 Connections of Thalamic Nuclei and Associated Functions

Nucleus

Afferents

Efferents

Functions

Reticular nucleus

Collateral branches of thalamocortical and corticothalamic axons

To each thalamic nucleus that sends afferents to the reticular nucleus

Inhibitory modulation of thalamocortical transmission

Intralaminar nuclei (the centromedian, parafascicular, and central lateral nuclei are the members of this group)

Cholinergic and central nuclei of reticular formation, locus coeruleus, collateral branches from spinothalamic and trigeminothalamic tracts, parabrachial nuclei, cerebellar nuclei, pallidum

Extensive cortical projections, especially to frontal and parietal lobes; striatum (seeChapter 12)

Stimulation of cerebral cortex in waking state and arousal from sleep; somatic sensation, especially pain (from contralateral sides of body and head); control of movement

Ventral group of nuclei:

Medial geniculate body (MGB)

Inferior colliculus

Primary auditory cortex (transverse temporal gyri)

Auditory pathway (from both ears)

Lateral geniculate body (LGB)

Ipsilateral halves of both retinas

Primary visual cortex

Visual pathway (from contralateral visual fields)

Ventral posterior lateral (VPl)

Contralateral gracile and cuneate nuclei; contralateral dorsal horn of spinal cord

Primary somatosensory area (postcentral gyrus)

Somatic sensation (principal pathway, from contralateral side of body below head)

Ventral posterior medial (VPm)

Contralateral trigeminal sensory nuclei

Primary somatosensory area (postcentral gyrus)

Somatic sensation (principal pathway, from contralateral side of head: face, mouth, larynx, pharynx, dura mater)

Ventral lateral, posterior division (VLp)

Contralateral cerebellar nuclei

Primary motor area (precentral gyrus)

Cerebellar modulation of commands sent to motor neurons

Ventral lateral, anterior division (VLa)

Pallidum

Premotor and supplementary motor areas (see Chapter 15)

Planning commands to be sent to motor neurons

Ventral anterior (VA)

Pallidum

Frontal lobe, including premotor and supplementary motor areas

Motor planning and more complex behavior

Posterior group of nuclei

Spinothalamic and trigeminothalamic tracts

Insula and nearby temporal and parietal cortex, including second somatosensory area

Visceral and other responses to somatic sensory stimuli

Lateral group of nuclei:

Lateral dorsal (LD)

Hippocampal formation; pretectal area, and superior colliculus

Cingulate gyrus; visual association cortex (occipital, posterior parietal, and temporal lobes)

Memory; interpretation of visual stimuli

Lateral posterior (LP)

Superior colliculus

Parietal, temporal, and occipital association cortex

Interpretation of visual and other sensory stimuli, formulation of complex behavioral responses

Pulvinar

Pretectal area; primary and all association cortex for vision; retinas

Parietal lobe, anterior frontal cortex, cingulate gyrus, amygdala

Interpretation of visual and other sensory stimuli, formulation of complex behavioral responses

Medial group of nuclei:

Mediodorsal (MD)

Entorhinal cortex, amygdala, collaterals from spinothalamic tract, pallidum (ventral parts and substantia nigra pars reticulata)

Prefrontal cortex

Behavioral responses that involve decisions based on prediction and incentives

Medioventral (MV, “midline nuclei”)

Amygdala, hypothalamus

Hippocampal formation and parahippocampal gyrus

Behavior, including visceral and “emotional” responses

Anterior group of nuclei

Mamillary body

Cingulate gyrus

Memory

For simplicity, some groups (e.g., intralaminar, anterior, mediodorsal) are treated as if they were individual nuclei. The functions are those of the larger circuits in which the nuclei of the thalamus participate.

CLINICAL NOTE

Hemiballismus

A lesion in the subthalamic nucleus is typically caused by local vascular occlusion. The resulting motor disturbance on the opposite side of the body is known as ballism or hemiballismus. The condition is characterized by involuntary movements that come on suddenly with great force and rapidity. The movements are purposeless and usually of a throwing or flailing type. The spontaneous movements occur most severely at proximal joints of the limbs, especially the arms. The muscles of the face and neck are sometimes also involved.

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Epithalamus

The epithalamus consists of the habenular nuclei and their connections and the pineal gland.

HABENULAR NUCLEI

A slight swelling in the habenular trigone marks the position of the medial and lateral habenular nuclei (see Figs. 11-3 and 11-7). Afferent fibers are received through the stria medullaris thalami, which runs along the dorsomedial border of the thalamus (see Figs. 11-2, 11-3, and 11-9) and is also considered part of the epithalamus.

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Most of the cells of origin of the stria are situated in the septal area. This area is located on the medial surface of the frontal lobe beneath the rostral end of the corpus callosum (seeFig. 11-2) and is part of the limbic system of the brain, considered in Chapter 18.

 

FIGURE 11-13 Cortical areas connected with the thalamic nuclei described in Table 11-1. (A) Lateral surface of left cerebral hemisphere. (B) Medial surface of left cerebral hemisphere.

The habenular nuclei give rise to a well-defined bundle of fibers known as the habenulointerpeduncular tract (fasciculus retroflexus of Meynert; see Fig. 11-7). The main destination of the fasciculus is the interpeduncular nucleus in the midline of the roof of the interpeduncular fossa of the midbrain. Through relays in the reticular formation of the midbrain, the interpeduncular nucleus influences neurons in the hypothalamus and preganglionic autonomic neurons. No clearly defined function is attributed to the habenular nuclei.

PINEAL GLAND

The pineal gland or body, also called the epiphysis, has the shape of a pine cone. It is attached to the diencephalon by the pineal stalk, into which the third ventricle extends as the pineal recess (see Figs. 11-2 and 11-3). The pineal gland and its stalk develop as an outgrowth from the ependymal roof of the third ventricle. The habenular commissure in the dorsal wall of the stalk includes fibers of the stria medullaris thalami that terminate in the opposite habenular nuclei. The ventral wall of the pineal stalk is attached to the posterior commissure, which carries axons involved in pupillary reflexes and eye movements (see Chapter 8).

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Pineal Anatomy

In mammals, the pineal organ has the structural organization of an endocrine gland. It receives an afferent nerve supply from the superior cervical ganglion of the sympathetic trunk through the nervus conarii, which runs subendothelially in the straight sinus (within the tentorium cerebelli) before penetrating the dura and distributing its branches to the pineal parenchyma. The characteristic cells of the gland (pinealocytes) have granular cytoplasm and processes that end in bulbous expansions close to blood vessels. The pineal gland is one of the four circumventricular organs associated with the third ventricle because its capillary blood vessels have endothelial fenestrations and are permeable to large molecules. The other circumventricular organs are reviewed in the last section of this chapter. After about age 16 years, granules of calcium and magnesium salts appear in the gland and later coalesce to form larger particles (brain sand). The deposits are useful for showing, in a simple radiograph of the head, whether or not the pineal gland is displaced from the midline by a space-occupying lesion.

Pineal Functions

In laboratory animals, the effects of pinealectomy and of administration of pineal extracts indicate an antigonadotrophic action of pineal secretions. Chemical extraction of pineal glands has produced several possible active principles, most notably melatonin, an indoleamine related to serotonin. In humans, the circulating level of melatonin decreases sharply with the onset of puberty. Women of reproductive age experience cyclic variations, with the melatonin levels reaching minimum values at the time of ovulation.

Clinical observations support the notion of an antigonadotrophic function for the human pineal gland. A pineal tumor developing around the time of puberty may alter the age of onset of pubertal changes. Puberty may be precocious if the tumor is of a type that destroys the pinealocytes, or puberty may be delayed if the tumor is derived from the pinealocytes. A pineal tumor can also impair vertical eye movements by pressing on the tectum (Parinaud's syndrome; see Chapter 8).

Pineal secretion of melatonin is influenced by ambient light. Some axons from the retina leave the optic tract near the optic chiasma and terminate in the nearby suprachiasmatic nucleus of the hypothalamus. This projects to other hypothalamic nuclei, which send axons caudally to the preganglionic neurons of the sympathetic nervous system in the thoracic segments of the spinal cord. The suprachiasmatic nucleus serves as a clock that regulates rhythmic activities of the brain and endocrine system. Melatonin can change the speed of the clock, and knowledge of this has led to popular use of the hormone as a treatment for jet lag and other sleep disorders. In principle, a dose of the hormone is taken before lying down and attempting to sleep. The popularity of melatonin (which can be taken by mouth and apparently has no toxic effects) was enhanced by claims in the 1980s that its administration to mice resulted in increased life span.

Hypothalamus

The hypothalamus has a functional importance that is quite out of proportion to its size. Input from the limbic system has a special behavioral significance, and afferents from the brain stem convey information that is largely of visceral origin. The hypothalamus is not influenced solely by neuronal systems; some of its neurons respond directly to properties of the circulating blood, including temperature, osmotic pressure, and the levels of various hormones. Hypothalamic function becomes manifest through efferent pathways to autonomic nuclei in the brain stem and spinal cord and through an intimate relationship with the pituitary gland by means of neurosecretory cells. These cells elaborate the hormones of the posterior lobe of the gland and produce releasing hormones that control the anterior lobe. By these means, the hypothalamus has a major role in producing responses to emotional changes and to needs signaled by hunger and thirst. It is instrumental in maintaining a constant internal environment (homeostasis) and is essential for reproductive function.

ANATOMY AND TERMINOLOGY

The hypothalamus surrounds the third ventricle ventral to the hypothalamic sulci (see Fig. 11-2). The mamillary bodies are distinct swellings on the ventral surface (see Fig. 11-1). The region

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bounded by the mamillary bodies, optic chiasma, and beginning of the optic tracts is known as the tuber cinereum. The pituitary stalk arises from the median eminence just behind the optic chiasma and expands to form the neural or posterior lobe of the pituitary gland. The median eminence and the neural components of the pituitary stalk and gland have similar cytological and functional characteristics; together they constitute the neurohypophysis. For reference, these and some other names applied to the hypothalamohypophysial system are summarized in Table 11-2. The neurohypophysis contains permeable blood vessels and is therefore one of the circumventricular organs associated with the third ventricle.

TABLE 11-2 Terminology of the Hypothalamohypophysial System*

Name

Definition

Adenohypophysis

The structures derived from the ectoderm of Rathke's pouch: pars distalis (i.e., anterior lobe), pars intermedia, and pars tuberalis

Anterior lobe

The largest part of the adenohypophysis, excluding the pars intermedia and pars tuberalis

Anterior pituitary

A term commonly applied to the anterior lobe and its hormones

Hypophysis

All the parts of the adenohypophysis and neurohypophysis (full name is hypophysis cerebri)

Infundibular process

The neural lobe of the pituitary gland

Infundibular stem

The nervous tissue joining the median eminence to the neural lobe; the major component of the pituitary stalk

Infundibulum

The most ventral part of the hypothalamus, with the third ventricle extending into the median eminence; in some animals, the infundibular recess of the ventricle continues through the infundibular stem into the neural lobe

Median eminence

The part of the neurohypophysis that is a small lump in the midline of the tuber cinereum of the hypothalamus; it contains the primary capillaries of the hypophysial portal system

Neural lobe

The larger part of the posterior lobe, excluding the pars intermedia

Neurohypophysis

The parts of the pituitary gland derived from the infundibulum of the embryonic diencephalon: median eminence, infundibular stem, and neural lobe (i.e., infundibular process or pars nervosa)

Neurosecretion

An activity of certain neurons that have synapse-like contacts with blood vessels and release physiologically important substances (hormones) into the blood

Pars distalis

The anterior lobe of the pituitary gland

Pars intermedia

The part of the adenohypophysis that intervenes between the anterior lobe and the neural lobe; it is smaller in humans than in most other animals and consists of several tiny cystic structures

Pars nervosa

The neural lobe of the pituitary gland

Pars tuberalis

A part of the adenohypophysis consisting of a thin layer of cells on the surface of the median eminence and pituitary stalk

Pituitary gland

The hypophysis cerebri, consisting of the neurohypophysis and adenohypophysis

Pituitary stalk

The infundibular stem, together with the adjacent parts of the pars tuberalis and the hypophysial portal veins

Posterior lobe

The part of the pituitary gland posterior (in humans) or dorsal (in most other animals) to the anterior lobe, from which it is separated by the pars intermedia

Posterior pituitary

A term commonly applied to the neural lobe and its hormones

*This list includes several terms that are not used in this textbook but that students may encounter when studying clinical endocrinology or neuroscience.

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The lamina terminalis limits the third ventricle anteriorly (see Figs. 11-2 and 11-14), extending in the midline from the optic chiasma to the anterior commissure. Embedded in the lamina is another of the four circumventricular organs associated with the third ventricle. This is the organum vasculosum laminae terminalis (OVLT). It has been implicated in mechanisms of fever and also in the regulation of sodium metabolism by way of appetite for salt. The lamina terminalis and anterior commissure are telencephalic structures and so is the preoptic area, which is the gray matter within and immediately lateral to and behind the lamina terminalis. The connections and functions of the preoptic area are inseparable from those of the anterior (rostral) part of the medial zone of the hypothalamus. One group of intensely staining cells in this area is notable for containing more than twice as many neurons in men as in women.

 

FIGURE 11-14 Some nuclei in the medial zone of the hypothalamus.

The columns of the fornix traverse the hypothalamus to reach the mamillary bodies and serve as points of reference for sagittal planes that divide each half of the hypothalamus into a medial and a lateral zone. The medial zone is subdivided into suprachiasmatictuberal, and mamillary regions, with ventral structures as landmarks. It contains several distinct nuclei and a thin layer of fine myelinated and unmyelinated axons beneath the ependymal lining of the third ventricle. The lateral zone contains fewer neuronal cell bodies, but there are many fibers, with most of them running longitudinally.

HYPOTHALAMIC NUCLEI AND CONNECTIONS

Several hypothalamic nuclei are recognized on the basis of cellular characteristics and connections. For reference, Figure 11-14 shows the positions of the major nuclei of the medial zone. The lateral zone of the hypothalamus contains the cells of the lateral nucleus, which are interspersed among the abundant myelinated axons

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of the region and the lateral tuberal nucleus, which consists of small groups of neurons near the surface of the tuber cinereum.

Some hypothalamic nuclei have distinct functions; some of these functions are discussed here. For physiological discussion, it is therefore convenient to consider the hypothalamus as a unit or “black box,” with functions localized to regions larger than individual nuclei. As the main integrator of the autonomic and endocrine systems and of many involuntary actions of skeletal muscles, the hypothalamus receives signals from diverse sources, including data of somatic and visceral origin and the special senses of taste and smell. Fibers from the amygdala and hippocampus provide input derived from the activities of the temporal and prefrontal cortex, which are concerned with emotional drives and memory. The output of the hypothalamus is directed caudally to the brain stem and spinal cord and rostrally to the thalamus and cerebral cortex. Some of these afferent and efferent connections are summarized in Figure 11-15.

Afferent fibers reach the hypothalamus by way of the anterior limb of the internal capsule (see Figs. 11-15 and 16-7), the fornix (see Figs. 11-10, 11-11, and 11-12, 11-16, and 16-7), the stria terminalis (see Figs. 11-12 and 16-9), the diagonal band (within the anterior perforated substance), the medial forebrain bundle, and the dorsal longitudinal fasciculus. Themedial forebrain bundle consists of ascending and descending myelinated axons of different lengths extending from the septal area and anterior perforated substance of the forebrain into the lateral zone of the hypothalamus. The dorsal longitudinal fasciculus is formed from unmyelinated periventricular axons in the medial zone of the hypothalamus; these converge into a distinct bundle in the periaqueductal gray matter of the midbrain, continuing caudally in the medial part of the floor of the fourth ventricle. Efferent fibers ascend from the hypothalamus to the thalamus in the mamillothalamic fasciculus (bundle of Vicq d'Azyr; Fig. 11-16) and to the basal cholinergic forebrain nuclei (see Chapter 12) in the diagonal band. Descending efferents are carried in the medial forebrain bundle and dorsal longitudinal fasciculus and in the mamillotegmental tract, which is a branch of the mamillothalamic fasciculus.

The other major output of the hypothalamus consists of hormones secreted into blood vessels by neurosecretory cells. This is explained in connection with the hypothalamic control of the pituitary gland.

AUTONOMIC AND RELATED FUNCTIONS OF THE HYPOTHALAMUS

Knowledge of hypothalamic function has been derived partly from human clinicopathological correlations but largely from experimentation in animals. In interpreting the effects of electrical stimulation or of destructive lesions, it is necessary to appreciate that the axons of neurons in the anterior parts of the medial zone of the hypothalamus pass through the posterior parts of the medial zone and through the lateral zone on their way to the brain stem. It is therefore difficult to infer the localization of functions from abnormalities that follow stimulation or ablation of individual hypothalamic nuclei.

The responses most regularly elicited by stimulation of the anterior hypothalamus (preoptic area and anterior nucleus) include slowing of the heart rate, vasodilation, lowering of blood pressure (BP), salivation, increased peristalsis in the gastrointestinal (GI) tract, contraction of the urinary bladder, and sweating. These effects are mediated peripherally by cholinergic neurons, including those of the parasympathetic system (see Chapter 24). Stimulation in the region of the posterior and lateral nuclei elicits noradrenergic sympathetic responses; these include cardiac acceleration, elevation of BP, cessation of peristalsis in the GI tract, dilation of the pupils, and hyperglycemia.

Regulation of body temperature is an instructive example of the role of the hypothalamus in maintaining homeostasis. Certain hypothalamic cells monitor the temperature of blood and initiate physiological changes necessary to maintain a normal body temperature. Thermosensitive neurons in the anterior hypothalamus respond to an increase in temperature of the blood and activate mechanisms that promote heat loss, such as cutaneous vasodilation and sweating. A lesion in the anterior hypothalamus may therefore result in hyperthermia.

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Cells in the posterior hypothalamic nucleus (see Fig. 11-14) respond to lowering of blood temperature, triggering such responses as cutaneous vasoconstriction and shivering, for conservation and production of heat, respectively. A lesion in the posterior part of the hypothalamus destroys cells involved in conservation and production of heat, and it also interrupts fibers running caudally from the heat-dissipating region. This results in a serious impairment of temperature regulation in either a cold or hot environment.

 

FIGURE 11-15 Diagram showing direct and indirect neural connections of the hypothalamus with other parts of the brain and spinal cord.

An abnormally high body temperature (fever) is typically associated with infectious disease. Products of bacterial decomposition (pyrogens) enter the circulation and pass into the preoptic area by way of the permeable blood vessels of the OVLT. Contact of pyrogens with the dendrites of anterior hypothalamic neurons results in inhibition of the mechanisms that cause loss of heat.

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FIGURE 11-16 Dissection showing the fornix and mamillothalamic fasciculus on the left side. Gray matter has been removed piecemeal from the wall of the third ventricle to display the bundles of myelinated fibers.

Hypothalamic regulation of food and water intake has been demonstrated by electrical stimulation and by placing small electrolytic lesions in the hypothalamus. Feeding is also regulated by various hypothalamic afferents, including those from visceral sensory neurons and the olfactory and limbic systems as well as by the level of glucose in the blood.Leptin, a hormone secreted by adipose tissue, acts on hypothalamic neurons and causes reduction of food intake. A hunger or feeding “center” located in the lateral zone of the hypothalamus is now known to include orexin-secreting neurons. In animals, intraventricular injection of orexin causes increased eating. A “satiety center” (inhibiting food intake) has been demonstrated in the region of the ventromedial hypothalamic nucleus. Destruction of the ventromedial nucleus in a laboratory animal results in excessive food intake and obesity.

The zona incerta of the subthalamus, the lateral and ventromedial hypothalamic nuclei, and the subfornical organ are interconnected to control water intake. (See also under “Third Ventricle” near the end of this chapter.) The volume of water excreted in the urine is controlled by one of the posterior pituitary hormones (see under “Hypothalamic Control of the Pituitary Gland”).

CLINICAL NOTE

Naturally occurring anterior hypothalamic lesions in humans can also result in obesity. The cell bodies or axons of cells that regulate the output of gonadotrophic hormones by the anterior lobe of the pituitary gland may be destroyed at the same time. The combination of obesity and deficiency of secondary sex characteristics is known as the adiposogenital or Fröhlich's syndrome.

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THE HYPOTHALAMUS AND SLEEP

Two nuclei in the posterior hypothalamus are active in the wakeful state, and one nucleus in the preoptic area is active in sleep. (For more about sleep and consciousness, seeChapter 9.)

The tuberomamillary nucleus (see Fig. 11-14) contains the brain's only histaminergic neurons, which have long, branched axons that extend caudally to the reticular formation of the brain stem and rostrally to the thalamus and all parts of the cerebral cortex. These neurons are active in the awake state and quiescent during sleep. They form part of the ascending arousal system described in Chapter 9. In the posterior part of the lateral hypothalamic area, neurons are present that use peptides known as orexins or hypocretins as excitatory transmitters. Orexin neurons are active in the waking state. They have axons that ramify extensively in the thalamus, basal cholinergic nuclei of the forebrain, and cerebral cortex, and they also stimulate tuberomamillary histaminergic neurons and the cholinergic and adrenergic neurons of the rostral pontine reticular formation.

The ventrolateral preoptic area includes a nucleus of neurons that produce γ-aminobutyrate and the peptide galanin. These neurons are most active during deep sleep. Their axons extend caudally to the tuberomamillary nucleus, where they inhibit the histaminergic neurons and to the cholinergic neurons of the reticular formation, which they also inhibit.

HYPOTHALAMIC CONTROL OF THE PITUITARY GLAND

Neurohypophysial hormones are synthesized in the hypothalamus, and hormone production by the anterior lobe of the pituitary gland is controlled by hormones of hypothalamic origin. Some of the anterior lobe hormones act on and interact with other endocrine organs. Consequently, through the neurosecretory function of hypothalamic cells, the brain controls much of the endocrine system. Only the major features of the hypothalamohypophysial system are discussed here; the subject is a large one, constituting much of the science of neuroendocrinology. The anatomical nomenclature special to this system is explained in Table 11-2 and illustrated in Figure 11-17. Some of the clinical and endocrinological terminology is explained in the Glossary at the end of the book.

CLINICAL NOTE

Encephalitis Lethargica

As the First World War was ending, a pandemic of an exceptionally severe influenza killed even more people than those who died from hostile action. A second pandemic soon followed. This was a neurological disorder, now generally guessed to have been a viral infection, that was given the name encephalitis lethargica. The infection usually caused excessive sleepiness. Some patients experienced a wide variety of other neurological symptoms, with some persisting for decades after the acute phase of the illness had subsided. In a minority of patients, the principal symptom was insomnia rather than somnolence. Many of the people afflicted with encephalitis lethargica died, and associations were made between the clinical manifestations and the sites of damage seen postmortem in the brain. Extensive studies of this kind were made by von Economo, who associated insomnia with lesions in the preoptic area and deduced that the posterior hypothalamus contained neurons needed for wakefulness.

A frequent long-term consequence of encephalitis lethargica was parkinsonism (see Chapters 7 and 23) caused by lesions in the substantia nigra.

NARCOLEPSY

Narcolepsy is a troublesome disorder in which the patient frequently passes from a wakeful state into REM sleep (see Chapter 9) for brief periods. The condition can also occur in dogs and several other mammals and is present in genetically modified mice that are unable to produce either orexin or one of its two receptor proteins. The brains of people and dogs with narcolepsy have been shown to have greatly reduced numbers of orexin-containing neurons in the hypothalamus. The presence of gliosis suggests that the cells have died as a result of a degenerative or autoimmune disease process.

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FIGURE 11-17 Hypothalamohypophysial tract and the parts of the neurohypophysis.

Neurohypophysis

As noted previously, the neurohypophysis consists of structures of diencephalic origin in the embryo: the median eminence, pituitary stalk, and the posterior or neural lobe of the pituitary gland (see Fig. 11-17). It contains axons, which end around blood vessels and atypical neuroglial cells. In the median eminence, tanycytes are present (see Chapter 2), and in the pituitary stalk and posterior lobe, atypical astrocytes known as pituicytes are present. Hormones released from the neural lobe of the pituitary gland enter the general circulation and act on cells in the kidney, mammary gland, and uterus. Hormones released from the median eminence act on cells in the anterior lobe of the pituitary gland.

Posterior Lobe Hormones

The two hormones of the posterior lobe of the pituitary gland are vasopressin (also called antidiuretic hormone [ADH]) and oxytocin. They are synthesized in the cell bodies of large neurosecretory cells in the supraoptic and paraventricular nuclei. Vasopressin-producing neurons are most abundant in the supraoptic nucleus, and oxytocin-producing neurons are most abundant in the paraventricular nucleus. The unmyelinated axons of the cells in these nuclei constitute the hypothalamohypophysial tract, and they terminate as expansions in contact with capillaries in the neurohypophysis (see Fig. 11-17). The hormones are stored in the expansions, which are known as Herring bodies. A Herring body has the physiological properties of a presynaptic terminal, and the arrival of an action potential results in the release of some of its contents. The hormone diffuses through the permeable endothelium of a nearby capillary and enters the general circulation.

Vasopressin Secretion and Action

A slight elevation of osmotic pressure of the blood causes the osmoreceptive cells of the supraoptic nucleus to propagate impulses with greater frequency.

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The arrival of impulses at the axonal terminals causes the release of ADH into the capillary blood of the neurohypophysis. Resorption of water from the distal and collecting tubules of the kidney is accelerated by the action of ADH, and the osmolarity of the blood plasma returns to normal. A delicate mechanism is thereby provided to ensure homeostasis with respect to water balance. Other endocrine mechanisms, outside the scope of this book, determine the renal excretion of sodium ions, which also contribute to the osmolarity of plasma and the volume of urine produced. ADH acting alone tends to lower the circulating level of Na+ (hyponatremia) by diluting the plasma with conserved water.

CLINICAL NOTE

Disordered Vasopressin Secretion

Destruction of the supraoptic nuclei, the hypothalamohypophysial tract, and the neurohypophysis results in neurogenic diabetes insipidus, which is characterized by excretion of large quantities of dilute urine (polyuria) and excessive thirst and water intake (polydipsia) to compensate. A destructive lesion restricted to the posterior lobe of the pituitary gland is not, as a rule, followed by diabetes insipidus because some ADH enters the blood from the median eminence and pituitary stalk. Diabetes insipidus is not necessarily caused by failure of ADH secretion. Nephrogenic diabetes insipidus can result from renal disease, with the kidneys failing to respond to the hormone.

Excessive secretion of ADH can result from disease processes that irritate the hypothalamus, such as meningitis or head injury. It occurs also as an occasional adverse effect of several commonly used drugs and in several nonneurological disorders. For example, a tumor in the lung, pancreas, or thymus may secrete ADH or a similar peptide. SIADH (syndrome of inappropriate secretion of antidiuretic hormone) consists of elevated plasma vasopressin in the absence of appropriate physiological stimuli. The resulting hyponatremia causes weakness and confusion followed by coma and seizures if untreated.

Oxytocin Secretion and Action

Oxytocin has a physiological role in parturition. It is secreted as a reflex response to dilatation of the uterine cervix, and it causes contraction of the uterus. Secretion of the hormone is induced also when the nipple is stimulated by a suckling infant. Oxytocin causes contraction of the myoepithelial cells of the mammary glands, with ejection of milk into the duct system and out of the ducts' openings at the tip of the nipple. Simultaneous contraction of the uterus contributes to the postpartum shrinkage (involution) of this organ for several hours after delivery. Involution of the uterus prevents the hemorrhage that can follow delivery of the placenta.

Pituitary Portal System

Secretion of hormones by the anterior lobe is under the control of the hypothalamus, by a vascular route rather than nervous connections.

Anterior Pituitary Hormones

The following hormones are produced in the anterior lobe:

  1. Follicle-stimulating hormone (FSH)stimulates the growth of ovarian follicles and

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induces their cells to secrete estradiol and other estrogens. In men, FSH makes cells of the seminiferous tubules respond to testosterone; this effect is necessary for the production of spermatozoa.

  1. Luteinizing hormone (LH)stimulates the formation of a corpus luteum in the ovary after ovulation and induces the luteal cells to secrete progesterone. FSH and LH act together to induce ovulation. LH is also known as interstitial cell-stimulating hormone in men because it induces the interstitial cells (Leydig cells) of the testis to secrete testosterone and other androgens.
  2. Prolactinstimulates development of the mammary glands and lactation. Its action, if any, in men is unknown.
  3. Thyrotrophicor thyroid-stimulating hormone (TSH) stimulates the thyroid gland to synthesize and release thyroxine and triiodothyronine.
  4. Adrenocorticotrophic hormone (ACTH)stimulates the cortex of the adrenal gland to produce and secrete cortisol (hydrocortisone) and other steroids (glucocorticoids) that modulate carbohydrate metabolism and protect against many effects of stress. (Secretion of aldosterone, the corticosteroid that limits sodium excretion and is necessary for life, is not under pituitary control.)
  5. Growth hormone (GH)or somatotrophic hormone (STH) stimulates growth at the epiphyses of the long bones and elsewhere. Its actions are largely mediated by another protein hormone, insulin-like growth factor 1 (ILGF-1), which is secreted by cells acted on by STH. The largest production of ILGF-1 is in the liver.

CLINICAL NOTE

Posterior Pituitary Hormones as Drugs

Vasopressin is used as replacement therapy for neurogenic diabetes insipidus. Larger doses are sometimes used to produce vasoconstriction to control some types of hemorrhage, such as bleeding esophageal varices. Oxytocin is used as a drug to induce labor. Both hormones are octapeptides. These were the first peptide hormones to be sequenced and synthesized, by Du Vigneaud in the 1950s. This achievement led to a Nobel Prize.

CLINICAL NOTE

Kallman's Syndrome

The neurons that produce LHRH (GnRH) have an unusual embryonic origin. They are generated in the olfactory placode, an area of ectoderm that gives rise to the olfactory epithelium of the nose, the glial cells of the olfactory nerves, and the tiny nervus terminalis (see Chapter 17). Neurons that synthesize LHRH migrate centrally along the nervus terminalis to the region of the lamina terminalis and enter the preoptic and anterior hypothalamic areas. Because they stimulate secretion of gonadotrophins, these neurons are essential for the functions of the testes and ovaries. Kallman's syndrome is a rare disorder in which defective development of the olfactory placode causes anosmia and nonfunctional gonads. The condition is associated with absence of hypothalamic LHRHcontaining neurons.

The pituitary portal system begins with the superior hypophysial arteries, which arise from the internal carotid arteries at the base of the brain and break up into capillary tufts and loops in the median eminence (Fig. 11-18). The capillaries are drained by veins that pass along the pituitary stalk and then enter the anterior lobe of the gland, where they empty into large capillaries or sinusoids among the hormone-producing cells. The preoptic area and hypothalamus contain neurons that produce releasing hormones, which are peptides and at least two release-inhibiting hormones (a peptide called somatostatin for STH and the catecholamine dopamine for prolactin). There is a separate hypothalamic-releasing hormone for each hormone of the anterior lobe, with the exception of FSH, which is secreted in response to the LH-releasing hormone, which is known as either LHRH or GnRH (gonadotrophin-releasing hormone). The releasing and inhibiting hormones pass distally by axoplasmic transport in the axons of the cells that produce them, enter the capillaries of the portal system in the median eminence, and are then delivered in locally high concentrations to cells of the anterior lobe. There they modulate the synthesis of the adenohypophysial hormones and their release into the general circulation.

The neurosecretory cells that produce releasing and release-inhibiting hormones are influenced by the various afferent fiber connections of the hypothalamus. Their activity is more directly regulated, however, by hormones of the target organs of pituitary hormones. For example, when the concentration of triiodothyronine in the blood is high, hypothalamic cells that produce thyrotrophin-releasing hormone (TRH) are suppressed. Conversely, if the circulating

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levels of thyroid hormones are low, the hypothalamic cells produce more TRH. This stimulates increased output of TSH, and the thyroid gland, in its turn, is induced to synthesize and release more of its hormones.

 

FIGURE 11-18 The pituitary portal system. Arteries are red, veins are blue, and neurons that secrete releasing hormones are black.

Third Ventricle

The diencephalic part of the ventricular system consists of the narrow third ventricle (see Fig. 11-2). The anterior wall of this ventricle is formed by the lamina terminalis; theanterior commissure crosses the midline in the dorsal part of the lamina terminalis. The rather extensive lateral wall is marked by the hypothalamic sulcus, which runs from the interventricular foramen to the opening of the cerebral aqueduct and divides the wall of the third ventricle into thalamic and hypothalamic regions. An interthalamic adhesion(massa intermedia) bridges the ventricle in 70% of human brains. The floor of the third ventricle is indented by the optic chiasma. An optic recess is located in front of the chiasma; behind the chiasma, the infundibular recess extends into the median

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eminence and the proximal part of the pituitary stalk. The floor then slopes upward to the cerebral aqueduct of the midbrain, with the posterior commissure forming a slight prominence above the entrance to the aqueduct. A pineal recess extends into the stalk of the pineal gland, and the dorsal wall of the pineal stalk accommodates the smallhabenular commissure. Immediately ventral to the body of the fornix, the membranous roof of the third ventricle is attached along the striae medullares thalami. A small choroid plexus is suspended from the roof. The body of the fornix (see Figs. 11-11 and 11-12) is located immediately above the membranous roof.

Cerebrospinal fluid enters the third ventricle from each lateral ventricle through the interventricular foramen (foramen of Monro). The crescent-shaped foramen is bounded by the fornix and by the anterior tubercle of the thalamus and is closed posteriorly by a reflection of ependyma between the fornix and the thalamus. The subfornical organ, mentioned earlier in this chapter, is a small eminence on the medial side of the column of the fornix, above the interventricular foramen. It is one of the circumventricular organs—a nucleus of neurons containing blood vessels that are permeable to circulating macromolecules, unlike the vessels of most parts of the brain. In laboratory animals, the nucleus responds to circulating levels of angiotensin II, a peptide whose concentration in plasma varies with circulating levels of sodium and potassium ions and with changes in blood volume. The neurons of the subfornical organ project to the zona incerta and hypothalamus, and their activity influences drinking.

Cerebrospinal fluid leaves the third ventricle by way of the cerebral aqueduct of the midbrain, through which it reaches the fourth ventricle and then the subarachnoid space surrounding the brain and spinal cord.

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