The Hypothalamus

Figure 30-1. The interrelationships among the autonomic, endocrine, and limbic systems. All three systems are under the control of the hypothalamus.

BOUNDARIES OF THE HYPOTHALAMUS

The rostral boundary of the hypothalamus is the lamina terminalis, a thin membrane that extends ventrally from the anterior commissure to the rostral edge of the optic chiasm and represents the anterior boundary of the third ventricle (Fig. 30-2A). The lamina terminalis separates the hypothalamus from the more rostrally located septal nuclei. Superiorly, the hypothalamus is bounded by the hypothalamic sulcus, a shallow groove that separates the hypothalamus from the dorsal thalamus (Fig. 30-2A, C). The lateral boundary of the hypothalamus is formed rostrally by the substantia innominata and caudally by the medial edge of the posterior limb of the internal capsule (Fig. 30-2B, C; see also Fig. 15-7). Medially, the hypothalamus is bordered by the inferior portion of the third ventricle. Caudally, the hypothalamus is not sharply demarcated, merging instead into the midbrain tegmentum and the periaqueductal gray. Externally, the boundary between the hypothalamus and the midbrain is represented by the caudal edge of the mammillary body. This is an especially good landmark to use when viewing a sagittal magnetic resonance image in the diagnosis of hypothalamic lesions.

Figure 30-2. Midsagittal view (A) of the brain emphasizing hypothalamic structures. Cross sections of the hypothalamus through preoptic (B), tuberal (C), and mammillary (D) regions. The myelin-stained sections in B, C, and D correspond to the comparably labeled lines in A. (B From Haines DE: Neuroanatomy: An Atlas of Structures, Sections, and Systems, 8th ed. Baltimore, Lippincott Williams & Wilkins, 2012.)

HYPOTHALAMUS AND PITUITARY

Inferiorly, the hypothalamus is continuous with the pituitary gland (located in the sella turcica and covered by the diaphragma sellae) by way of the infundibulum and the hypophysial stalk (Fig. 30-3). The infundibulum is located immediately caudal to the optic chiasm, is somewhat funnel shaped (hence its name), and contains a small portion of the third ventricle, the infundibular recess. The infundibulum continues into the pituitary by a stalk of tissue that is sometimes called the hypophysial stalk. This stalk passes through an opening in the diaphragma sellae.

Figure 30-3. The contributions from the stomodeum and the developing brain to the formation of the pituitary of the adult. Developmental defects in this area may give rise to a craniopharyngioma, also called a Rathke pouch tumor.

The pituitary originates from two sources and directions. The posterior lobe (pars nervosa) arises as an outpocketing of the inferior surface of the developing diencephalon (Fig. 30-3). The anterior lobe (adenohypophysis) arises as an infolding of the ectodermal lining of the roof of the developing oral cavity (the stomodeum) and is commonly referred to as the Rathke pouch (Fig. 30-3). The smaller portions of the pituitary, the tuberal part (pars tuberalis) and the intermediate part (pars intermedia), also originate in association with the anterior lobe. As development progresses, these separate structures join to form the pituitary of the adult (Fig. 30-3).

Although the pituitary is well protected in the sella turcica, it is, at the same time, subject to a variety of potential insults (tumor, vascular, surgical) in this confined location. In addition, the extension of the hypophysial stalk and infundibulum through the diaphragma sellae is a vulnerable relationship. For example, trauma to the head may result in a shearing of the stalk and the eventual development of diabetes insipidus.

DIVISIONS OF THE HYPOTHALAMUS

The hypothalamus can be divided into the preoptic area and the lateral, medial, and periventricular zones (Fig. 30-4). The preoptic area is a transition region that extends rostrally, by passing laterally to the lamina terminalis, to form a continuation with structures in the basal forebrain. Three zones are located caudal to the preoptic area. The thin periventricular zone is the most medial and is subjacent to the ependymal cells that line the third ventricle. The medial zone is located lateral to the periventricular zone, and a line drawn from the postcommissural fornix to the mammillothalamic tract separates it from the lateral zone (Fig. 30-4).

Figure 30-4. Diagrammatic representation of the hypothalamus in the axial (horizontal) plane showing the zones and regions.

Preoptic Area

The preoptic area, although functionally a part of the hypothalamus (and diencephalon), is embryologically derived from the telencephalon. This area is composed primarily of the medial and lateral preoptic nuclei (Fig. 30-4). The medial preoptic nucleus contains neurons that manufacture gonadotropin-releasing hormone (GnRH). GnRH is transported along the tuberoinfundibular tract to capillaries of the hypophysial portal system and thence to the anterior lobe of the pituitary gland (Fig. 30-5; see Table 30-2), where it causes the release of gonadotropins (luteinizing hormone and follicle-stimulating hormone). Because gonadotropin release is continuous in males and cyclic in females, the medial preoptic nucleus of males tends to be more active and consequently larger than that of females. Accordingly, the medial preoptic nucleus is often referred to as the sexually dimorphic nucleus of the preoptic area. The medial preoptic nucleus also influences behaviors that are related to eating, reproductive activities, and locomotion. The lateral preoptic nucleus is located immediately rostral to the lateral hypothalamic zone (Fig. 30-4). The function of this nucleus is not fully established. However, through its connections with the ventral pallidum, it may function in part in locomotor regulation. Some investigators consider the nuclei of the preoptic area to be part of the supraoptic region of the medial hypothalamic zone.

Figure 30-5. Midsagittal view of the hypothalamus emphasizing the nuclei that contribute to the tuberoinfundibular and supraopticohypophysial tracts, the hypophysial portal system, and the general relations of the fornix and mammillothalamic tract.

Lateral Zone

The lateral zone (Fig. 30-4) contains a large bundle of axons collectively called the medial forebrain bundle (Fig. 30-4; see also Fig. 30-9). This diffuse bundle of fibers traverses the lateral hypothalamic zone and interconnects the hypothalamus with rostral areas, such as the septal nuclei, and with caudal regions, such as the brainstem reticular formation.

The lateral hypothalamic zone comprises a large, diffuse population of neurons commonly called the lateral hypothalamic area as well as smaller condensations of cells located in its anterior (ventral) portions. The latter cell groups are the lateral hypothalamic nucleus and the tuberal nuclei. The lateral hypothalamic nucleus is a loose aggregation of relatively large cells that extends throughout the rostrocaudal extent of the lateral hypothalamic zone. This nucleus constitutes a “feeding center.” Stimulation of this nucleus in laboratory animals promotes feeding behavior; destruction of it causes feeding behavior to attenuate, and the animal loses weight (Table 30-1). The tuberal nuclei consist of small clusters of neurons, each containing small, pale, multipolar cells. Some tuberal neurons project into the tuberoinfundibular tract and therefore may convey releasing hormones to the hypophysial portal system. Others send a histaminergic input to the cerebellum that may be involved in the regulation of motor activity.

Table 30-1 Effect of Stimulation or Lesion of the Principal Hypothalamic Nuclei

Medial Zone

The medial zone is a cell-rich region composed of many individual nuclei (Figs. 30-4 and 30-5). It is divided into three regions: the supraoptic (chiasmatic) region, the tuberal region, and the mammillary region (Fig. 30-4).

Before the major nuclei of the medial zone are considered, it should be stressed that the nuclei comprising each region of this zone are located internal to surface structures that specify the location or position of that specific region (Fig. 30-6). For example, the supraoptic region is located internal to the position of the optic chiasm (Figs. 30-5 and 30-6). The tuberal region is the widest part of the hypothalamus and in general is located internal to the position of the tuber cinereum (Figs. 30-5 and 30-6). The mammillary region is the most posterior of the three regions of the medial zone, and it is located internal to the mammillary bodies (Figs. 30-5 and 30-6).

Figure 30-6. The inferior aspect of the forebrain showing the external structures that correspond with the locations of the three internal regions that collectively comprise the medial hypothalamic zone; each region has its own respective nuclei (compare with Figs. 30-4 and 30-5). The internal region appears in parentheses under the name of the corresponding external structure.

The supraoptic region contains four nuclei: the supraoptic, paraventricular, suprachiasmatic, and anterior nuclei (Fig. 30-5). Neurons of the supraoptic and paraventricular nuclei contain oxytocin and antidiuretic hormone (ADH, vasopressin) and transmit these substances to the posterior pituitary by way of the supraopticohypophysial tract for release into the circulatory system (Fig. 30-5). The functions of these hormones are discussed later in this chapter. The suprachiasmatic nucleus receives direct input from the retina and can influence other hypothalamic structures, such as the medial preoptic nucleus. It is believed that the suprachiasmatic nucleus may mediate circadian rhythms, these being the hormonal fluctuations that are secondary to light-dark cycles. The anterior nucleus is located immediately caudal to the preoptic area. Although this nucleus participates in a wide range of visceral and somatic functions, many of its neurons are involved in the maintenance of body temperature.

The tuberal region contains three nuclei: the ventromedial, dorsomedial, and arcuate nuclei (Figs. 30-2C and 30-5). The ventromedial nucleus, one of the largest and best defined of the hypothalamic nuclei, is considered to be a “satiety center.” If this nucleus is stimulated in the laboratory, the experimental animal will not engage in feeding behavior. Conversely, a lesion to this nucleus causes the animal to eat excessively and to gain weight (Table 30-1). The dorsomedial nucleus, located immediately posterior (dorsal) to the ventromedial nucleus, subserves a function relating to emotion or, at least, to emotional behavior. In laboratory animals, stimulation of the dorsomedial nucleus results in unusually aggressive behavior, which lasts only so long as the stimulation is present (Table 30-1). This phenomenon, known as sham rage, can also be elicited by the stimulation of other hypothalamic and extrahypothalamic sites. The arcuate nucleus is the primary location of neurons that contain releasing hormones. These substances are transmitted to the anterior pituitary by way of the tuberoinfundibular tract and hypophysial portal system, whereupon they influence the release of various pituitary hormones (Fig. 30-5). Lesions of the human hypothalamus frequently involve multiple nuclei. Elements of the deficits seen in animal experiments are present in various combinations or, to various degrees, in humans with lesions in, or impinging on, hypothalamic structures.

The mammillary region contains four nuclei: the medial, intermediate, and lateral mammillary and the posterior hypothalamic nuclei (Figs. 30-2A, D and 30-5). The medial mammillary nucleus is large and especially well developed in the human. It represents the primary termination point for the axons of the postcommissural fornix, which originate primarily from the subiculum of the hippocampal complex. The medial mammillary nucleus is also the source of axons that are directed to the anterior nucleus of the dorsal thalamus as the mammillothalamic tract (Fig. 30-5; see also Fig. 30-8). The latter pathway represents an important part of the limbic system. The much smaller intermediate and lateral mammillary nuclei are located lateral to the medial mammillary nucleus. The lateral mammillary nucleus receives input from the medial aspects of the midbrain reticular formation by way of the mammillary peduncle (see Fig. 30-9).

Insight into the function of the mammillary nuclei comes from experimental and clinical observations. For example, lesions of the mammillary bodies tend to impede the retention of newly acquired memory, so that an immediate memory or a short-term memory is not processed into long-term memory (Table 30-1). A patient with a mammillary lesion has no difficulty in remembering events occurring months or years before the lesion. Memory for events occurring after the lesion is, however, limited to the short term (a period of minutes), and long-term memories are not established. As a result of this anterograde amnesia, affected patients typically have severe difficulties learning new tasks and transforming these experiences into long-term memory. These specific memory deficits are characteristic of the Korsakoff syndrome, a condition that is caused by thiamine deficiency and is typically associated with chronic alcoholism. The memory deficits in this syndrome are caused by progressive degeneration in the mammillary bodies and in functionally related brain structures, such as the hippocampal complex and the dorsomedial thalamic nucleus.

Patients with the Korsakoff syndrome may have difficulty in understanding written material and in conducting meaningful conversations because they tend to forget what was just read or said. An interesting feature of this syndrome is the patient’s tendency to confabulate, that is, to string together fragmentary memories from various events into a synthesized memory of an “event” that never occurred.

The posterior hypothalamic nucleus merges almost imperceptibly with the midbrain periaqueductal gray. Accordingly, this nucleus is associated with the same myriad emotional, cardiovascular, and analgesic functions that have been attributed to the periaqueductal gray.

Periventricular Zone

The periventricular zone (Fig. 30-4), not to be confused with the paraventricular nucleus, is a very thin region composed of small cell bodies lying medial to the medial zone and immediately subjacent to the ependymal cells of the third ventricle. Many neurons of the periventricular zone synthesize releasing hormones. These neurons project by way of the tuberoinfundibular tract to the hypophysial portal system and thus influence the release of various hormones by the anterior pituitary. Consequently, many of the neurons in the periventricular zone serve a function similar to that of neurons located in the arcuate nucleus.

FEEDING MOTIVATION

The lateral hypothalamic nucleus, as stated earlier, is commonly referred to as a feeding center. This is because stimulation of this nucleus will elicit feeding behaviors, whereas a lesion of this nucleus will inhibit the motivation to feed. Stimulation and lesions of the ventromedial nucleus have the opposite effects (Table 30-1). Consequently, the ventromedial nucleus is generally thought of as a satiety center. In recent years, new concepts about feeding motivation have emerged that expand what is known about this topic. These concepts, involving a variety of hormones and peptides, are only briefly explained as follows.

Fat cells secrete a hormone (leptin) that is carried to leptin receptors on various neurons of the arcuate nucleus. Some of these neurons contain the peptides α-melanocyte–stimulating hormone (αMSH) and cocaine- and amphetamine-regulated transcript (CART). Other neurons within the arcuate nucleus contain neuropeptide Y (NPY) and agouti-related peptide (AgRP).

Neurons containing αMSH and CART project to the lateral hypothalamus, paraventricular nucleus, and lateral horn of the spinal cord. These projections promote an increase of thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH). This causes an increase in metabolism, an increase in sympathetic tone, and a decrease in feeding.

Neurons containing NPY and AgRP also project to the lateral hypothalamus and paraventricular nucleus. These projections promote the decrease of TSH and ACTH and cause a decrease in metabolism, an increase in parasympathetic tone, and an increase in feeding. This increase in feeding is thought to be partly mediated by lateral hypothalamic neurons containing the peptide neurotransmitters melanin-concentrating hormone and orexin. Neurons containing these peptides project to widespread areas of cerebral cortex and are thought to be involved in the promotion of various feeding strategies.

BLOOD SUPPLY OF THE HYPOTHALAMUS

The hypothalamus and some immediately adjacent structures are served by small perforating arteries that arise from the circle of Willis (Fig. 30-7). Those branches from the anterior communicating artery and the A₁ segment of the anterior cerebral artery constitute the anteromedial group of perforating arteries (also see Fig. 8-17). In general, these vessels serve the nuclei of the preoptic area and supraoptic region, the septal nuclei, and rostral portions of the lateral hypothalamic area. A few perforating arteries may also arise from the bifurcation of the internal carotid artery.

Figure 30-7. The blood supply to the hypothalamus.

The small perforating arteries that originate from the posterior communicating artery and the P₁ segment of the posterior cerebral artery constitute the posteromedial group (see Fig. 30-7; also see Fig. 8-17

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