Principles and Practice of Endocrinology and Metabolism



Overview of the Hypothalamus
Nuclear Topography

Hypothalamic Zones

Preoptic Area
Classic Pathways

Afferent Pathways

Efferent Pathways

Hypothalamo-Neurohypophysial System
Chemical Neuroanatomy

Hormones as Chemical Neurotransmitters

Vasopressin Release as a Model of Interactive Chemical Circuitry
Chapter References

The human hypothalamus is a tiny wedged-shaped mass of tissue, composed primarily of gray matter, that subserves widespread functions, ranging from those considered somewhat automatic (i.e., autonomic) to more complex behaviors requiring a high level of integration. The hypothalamus is situated in the ventralmost diencephalon (Fig. 8-1). It is bounded laterally by portions of the subthalamus; medially by the vertically oriented, slitlike third ventricle; rostrally by the lamina terminalis; caudally by the mesencephalon; and dorsally by the thalamus. Ventrally, the hypothalamus is contiguous with the infundibulum and pituitary stalk; the latter serves to transmit axons en route to the neurohypophysis. On the ventral surface of the brain, the hypothalamus appears as a prominent set of protuberances, the paired mammillary bodies caudally, and the midline infundibular eminence. The boundaries of the hypothalamus are easily identified by the optic chiasm rostrally and by the caudal edge of the mammillary bodies as they are situated at the rostral limit of the interpeduncular fossa. Here, the caudal limits of the hypothalamus merge with the midbrain.

FIGURE 8-1. Human hypothalamus in sagittal section. The hypothalamus is bounded anteriorly by the lamina terminalis, the tissue that bridges the anterior commissure and optic chiasm; posteriorly by the brainstem; and dorsally by the overlying thalamus (adjacent to the label for the third ventricle). The hypothalamus is relatively small in comparison to other brain regions, yet is intimately involved in mediating or moderating many brain and endocrine functions. (From Krieger DT, Hughes JC, eds. Neuroendocrinology. Sunderland, MA: Sinauer Associates, 1980:3.)

Classic neuroanatomic techniques have been used to identify hypothalamic nuclei cytoarchitectonically. Some nuclei are relatively easy to identify microscopically, based on size or packing density of neurons; others benefit from placement close to readily identified landmarks such as the third ventricle or the optic chiasm. Prominent myelinated fiber bundles punctuate the relatively nondescript nuclear divisions of the hypothalamus, indicating the diverse reciprocal connections that exist between the hypothalamus and numerous brain regions. The fornix and mammillary fasciculus interconnect the hypothalamus with, for example, the hippocampus, the thalamus, and the brainstem. Other brain regions influence hypothalamic function through pathways that are seen to advantage with current histochemical methods. These systems, which include the medial forebrain bundle and the dorsal longitudinal fasciculus, interconnect the hypothalamus with olfactory areas rostrally and with autonomic centers of the brainstem and spinal cord caudally. Thus, the hypothalamus is an important link between the forebrain and brainstem, integrating visceral, endocrine, and behavioral functions through a highly ordered set of reciprocating circuits.
Because the hypothalamus is so rich in perikaryal groups and so poor in landmarks (e.g., myelinated fiber bundles), the prudent approach is to consider easily identified hypothalamic zones as geographic points with respect to the more than two dozen classically identified hypothalamic nuclei, as detailed by Nauta and Haymaker.1 Zones in both longitudinal and coronal planes are illustrated in Figure 8-2.

FIGURE 8-2. Diagram showing anatomic relationship of hypothalamic nuclei, by zones. Here, the hypothalamus is considered as a hexagon, bordered anteriorly by the preoptic area and posteriorly by the midbrain. The third ventricle (wide black line) forms its midline. Most hypothalamic nuclei can be found within three longitudinal zones, designated as midline, medial, and lateral in relation to the third ventricle and fornix. These zones can be further subdivided into three anteroposterior regions or levels (supraoptic, tuberal, and mammillary), allowing identification of hypothalamic nuclei by position, an approach that is much simpler than distinguishing the nuclei by the classic cytoarchitectonic method. The three levels, shown in the coronal plane in Figure 8-3, depict the essential hypothalamic nuclei.

Longitudinal Plane. The longitudinal zones are based on the phylogenetically primitive organization of lower vertebrates, in which the hypothalamus is characterized by a relatively cell-rich medial zone. A somewhat acellular lateral zone is separated from the medial zone by a prominent fiber bundle, the fornix. The medial zone can be subdivided further into a midline zone that is immediately adjacent to the third ventricle and contains a relatively homogeneous nuclear mass called the periventricular stratum. The more laterally placed portions of the medial hypothalamic zone contain reasonably differentiated cell clusters, including the medial preoptic, anterior hypothalamic, ventromedial, dorsomedial, paraventricular, posterior, and premammillary nuclei.
Coronal Plane. For convenience, the hypothalamus in the coronal plane can be further subdivided anteroposteriorly into three regions: the supraoptic, tuberal, and mammillary regions (Fig. 8-3 and Fig. 8-4). The supraoptic region includes that portion of the hypothalamus situated between the optic chiasm and tuber cinereum. The tuberal zone extends caudally to the most anterior portion of the mammillary bodies. The mammillary region includes the most caudal hypothalamus to the mesodiencephalic junction.

FIGURE 8-3. The hypothalamus in the coronal plane, demonstrating the relative positions of hypothalamic nuclei. At the supraoptic level, the midline zone (dashed line) consists of the periventricular nucleus (Peri) and its ventral expansion, the suprachiasmatic nucleus (SCN). The periventricular nucleus continues through the more caudal levels. At tuberal levels, the SCN is replaced by the arcuate nucleus (Arc). The medial zone, defined as all the tissue between the fornix laterally and the periventricular nucleus medially, contains five major hypothalamic nuclei that essentially replace each other positionally at each level. Thus, the paraventricular (PVN) and anterior (AN) nuclei, which occupy the supraoptic level, are replaced by the dorsomedial (DM) and ventromedial (VM) nuclei at tuberal levels; these nuclei in turn are replaced by the posterior nucleus (POST) at the most caudal, mammillary level. The lateral zone consists almost exclusively of the lateral hypothalamic area (LHA), with the exception of the supraoptic nucleus (SON), which is seen at supraoptic levels. The third ventricle appears as the dark structure in the midline. (F, fornix; ME, median eminence; MM, mammillary body; OC, optic chiasm; OT, optic tract.)

FIGURE 8-4. The hypothalamus in a parasagittal plane, showing the relative positions of major nuclei. These relationships can be better appreciated by comparing this figure with Figure 8-1 and Figure 8-3. For example, three nuclear groups, the paraventricular, dorsomedial, and posterior, appear to replace one another as one proceeds anatomically, rostrally to caudally, through the three major coronal levels—supraoptic, tuberal, and mammillary (see Fig. 8-3). (From Carpenter MB, Sutin J, eds. Human neuroanatomy. Baltimore: Williams & Wilkins, 1983:553.)

The midline zone accordingly contains the periventricular stratum throughout most of its rostrocaudal extent. At tuberal regions, the ventral periventricular stratum expands laterally to accommodate the arcuate (infundibular) nucleus. At supraoptic levels, a ventral region of the periventricular stratum is identified as the suprachiasmatic nucleus. Although numerous other fine points of periventricular zone anatomy exist, one could consider the two subcomponents of this region as the suprachiasmatic and arcuate nuclei. The medial hypothalamic zone, defined as all remaining tissue lateral to the periventricular stratum and medial to the descending limb of the fornix, contains the paraventricular and anterior hypothalamic nuclei at supraoptic levels, the dorsomedial and ventromedial nuclei at tuberal levels, and the posterior hypothalamic nucleus at mammillary levels (see Fig. 8-3). Thus, as one proceeds rostrally to caudally through the three hypothalamic regions, a gradual replacement of these well-differentiated nuclei is seen. The lateral hypothalamic zone is relatively undistinguished, with the lateral hypothalamic area occupying most of this zone in all three regions. The lone exception is the supraoptic nucleus, which is seen at the supraoptic level. Because of the complex nature of the paraventricular nucleus, it is sometimes considered as part of the periventricular zone, but the alarlike lateral extensions of this nucleus clearly place a large part of it within the medial zone.
The preoptic area, located rostral to the strict limits of the hypothalamus, contains nuclei in all three (medial to lateral) zones, including the preoptic periventricular, medial preoptic, and lateral preoptic nuclei (see Fig. 8-4). Functionally, the preoptic region is integrated with the remainder of the hypothalamus because it includes neurons that regulate anterior pituitary function as well as structures that are essential for fluid and electrolyte balance. A full description of these hypothalamic regions and nuclei may be found in two classic accounts.1,2
Afferent pathways to hypothalamic nuclei arise primarily from the brainstem, thalamus, basal ganglia, cerebral cortex, and olfactory areas. The detailed anatomy of these connections and hypothalamic interconnections is described in several fine reviews.1,3,4 Briefly, the reticular formation and visceral centers of the brainstem connect with the hypothalamus through two prominent pathways, the mammillary peduncle and the dorsal longitudinal fasciculus. Visceral and somatic information also reaches the hypothalamus from the locus ceruleus, vagal nuclei, periaqueductal gray area, and nuclei of the solitary tract (Fig. 8-5). The fornix transmits fibers from the hippocampus by direct projections to the mammillary bodies. Additional afferents from the piriform cortex and the amygdala also reach the hypothalamus, probably by other routes. Olfactory information through the medial forebrain bundle and stria terminalis reaches the hypothalamus either directly or indirectly through the previously mentioned cortical regions, the stria terminalis being the primary pathway from the amygdala. Most of the afferent pathways are reciprocal; thus, the hypothalamic efferent connections are extensive.

FIGURE 8-5. Major hypothalamic pathways. Pathways to the hypothalamus arise from several areas, including olfactory, limbic, and brainstem regions; reciprocal circuits exist, particularly to autonomic centers of the caudal medulla and spinal cord. The dorsal longitudinal fasciculus conveys most of the descending information to brainstem nuclei and is identified by the parallel, opposite arrows in this drawing. Another major pathway, the fornix, carries higher cortical information from the hippocampus (Hipp.) to the mammillary nucleus. (AV, nucleus ventralis anterior of thalamus; BL, Ce., and Co., basolateral, central, and cortical amygdaloid nuclei; Bulb. olf., olfactory bulb; Coll. sup., superior colliculus; H, hypothalamus; M, mammillary body; MD, dorsomedial thalamic nucleus; N. Dors. n. X, dorsal motor vagal nucleus; N. loc. coer., locus coeruleus; N. raphe, nuclei of the raphe; N. tr. solit., nucleus tractus solitarius; Olf. Cort., olfactory cortex; Optic ch., optic chiasma; Periaq. gr., periaqueductal gray; Prefr. cort., prefrontal cortex; RF, reticular formation; S, septum; VM, ventromedial hypothalamic nucleus.) (From Brodal A, ed. Neurological anatomy in relation to clinical medicine, 3rd ed. New York: Oxford University Press, 1981:698.)

The dorsal longitudinal fasciculus transmits information to brainstem reticular centers as well as to visceral and somatic efferent nuclei. This system descends caudally to innervate preganglionic autonomic centers of the spinal cord, particularly the intermediolateral gray column.5,6 Although the hypothalamus was once thought to interconnect with autonomic centers by multisynaptic pathways, it is now clear that the dorsal motor nucleus of the vagus, the nuclei of the solitary tract, and the nucleus ambiguus receive direct projections from the paraventricular nucleus of the hypothalamus. Thus, reciprocal connections between these regions form an integrated autonomic circuit. Other fibers reach the brainstem through the medial forebrain bundle.
Hypothalamic efferents projecting to the thalamus traverse the mammillothalamic tract to the anterior nucleus of the thalamus, where they are relayed to the cerebral cortex. Other efferent fibers ascend over the more diffuse periventricular system. The hypothalamus is connected with the neurohypophysis by the hypothalamo-neurohypophysial tract, a system of unmyelinated fibers that terminates in the neurohypophysis for the purpose of storing and then delivering vasopressin, oxytocin, and possibly other endogenous peptides such as dynorphin to the pituitary blood.
In contrast to other hypothalamic nuclei, the paraventricular and supraoptic nuclei are easy to identify (Fig. 8-6). Each nucleus contains the largest nerve cells in the hypothalamus (Fig. 8-7). The cells stain densely with common dyes that reveal the abundant ribonucleoprotein (i.e., Nissl substance) in their perikaryal cytoplasm. Ultrastructurally, the protein-synthesizing machinery of these neurons also is evident and reflects their high level of activity with respect to the manufacture of vasopressin, oxytocin, and coexistent peptides. The neurons are revealed in excellent detail when stained immunohistochemically with antibodies directed against specific hypothalamic peptides (see Fig. 8-7).7,8 Such analysis has revealed that oxytocin neurons also contain cholecystokinin9 and that vasopressin neurons also contain dynorphin.10 Axons from the supraoptic and paraventricular nuclei as well as associated accessory nuclei of the hypothalamus project ventrally and caudally (see Fig. 8-6) to the underlying neurohypophysis, where they release oxytocin, vasopressin, and associated peptides into the peripheral circulation to regulate fluid and electrolyte balance and to initiate the smooth muscle contraction that is associated with lactation and parturition.

FIGURE 8-6. Immunohistochemical staining for neurophysins associated with vasopressin and oxytocin reveals the extent of the neurohypophysial system at the supraoptic level of the rat hypothalamus. Dense staining is seen within neurons of the paraventricular (PVN) and supraoptic (SON) nuclei. A ventral flow of axons from each nucleus (arrows) represents the origin of the hypothalamo-neurohypophysial tract as it courses to the posterior pituitary. Stained neurons also are seen within the suprachiasmatic nucleus (SCN); however, this nucleus does not contribute fibers to the neural lobe. (OC, optic chiasm; V, third ventricle.) Original magnification ×30

FIGURE 8-7. Appearance of neurons of the paraventricular nucleus after immunohistochemical staining for vasopressin. This set of magnocellular neurons occupies a subnucleus of the paraventricular nucleus that contains primarily vasopressin neurons that project to the neural lobe.30 The neurons are large, multipolar, and possess beaded processes. The position of the third ventricle is indicated (V). Original magnification ×350

Other neurons of the paraventricular nucleus are global, with widespread connections to autonomic centers of the brainstem and spinal cord, and to the forebrain and cortical areas, including the septum, cingulum, and hippocampus.11a These far-reaching interconnections focus attention on oxytocin and vasopressin as more than simply neurohypophysial hormones. The demonstration of these peptides in presynaptic nerve terminals suggests that they may function as neurotransmitters.
The hypothalamus is one of the most complicated areas of the brain with respect to chemical neurotransmitters because of the small amount of tissue occupied by the hypothalamus and the great number of transmitter substances located within hypothalamic nerve cells and associated fiber systems.12 The classic studies of Bargmann13 and of Scharrer and Scharrer,14 who are credited with describing the principles of neurosecretion, brought to light the unique chemical characteristics of neurons of the supraoptic and paraventricular nuclei. The introduction in the early 1960s of the Falck-Hillarp histofluorescence method15 allowed identification of the catecholamines dopamine and norepinephrine within the hypothalamus. Most notable were the dopaminergic neurons of the tuberoinfundibular system, which are involved in regulating the release of anterior pituitary substances.16 A decade later, immunohistochemical methods17 increased the list of known hypothalamic chemical neurotransmitters and modulators to include substances such as luteinizing hormone–releasing hormone, corticotropin-releasing hormone, vasoactive intestinal peptide, neurotensin, somatostatin, enkephalin, endorphin, cholecystokinin, galanin, and several others.18,19 Although the discovery of luteinizing hormone–releasing hormone20 and somatostatin within hypothalamic, preoptic, and adjacent regions of the endocrine hypothalamus was not surprising, the finding of “gut peptides” and the discovery of a complex system of opioid neurons21 have redefined the hypot halamus, based on the chemical cytoarchitecture of transmitters and hormones.18,21a
The application of in situ hybridization techniques to localize messenger RNA for these peptides indicates that this wide array of peptides is synthesized in the hypothalamus and that neurons have the capacity to synthesize multiple regulatory peptides simultaneously.22 The specific peptides produced by a given neuron are not static but depend on the stimuli received by that cell.22,23 For example, hypophysectomy dramatically increases the expression of galanin in the vasopressin neurons of the supraoptic nucleus and of cholecystokinin in the oxytocin neurons, but salt loading induces the expression of tyrosine hydroxylase in the vasopressin neurons and of corticotropin-releasing hormone in the oxytocin neurons.24 The role of these simultaneously released peptides is not completely defined, but in at least some instances, they interact to regulate hormone release from the anterior pituitary or to modulate hormone release from the posterior pituitary.
The role of afferents to the paraventricular and supraoptic nuclei is considered relative to the regulation of vasopressin release as exemplary of the kind of functionally interactive chemical circuitry that is being revealed with respect to hypothalamic neuroanatomy. The supraoptic and paraventricular nuclei receive dense, diverse afferent inputs, many arising from the brainstem reticular formation. One of these is a well-defined system of noradrenergic afferents to vasopressin neurons of the supraoptic and paraventricular nuclei (Fig. 8-8). The paraventricular nuclei in turn send reciprocal peptidergic fibers to the reticular core of the brainstem. Norepinephrine-containing perikaryal groups in the brainstem have been designated A1 to A7.25 These noradrenergic neurons originally were seen primarily within the reticular formation of the pons and medulla. Later, attention focused on groups A1, A2, A5, and A7 as projecting to the hypothalamus through a ventral pathway that ascends within the dorsal portion of the reticular formation of the brainstem, entering the medial forebrain bundle at hypothalamic levels in association with serotonergic and dopaminergic systems from the brainstem.26 On reaching the hypothalamus, these fibers exit the medial forebrain bundle to supply the supraoptic and paraventricular nuclei. The densest patterns of noradrenergic fibers—perhaps the densest patterns in the entire brain—are seen in the mammalian hypothalamus27,28 (Fig. 8-9). These fibers appear in contact with the cell bodies of the magnocellular neurons, lending further support to the concept that norepinephrine plays a role in the regulation of neurohypophysial peptides.29

FIGURE 8-8. Ascending noradrenergic axons reach the magnocellular nuclei of the hypothalamus through the ventral norepinephrine pathway (VNE) of the brainstem, which continues rostrally in the medial forebrain bundle (MFB) of the diencephalon. The neurons of origin of this system (A1, A2) are located in the lateral reticular formation of the medulla near the lateral reticular nucleus (LRN) and in an area of the dorsomedial medulla that is important in cardiovascular regulation—the nucleus solitarius (SOL) and the dorsal motor vagal nucleus (DMX), respectively. This pathway, which is probably reciprocal from the paraventricular nucleus (PVN), supplies a dense noradrenergic innervation to the magnocellular nuclei, as shown for the monkey (also see Fig. 8-9). (CC, corpus callosum; MLF, medial longitudinal fasciculus; OC, optic chiasm; PY, pyramidal tract; SON, supraoptic nucleus.)

FIGURE 8-9. Patterns of catecholamine innervation of hypothalamic nuclei at a supraoptic level in the rhesus monkey. Exceptionally dense patterns exist in the paraventricular (Pa) and supraoptic (So) nuclei; less impressive patterns are seen in other nuclei at this level. Depictions such as this led to intense examination of the role of catecholamines in the release of neurohy-pophysial peptides. (An, anterior nucleus; op ch, optic chiasma; Prl, lateral preoptic nucleus; Sc, suprachiasmatic nucleus; v, third ventricle.) (From Hoffman GE, Felten DL, Sladek JR Jr. Monoamine distribution in primate brain. III. Catecholamine-containing varicosities in the hypothalamus of Macaca mulatta. Am J Anat 1976; 147:501.)

In subsequent studies, the simultaneous demonstration of catecholamine fluorescence and peptide immunohistochemistry30 revealed a consistent juxtaposition between catecholamine varicosities and magnocellular perikarya in the supraoptic and paraventricular nuclei in both rodents31 and primates.32 Specifically, vasopressin-containing neurons in ventral portions of the supraoptic nucleus and the major vasopressin subcomponent of the paraventricular nucleus were seen to be studded with brightly fluorescent catecholamine-containing varicosities. In contrast, oxytocin neurons received far fewer fluorescent fibers on their cell bodies and proximal dendrites. The preferential innervation of vasopressin neurons primarily reflects innervation by the A1 noradrenergic cells of the ventrolateral medulla.33,34 and 35 The sparse innervation of the oxytocin neurons reflects innervation of the nuclei by the A2 noradrenergic cell group that does not differentiate between oxytocin and vasopressin neurons.35
The noradrenergic cell groups in the brainstem that innervate the vasopressin neurons are intimately involved in autonomic regulation. The A2 catecholamine neurons are located in the nucleus of the tractus solitarius, which receives baroreceptor information from the carotid sinus and aortic arch. This information is also transmitted to the A1 cells in the ventrolateral medulla that project to the vasopressin neurons.36 The paraventricular nucleus also is innervated by the locus ceruleus (A6), an important autonomic relay center.37 Thus, the catecholamine input to the supraoptic and paraventricular nuclei represents a source of autonomic regulation of neurohypophysial function. These pathways are important because blood pressure, blood volume, and the partial pressure of oxygen are potent regulators of vasopressin release from the neural lobe.
Stimulation of the A1 region results in an increase in blood pressure and enhanced vasopressin release, and inhibition of this region prevents baroreceptor-initiated secretion of vasopressin.38 This response is prevented by destruction of the catecholamine terminals in the supraoptic and paraventricular nuclei39 but is not prevented by administration of adrenergic antagonists.40 This can be explained by the finding that, in addition to norepinephrine, the A1 neurons produce neuropeptide Y, adenosine triphosphate (ATP), and substance P.41,42 Pharmacologic evidence indicates that these neuroactive substances participate in the excitation of vasopressin neurons by the A1 pathway.43,44
The central role of the paraventricular nucleus and vasopressin in blood pressure regulation and other autonomic functions was underscored by the finding of reciprocal pathways containing vasopressin and oxytocin in the same brainstem regions that give origin to the ascending noradrenergic fibers to the supraoptic and paraventricular nuclei. The finding of neurophysin-positive varicosities in juxtaposition to norepinephrine perikarya in the A1, A2, A5, and A7 brainstem groups suggests a functionally interactive reciprocal circuit.45 Moreover, microinjection of vasopressin into these regions has profound effects on cardiovascular function. Thus, a reciprocal pathway involving catecholamine afferents and vasopressin efferents is one mechanism involved in hypothalamic modulation of the autonomic nervous system.
The paraventricular and supraoptic nuclei receive chemically defined afferents from other central nervous system sites.46,47 These include serotonergic projections from the midbrain raphe nuclei, GABAergic (transmitting or secreting g-aminobutyric acid) projections from the region of the nucleus accumbens, and several hypothalamic projections. The hypothalamic afferents include cholinergic48 and GABAergic projections arising from cells near the paraventricular and supraoptic nuclei, b-endorphinergic afferents from the arcuate nucleus, histaminergic afferents from the tuberomammillary nuclei,49,50 dopaminergic afferents from neurons in the A11, A12, and A13 groups,51 and numerous projections from the preoptic region, including projections from the subfornical organ and the organum vasculosum of the lamina terminalis. The chemical nature of these last projections includes glutamatergic, GABAergic, angiotensinergic, and atriopeptidergic fibers. The functional role of many of these afferents is unknown, but the afferents from the preoptic region and the circumventricular organs clearly are intimately involved in the osmotic regulation of vasopressin release as part of their role in fluid and electrolyte balance. A particularly important role for the classic excitatory amino acid neurotransmitter glutamate in regulating hypothalamic activity has been suggested by the presence of numerous immunocytochemically identified glutamatergic synapses in the hypothalamus and the finding that glutamate antagonists virtually eliminate excitatory postsynaptic potentials in the paraventricular, supraoptic, and arcuate nuclei. Thus, the hypothalamus continues to emerge as a complex brain region in which a wide variety of classic and more recently discovered transmitters serve numerous endocrine and other functions related to autonomic, limbic, and pituitary activity.52

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