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Anatomy of the Hypothalamus

Gross Anatomy

The hypothalamus lies directly above the pituitary gland (Fig. 10) and occupies approximately 2 per cent of the brain volume. It is composed of a number of cell groups as well as fiber tracts that are symmetic about the third ventricle (Fig. 11). In saggital section, the hypothalamus extends from the optic chiasm, lamina terminalis and anterior commissure rostrally to the cerebral peduncle and interpeduncular fossa caudally (Fig. 10). The cavity of the third ventricle lies in the midline. In coronal section (Fig. 12), each of the two symmetric walls of the hypothalamus can be divided into four surfaces: a lateral surface contiguous with the thalamus, subthalmus and internal capsule, the latter dividing the hypothalamus from the corpus striatum; a medial surface extending to the wall of the third ventricle, covered by ependymal cells; a superior surface corresponding to the hypothalamic sulcus that separates the hypothalamus from the central mass of the thalamus; and an inferior surface that is in continuity with the floor of the third ventricle. The external surface of the hypothalamic floor (Fig. 13) gives rise to a median protuberance called the tuber cinereum (or gray swelling due to the pale bluish color of the blood vessels seen in the postmortem human brain), whose central part extends anteriorly and downward into a funnel-like process, the infundibulum or median eminence. The infundibulum is in direct continuity with the infudibular stem of the posterior pituitary gland, and together with the pars tuberalis of the anterior pituitary, forms the pituitary stalk (Fig. 5). Two additional symmetric eminences, the lateral eminences, corresponding to the most lateral portion of the hypothalamic wall and the postinfundibular eminence, as well as the symmetric mammillary bodies, complete the macroscopic morphology of the hypothalamic floor.

Figure 10. Midsaggital section of the human brain (from the XIX century wax collection of human brains at the Museum of the Department of Human Anatomy of the Unversity of Bologna, Italy). The hypothalamus (asterisk) lies above the pituitary gland (cross) and has as its boundaries (1) the anterior commisure and lamina terminalis anteriorly; (2) mamillary bodies and midbrain posteriorly, and (3) thalamus superiorly.(From Lechan R.M. and Toni R., Regulation of Pituitary Function, in Korenman S.G (Ed), Atlas of Clinical Endocrinology, Current Medicine, vol IV, 1-25, 2000).

Figure 11. Magnified view of an immersed fixed human brain in midsagittal orientation. The third ventricle makes up the core of the hypothalamus and extends into the pituitary (or infundibular) stalk, creating the infundibular recess. Many of the major cell groups are located near the midline. These include (from rostral to caudal) the preoptic nucleus (Pop), paraventricular nucleus (Pvn), dorsomedial nucleus (Dm), ventromedial nucleus (Vm), arcuate (or infundibular) nucleus (If), posterior hypothalamic nucleus (Po), and medial mammillary nucleus (mm). Ac = anterior commissure, fx = fornix, lt= lamina terminalis, ot = optic tract and chiasm, Lv = lateral ventricle, MB = midbrain, PN = pons, Sr = supraoptic recess, T = thalamus. (From Lechan R.M. and Toni R., Regulation of Pituitary Function, in Korenman S.G (Ed), Atlas of Clinical Endocrinology, Current Medicine, vol IV, 1-25, 2000).

Figure 12. Coronal section of an immersed fixed human brain at the level of the posterior hypothalamus. The third ventricle (III) lies in the midline directly above the mammillary bodies (m). The subthalamus (sb), zona incerta (zi) and thalamus (T) are located at the superior border of the hypothalamus, whereas the corpus striatum (ST) is located laterally. FL = fasciculus lenticularis, FT = fasciculus thalamicus, ic = internal capsule, SN = substantia nigra, H1 = field H1 of Forel; H2 = field H2 of Forel. (From Toni R., The human hypothalamus: clinical anatomy of endocrine, autonomic and behavioral responses, J. Endocrinol. Invest 2003, in press).

Figure 13. Basal view of the brain showing the external surface of the floor of the hypothalamus and its arterial vessels. The infundibulum (I) lies posteriorly to the optic tracts and chiasm (ot) and anterior to the mammillary bodies (m). The arterial circle of Willis surrounds the hypothalamic floor and provides the arterial supply to the hypothalamic nuclei and fiber tracts. ac = anterior cerebral artery, aco = anterior communicating artery, b = basilar artery, ic = internal carotid artery, P = pons, pc = posterior cerebral artery, pco = posterior communicating artery. (From the XIX century wax collection of human brains at the Museum of the Department of Human Anatomy of the University of Bologna, Italy.)

Embryologic Anatomy

The diencephalon derives from the caudal part the proencephalic vesicle, which is the cranial expansion of the primitive neural tube, and the hypothalamus develops from the lateral wall of the diencephalon by extending ventrally to a groove called the "hypothalamic sulcus" that appears early in the lateral wall of the diencephalon (Figure 14). Therefore, the hypothalamus can be considered a ventral derivative of the neural tube and to originate from the embryonic basal plate (21). Since the basal plate is the source of all skeletal and autonomic motor neurons in the CNS, by inference, the hypothalamus has also been considered a motor system (22). Indeed, neuroendocrine neurons that are involved in the regulation of the anterior and posterior pituitary secretion clearly have secretomotor functions. However, some authorities believe that the basal (motor) plate of the neural tube ends at the level of the mesencephalon, and that the diencephalon (hypothalamus included), is actually a derivative of the dorsal or alar plate, which is primarily sensory (23).

Figure 14. Three-dimensional reconstruction of the developing proencephalon in the human embryo. Note that at the level of the inferior portion of the lateral wall is the region of the hypothalamus (Hyp) with the infundibular bud (I) and pituitary anlage (P) (Redrawn from Hines M, J Comp Neurol 34: 73-171,1922.) ap = alar plate, bp = basal plate, ce = cerebral hemisphere, cp = choroidal plexus, CS = corpus striatum, ep = epiphysis, EP = epithalamus, eps = epithalamic sulcus, h = hippocampal fissure, hs = hypothalamic sulcus, if = interventricular foramen, lt = lamina terminalis, oc = optic chiasm, sl = sulcus limitans, sr = supraoptic recess, T = thalamus.

Regardless of the point of view, certain basic concepts regarding development of the hypothalamus are well established. Within the neural tube, dividing hypothalamic neuroblasts remain confined within the cell layer adjacent to the ependymal canal (ependymal or ventricular layer), whereas postmitotic elements migrate more laterally into a cell-dense region (mantle layer) before reaching their final destination (24) (Figure 15). Outgrowth of neural process occurs at the most lateral borders of the hypothalamic mantle layer to give rise to tangential fiber tracts that course parallel to the ependymal canal and connect hypothalamic neurons with cranial and caudal portions of the developing neural tube. These fiber tracts are highly ordered into spatial and temporal patterns (25). Early connections include those with the midbrain (mammilotegmental tract) and hippocampus (stria terminalis), followed by those with the thalamus (mammilothalamic tract) (26).

Figure 15. Coronal section of the anterior hypothalamus in a human fetus of gestational age 12-14 weeks, counterstained with methylgreen and thionine. (A) Note that from the wall of the third ventricle, constituting the ependymal layer of the neural tube, a front of developing cells (arrows) migrate laterally towards the mantle layer to give rise to the primordium of the paraventricular nucleus (PVN); (B) High magnification of the image included in the rectangle shown in A. Note the high cellular density in the ependymal layer (EL) of the neural tube contrasts with the more diffuse distribution of migrating neuroblasts in the developing mantle layer (ML). III = third ventricle.

Organization of the hypothalamus into specific nuclear groups also occurs in a temporal pattern, such that the lateral hypothalamus, neurohypophysial centers, major portions of the tuberal hypothalamus, and central portion of the periventricular hypothalamus all arise during an early phase of development, whereas the preoptic region, anterior hypothalamus, and posterior hypothalamus develop later (ssee Section C, Microscopic Anatomy). Peak birth dates of specific hypothalamic nuclei in the primate are shown in Table 3.

In addition to generalizations above regarding the development of specific hypothalamic nuclei, there are developmental differences that distinguish neuroendocrine neurons in the hypothalamus from non-neuroendocrine neurons. Namely, neuroendocrine neurons, including those that give rise to the tuberoinfundibular and magnocellular neurohypophysial systems that are involved in regulation of the anterior and posterior pituitary, respectively (see later), differentiate immediately after closure of the neural tube, even before reaching their final destination within hypothalamic nuclei (27). This phenomenon has been clearly demonstrated for GnRH neurons, that are fully differentiated at the level of the olfactory placode, even before migrating into the preoptic region of the hypothalamus (28). Similarly, neuroblasts immunoreactive for the hypophysiotropic peptides, somatostatin and thyrotropin-releasing hormone, can be identified in the human fetal hypothalamus at the interface between the ependymal and mantle layers during a developmental stage that precedes complete formation of the PVN (29,30).

A number of genes have now been identified that regulate the temporal and spatial patterns of differentiation of hypothalamic cell groups. The POU III-related homeobox genes Brn-1, Brn2, and Brn4 are involved in the development of the periventricular and medial parts of the hypothalamus (31). Transgenic mice with loss of function mutations or with targeted disruption of the Brn-2 gene, lack both the PVN and supraoptic nuclei, and have no somatostatin-producing neurons in the periventricular hypothalamus (32,33). Expression of Brn-2 is dependent upon transcription factors Sim1 and ARNT2, since mutations of these genes in transgenic mice result in a phenotype that is similar to the Brn-2 KO mice (34,35). A number of other genes have been identified that are involved in differentiation of specific hypothalamic nuclei and are listed in Table 4.

Microscopic Anatomy

Boundries and Organization of Neuronal Cell Groups

Using phylogenetic and cytoarchitectonic criteria (36), a number of nuclear groups and fiber tracts are recognized in the vertebrate hypothalamus. These are organized into three major regions including the lateral, medial and periventricular hypothalamus, each having distinct morphological and functional features. In the human hypothalamus, the anterior column of the fornix that extends rostro-caudally through the substance of the hypothalamus to end in the mammillary bodies, and the mammillo-thalamic tract that projects from the mammilary bodies upward to the thalamus, create an anatomical boundary that divides the hypothalamus into medial and lateral subdivisions (Fig. 16). Contained within the medial subdivision is the periventricular subdivision, a 5-6 cell layer thick nuclear group surrounding the third ventricle that is easily recognized in rodents using standard vital stains, but has less clear anatomical boundaries in the human brain.

Figure 16. Schematic representation of the human hypothalamus in coronal orientation (A-D: rostral to caudal), demonstrating the location of major nuclear groups. Drawings correspond to MRI images in Fig. 26. Using the fornix (fx) as an anatomic landmark as it passes through the mid-portion of the hypothalamus on each side of the third ventricle, it is convenient to divide the hypothalamus into medial and periventricular zones (that lie largely medial to the fornix) and a lateral zone (that lies lateral to the fornix). The medial and periventricular zones contain most of the hypothalamic cell groups, and the lateral zone contains relatively fewer neurons. This is because the lateral zone is largely composed of a massive bidirectional fiber pathway - the medial forebrain bundle - that extends through the hypothalamus and interconnects it with the limbic system and brainstem autonomic centers.

Both the medial and periventicular subdivisions of the hypothalamus contain a high density of neuronal cell bodies organized into nuclear groups (Table 5 and Fig. 16), and are crucial for the regulation of the anterior and posterior pituitary gland. The medial hypothalamus also contains nuclear groups that serve as relay centers for highly differentiated neural information coming from the limbic system and autonomic sensory centers in the brainstem involved in initiation phases of specific homeostatic behaviors such as thirst, hunger, thermoregulation, the sleep-wake cycle, and reproductive behavior (36).

The lateral hypothalmus occupies the largest portion of the hypothalamus by volume. However, it has relatively fewer neurons compared to the medial hypothalamus, and only a limited number of nuclear groups intercalated within a massive fiber system, the medial forebrain bundle (MFB). It is through this fiber system that information from the medial forebrain (amygdala, hippocampus, septum, olfactory system) and the brainstem is carried to the medial and periventricular hypothalamic subdivisions, delegating an important role to the lateral hypothalamus to influence homeostatic control systems elaborated by the medial hypothalamus. Figure 17 schematically depicts the major interrelations between the periventricular, medial and lateral hypothalamic subdivisions and the rest of the brain.

Figure 17. Schematic representation of the major neural pathways connecting the periventricular, medial and lateral hypothalamic subdivisions with the rest of the brain. Groups with identical colors are functionally llinked.

Each of the three hypothalamic subdivisions can be further divided along the rostral-caudal axis into the: a) anterior or chiasmatic region, extending between the lamina terminalis and the anterior limit of the infundibular recess; b) median or tuberal region, extending between the infudibular recess and the surface of the anterior column of the fornix; and c) posterior or mammillary region, extending between the anterior column of the fornix and the caudal limit of the mammillary bodies.