III. ANATOMY OF THE HYPOTHALAMUS

A.  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 (Fig. 11) as well as fiber tracts that are symmetric about the third ventricle.  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.

B.  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 (25).  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 (26).  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 (27).  Partial confirmation of this idea has been recently provided by the evidence that mouse embryonic stem cells may spontaneously differentiate into neurons expressing the Rax gene, a marker common to both the preoptic / tuberal hypothalamus and neural retina (a sensory structure), but do not express the Irx3 and En2 genes, typical of the midbrain structures (28). These findings are consistent with the presence of neurosecretory cells with sensory properties in the forebrain of invertebrates and fishes (29), suggesting evolutionarily conserved sensory properties of neuroendocrine hypothalamic cells.

    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 (30) (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 (31).  Early connections include those with the midbrain (mammilotegmental tract) and hippocampus (stria terminalis), followed by those with the thalamus (mammilothalamic tract) (32).

Fig. 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 occurs in a temporal and spatial pattern both in rodents (31, 32) and man (33), such that the entire preoptic to posterior lateral hypothalamus followed by the medially-located, neurohypophysial centers and main part of the medial preoptic and tuberal hypothalamus all arise during an early phase of development, whereas the periventricular hypothalamus, floor of the third ventricle and mammillary complex develop later (see 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 (34).  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 (35).  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 (36,37).
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 (38).  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 (39,40).  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 (41,43).  A number of other genes have been identified that are involved in differentiation of specific hypothalamic nuclei and are listed in Table 4.  Temporal and spatial expression of many of these genes is selectively regulated by circulating sex hormones (44) and peripheral satiety signals such as leptin (45), suggesting that innate neuroendocrine behavioral responses are epigenetically influenced during the embryonic and fetal life.