Hypothalamus Anatomy

The hypothalamus is a region of the brain composed of many small nuclei with diverse functions. Located above the midbrain and below the thalamus, the hypothalamus makes up the ventral diencephalon. The diencephalon is an embryologic region of the vertebrate neural tube that gives rise to posterior forebrain structures. By synthesizing and secreting neurohormones, the nuclei of the hypothalamus act as a conduit between the nervous and endocrine systems via the pituitary gland (hypophysis), regulating homeostatic functions such as hunger, thirst, body temperature, and circadian rhythms. ^[1]

The hypothalamus occupies the ventral diencephalon and is composed of numerous fiber tracts and nuclei situated symmetrically about the third ventricle. In sagittal section, the hypothalamus is roughly diamond shaped; although its boundaries are not sharply demarcated, its perimeters can be correlated using neuroanatomic landmarks. ^[2] Rostrally, the hypothalamus extends from the anterior commissure, lamina terminalis, and optic chiasm. Caudally, the hypothalamus extends to the periaqueductal gray matter of the midbrain, approximated by (from ventral to dorsal) the mammillary bodies, interpeduncular fossa, and cerebral peduncles. See the figure below.

In the coronal plane, the boundaries of the hypothalamus are more distinct. ^[2] Superiorly, the hypothalamus is divided from the thalamus by a groove in the lateral wall of the third ventricle, the hypothalamic sulcus. The lateral surface is contiguous with the thalamus and subthalamus and is bordered by the internal capsule and optic tracts. Medially, the hypothalamus is bound by the ependyma of the third ventricle. Finally, the inferior surface is continuous with the floor of the third ventricle.

The external surface of the hypothalamic floor projects into the interpeduncular cistern. A median protuberance, the tuber cinereum lies between the optic chiasm (rostrally) and mammillary bodies (caudally) and is continuous anteriorly with the lamina terminalis. This projection continues as the infundibulum, terminating inferiorly on the pituitary gland.

The nuclei of the hypothalamus are organized into the following 3 subdivisions ^[1] :

• Anterior (or chiasmatic) region, which extends between the lamina terminalis and the anterior infundibular recess

• Median (or tuberal) region, which proceeds to the anterior column of the fornix

• Posterior (or mammillary) region, which stretches to the caudal mammillary bodies

These subdivisions are derived primarily from the hypothalamic blood supply. The anterior hypothalamus is supplied by branches of the anterior cerebral and anterior communicating arteries; the tuberal hypothalamus is supplied by the posterior communicating artery; and the mammillary region is supplied by the posterior communicating, posterior cerebral, and basilar arteries.

Anatomic subdivisions can be further segregated into 3 morphological and functional areas: lateral, medial, and periventricular. ^[2] The medial and lateral regions are anatomically divided by the anterior column of the fornix and the mammillothalamic tract; the periventricular region is a further subdivision of the medial hypothalamus that lacks a gross anatomic boundary. Although the lateral region is the most voluminous, the medial and periventricular regions contain the majority of hypothalamic nuclei.

The lateral region is largely composed of a massive bidirectional fiber pathway, the medial forebrain bundle (MFB), which connects the hypothalamus to the limbic system and brainstem autonomic centers. ^[2] Through the MFB, signals from the brainstem, amygdala, hippocampus, retina, and olfactory system are conveyed to hypothalamic nuclei, underlying the crucial role of the hypothalamus in systemic homeostasis. ^[2] See the figure below.

Anterior Hypothalamic Nuclei

Nuclei within the anterior subdivision of the hypothalamus include the medial/lateral preoptic, periventricular, supraoptic, suprachiasmatic, and anterior/lateral hypothalamic nuclei.

The medial preoptic nucleus abuts the third ventricle and periventricular nucleus medially and is bound laterally by the lateral preoptic nucleus, superiorly by the anterior commissure, and inferiorly by the supraoptic and suprachiasmatic nuclei. The medial preoptic nucleus generates gonadotropin-releasing hormone (GnRH); also known as the sexually dimorphic nucleus, its growth is regulated by testosterone exposure in utero and its volume is increased nearly 2-fold in males compared with females. ^[3] Its role in both sexes relates to sexual behavior and partner preference.

The supraoptic nucleus lies dorsal to the optic tract and ventral to the medial preoptic nucleus, adjoining the intrapeduncular cistern. It is composed of neurosecretory cells, which produce vasopressin (or antidiuretic hormone) and oxytocin; the axons of these neurons are conveyed ventrally through the median eminence and infundibulum (in the supraopticohypophyseal tract), and vesicle contents are released from the posterior pituitary gland.

The paraventricular nucleus (PVN) adjoins the third ventricle ventral to the fornix and dorsal to the anterior hypothalamic nucleus and extends across the rostrocaudal axis of the hypothalamus. Like the supraoptic nucleus, it maintains systemic osmotic balance through secretion of vasopressin and oxytocin from the posterior pituitary gland. ^[1] Additionally, it houses parvocellular neurosecretory neurons projecting to the median eminence, where axon terminals release corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), GnRH, growth hormone–releasing hormone (GHRH), and somatostatin into the perivascular spaces of the hypothalamic-pituitary portal system. Finally, the PVN houses a heterogeneous collection of additional neurons projecting to the anterior pituitary, limbic system, brainstem, and spinal cord. ^[1]

The anterior hypothalamic nucleus plays a critical role in thermoregulation and circadian rhythms. ^{[1, 2]} It is situated at the inferior border of the PVN and is bound dorsolaterally by the lateral hypothalamic nucleus (LHN), ventromedially by the arcuate nucleus, and ventrolaterally by the supraoptic nucleus.

The suprachiasmatic nucleus (SCN) lies dorsal to the optic chiasm and optic tracts at the floor of the third ventricle. This position allows the SCN to receive afferent input directly from the retina, as well as projections from the lateral geniculate nucleus and superior colliculus. With these photic afferents, the SCN acts as a dominant regulator of circadian rhythms. ^{[1, 2]}

The lateral preoptic nucleus mediates non–rapid-eye movement sleep onset. It is contiguous caudally with the LHN, which extends through the tuberal and posterior divisions of the hypothalamus. The LHN responds to blood glucose concentrations to regulate hunger. ^[2]

Tuberal Hypothalamic Nuclei

The tuberal region is the largest of the hypothalamus with the most pronounced anatomic distinction between medial and lateral hypothalamic areas. ^[2] The dorsomedial and ventromedial nuclei abut the third ventricle, ventrolateral to the PVN and ventromedial to the fornix. Both nuclei regulate hunger and satiety, although the more-voluminous ventromedial nucleus appears to be the dominant regulator. ^[4] The ventromedial nucleus additionally appears to play a role in fear and aggression. ^{[1, 4]}

The arcuate nucleus overlies the median eminence at the floor of the third ventricle. Roughly horseshoe shaped, it surrounds the lateral and caudal exit of the infundibulum. The arcuate nucleus contains the bodies of neuroendocrine neurons, which produce GHRH and dopamine for release into the hypophyseal portal circulation. Consequently, it plays a critical role in the function of the hypothalamic-pituitary-gonadal (HPG) axis. ^[4] Arcuate neurons also have diverse projections to other hypothalamic nuclei, particularly the lateral hypothalamus, PVN (a pathway critical in regulating hunger), and medial preoptic nucleus (regulating sexual drive). ^{[1, 2]}

Posterior Hypothalamic Nuclei

The posterior nucleus lies dorsal to the mammillary bodies and medial to the caudal end of the LHN, adjoining the third ventricle. It is primarily involved in thermoregulation.

The mammillary nuclei, situated at the caudal hypothalamic floor, lie within the mammillary bodies. Although functionally a component of the limbic system, neuroanatomists frequently categorize them as hypothalamic constituents. ^[1] Mammillary neurons act as a conduit for signals originating in the ipsilateral amygdala and hippocampus, and they convey these signals to the thalamus via the mammillothalamic tract (a limb of the circuit of Papez, which regulates cortical control of emotion). ^[2] Mammillary nuclei are additionally critical in recognition memory. ^[1]

The tuber cinereum lies dorsal to the median eminence, interposed between the mammillary bodies and infundibulum. It houses the tuberoinfundibular nucleus, which globally governs alertness through histamine secretion. ^[4]

Hypothalamic Connections

The many nuclei of the hypothalamus act in chorus as an important relay center with diverse central nervous system connectivity. Afferents from the limbic system arrive via the MFB, stria terminalis, and fornix. The stria terminalis originates at the amygdala and the fornix at the hippocampus. In addition, the brainstem reticular formation sends afferents via the dorsal longitudinal fasciculus, and afferents from the basal nuclei (formerly, basal ganglia) arise in the nucleus accumbens and travel via the substantia innominata. Collectively, these fiber bundles enter the rostromedial hypothalamus near the third ventricular surface, and then they course diagonally through the length of the lateral hypothalamus and deposit axon terminals among its nuclei. ^[2] The major exceptions to this route are afferents from the retina, which travel through the optic nerves, synapsing on the SCN after brief transit from the optic chiasm via the retinohypothalamic tract. ^[1]

Hypothalamic efferents to the limbic system, basal ganglia, and neocortex course primarily through the MFB. Efferents to the brainstem reticular formation (as with afferents from the same region) travel retrograde through the dorsal longitudinal fasciculus. The mammillothalamic tract is an important efferent, which, as a component of the circuit of Papez, links the hypothalamus and thalamus to the limbic system. ^[1]

Median Eminence, Tuberoinfundibular Portal System, and Hypophyseal Portal System

The median eminence of the hypothalamus projects from the hypothalamic floor ventral to the arcuate nucleus. It is an integral component of the hypophyseal portal system, which allows the hypothalamus to regulate anterior pituitary gland function. The median eminence is organized into 3 zones across a dorsoventral axis: the ependymal zone, the zona interna, and zona externa. The ependymal zone forms the floor of the third ventricle and is primarily characterized by the bodies of specialized ependymal cells called tanycytes. Tanycytes extend along the dorsoventral axis of the median eminence, with protrusions both into the cerebrospinal fluid (CSF) of the third ventricle and ventral projections deep into the median eminence. ^[2] Their morphology suggests a role in dynamic regulation of blood-CSF hormone trafficking, and their close association to the arcuate nucleus additionally implies involvement in appetite and satiety regulation.

The zona interna (internal zone) lies directly ventral to the ependymal zone and is primarily composed of unmyelinated axons passing from hypothalamic nuclei (principally the PVN and supraoptic nucleus) to the posterior pituitary. These axons transport vasopressin and oxytocin in neurosecretory granules that are secreted directly from terminals in the posterior pituitary gland. The zona interna additionally contains axons passing from the tuberoinfundibular system into the zona externa. These unmyelinated axons originate at hypothalamic nuclei, principally the arcuate, paraventricular, and medial preoptic nuclei, and terminate in the portal capillary plexus within the zona externa. ^[2] At the portal capillary plexus, vesicles containing hypophysiotropic (“releasing”) hormones (ie, CRH, GnRH, TRH, GHRH, dopamine, somatostatin) are secreted. These hormones percolate through the fenestrated capillary endothelium to reach the anterior pituitary gland. See the figure below.

Vascular supply to the pituitary gland comes primarily from 2 branches of the internal carotid, the superior and inferior hypophyseal arteries. ^[5] The superior hypophyseal artery forms a ring around the dorsal infundibulum, while the inferior hypophyseal artery similarly encircles the ventral infundibulum and anterior pituitary. These arteries disseminate into connected capillary plexuses within the median eminence and anterior pituitary. Hormones deposited into the zona externa of the median eminence make a brief ventral transit to the capillary plexus of the anterior pituitary, where they diffuse into the parenchyma of the gland to modulate its endocrine activity.

Given the fundamental role of the hypothalamus in essential physiologic functions, substantial anatomical variations are generally not viable. The hypothalamus does characteristically vary with sex, development, and age, but these distinctions are seldom-evident grossly. ^[3]

In elderly persons, functional changes in both temporal organization and circadian rhythms, such as abridged sleep cycles and forward-shifted sleep phases, have been attributed to degeneration of the suprachiasmatic nucleus (SCN). The gross volume of the SCN is reduced in individuals older than 80 years, ^[3] a finding that is especially pronounced in males. ^[6]

The medial preoptic nucleus is sexually dimorphic, with the male component being twice as large as that of correspondingly aged females. ^[3] This difference becomes less exaggerated between ages 50 and 60 years, a phenomenon attributed to waning testosterone circulating in aging males. In females, the volume of the arcuate nucleus—a critical component of the hypothalamic-pituitary-gonadal axis—is significantly increased in postmenopausal women, an effect recapitulated by pathophysiologic hypogonadal states. ^[3]

The best-known variant of hypothalamic anatomy/function leads to Kallmann syndrome, a condition characterized by delayed or absent puberty and anosmia. ^[7] Under normal circumstances, gonadotropin-releasing hormone–secreting neurons migrate to the hypothalamus (primarily the arcuate and paraventricular nuclei) from the olfactory placode during embryogenesis. Failure of this migration results in an absence of these hypothalamic neurons, with downstream effects on the hypothalamic-pituitary-gonadal axis, mediated by the anterior pituitary gland. Although this deficiency is not evident grossly, a diminution in paraventricular nucleus volume is microscopically evident.

Numerous disease processes may impinge on the hypothalamus, causing secondary detriment of normal function. Tumors of the hypothalamus, pituitary gland, or suprasellar region may impinge on nuclei and fiber tracts, disrupting the endocrine conduit between the hypothalamus and pituitary gland and globally modifying normal hormone concentrations. Systemic infiltrative disease may also affect the hypothalamus or pituitary, disrupting function and distorting anatomy.

Certain developmental disorders (particularly Prader-Willi and Bardet-Biedl syndromes) are known to arise in part from disrupted hypothalamic function, but are not associated with aberrations in hypothalamic anatomy. ^[2] Of note, the lateral hypothalamic nucleus is severely affected by Huntington disease, and neuronal loss in the area has even been posited as a marker for disease progression. ^[3] Histologic changes of the mammillary nucleus occur with Alzheimer and Parkinson diseases, but no gross changes or microscopic cell loss have been observed. ^[6]

Although neuroanatomists have arrived at functionally relevant hypothalamic nuclei, tracts, and regions, it must be noted that considerable overlap (both anatomically and functionally) exists between adjacent hypothalamic areas. Additionally, nuclei and tracts tend to be diffuse and may be morphologically indistinct. Specific functions have been attributed to individual nuclei (and/or groups of nuclei), but more regionally disseminated functions also exist.

An imprecise but definite hypothalamic organization exists with respect to the autonomic nervous system. The anterior and medial hypothalamus, as well as the tuber cinereum, appear to govern parasympathetic activities. Conversely, the lateral and posterior hypothalamus exert sympathetic pressures. ^[1] A similar dichotomy exists with respect to temperature; the anterior hypothalamus functions to dissipate excess heat, while the posterior hypothalamus functions to conserve it. Limbic contributions appear to be grossly disseminated, complicating functional mapping of hypothalamic contributions to complex behaviors. ^[1]