Hypothalamus, Pituitary, Sleep, and Thalamus

Anatomic Relationships of the Hypothalamus

The hypothalamus is a small area, weighing about 4 g of the total 1,400 g of adult brain weight, but it is the only 4 g of brain without which life itself is impossible. The hypothalamus is so critical for life because it contains the integrative circuitry that coordinates autonomic, endocrine, and behavioral responses that are necessary for basic life functions, such as thermoregulation, control of electrolyte and fluid balance, feeding and metabolism, responses to stress, and reproduction.

Perhaps for this reason, the hypothalamus is particularly well protected. It lies at the base of the skull, just above the pituitary gland, to which it is attached by the infundibulum, or pituitary stalk. As a result, trauma that affects the hypothalamus would almost always be lethal. It receives its blood supply directly from the circle of Willis (see Plate 5-3 ), so it is rarely compromised by stroke, and it is bilaterally reduplicated, with survival of either side being sufficient to sustain normal life.

On the other hand, the hypothalamus may be involved by a number of pathologic processes that arise from structures that surround it, and the signs and symptoms that first attract attention in those disorders are often due to the involvement of those neighboring structures. Examination of the ventral surface of the brain shows that the hypothalamus is framed by fiber tracts. The optic chiasm marks the rostral extent of the hypothalamus, and the optic tracts and cerebral peduncles identify its lateral borders. The pituitary stalk emerges from the midportion of the hypothalamus, sometimes called the tuber cinereum (gray swelling), just caudal to the optic chiasm. As a result, tumors of the pituitary gland, which are among the more common causes of hypothalamic dysfunction, typically involve the optic chiasm (producing bitemporal visual field defects) or the optic tracts as an early sign.

The posterior part of the hypothalamus is defined by the mammillary bodies, which are bordered caudally by the interpeduncular cistern, from which emerge the oculomotor nerves. These are joined in the cavernous sinus, which runs just below the hypothalamus and lateral to the pituitary gland, by the trochlear and abducens nerves. Hence pathologies such as aneurysms of the internal carotid artery or infection or thrombosis of the cavernous sinus, which may impinge on the hypothalamus, typically involve the nerves controlling eye movements at an early stage. If there is a mass of sufficient size, it may also involve the trigeminal nerve. The ophthalmic division, which traverses the cavernous sinus, is most commonly involved, but if the mass is large enough and posteriorly located, it can involve the maxillary or even the mandibular division of the trigeminal nerve as well. Just lateral to the cavernous sinus sits the medial temporal lobe. As a result, pathology in this area can also cause seizures, most commonly of the complex partial type, with loss of awareness for a brief period.

In the midline, the hypothalamus borders the ventral part of the third ventricle. The supraoptic recess of the third ventricle, which surmounts the optic chiasm, ends at the lamina terminalis, the anterior wall of the ventricle. This is the most anterior part of the diencephalon in the developing brain. The infundibular recess defines the floor of the hypothalamus that overlies the pituitary stalk. This portion of the hypothalamus is called the median eminence and is the site at which hypothalamic releasing hormones are secreted into the pituitary portal circulation (see Plate 5-3 ).

Development and Developmental Disorders of the Hypothalamus

The hypothalamus in mammals arises as a part of the ventral diencephalon and the adjacent telencephalon, and its embryologic origins are intimately related to those of the optic chiasm and tracts and to the pituitary gland. Thus disorders that affect the hypothalamus frequently manifest with signs and symptoms resulting from dysfunction of neighboring, developmentally related structures. The developing neural tube is divided into three primary regions: forebrain, midbrain, and hindbrain. The forebrain is further subdivided into the telencephalon, which gives rise to the cerebral cortex and basal ganglia, and the diencephalon, from which the thalamus and hypothalamus are derived. The hypothalamus develops from the anterior portion of the diencephalon in a series of steps that involve the activation of suites of transcription factors, which determine the fates of the developing cell populations.

First, the prechordal mesoderm that underlies the developing neural tube secretes sonic hedgehog (Shh) that induces the normal patterning of the anterior midline of the brain, including the formation of the hypothalamus and the separation of the optic system. Abnormal mesodermal induction occurs with mutations that affect Shh signaling and can result in one of the most common human brain malformations, holoprosencephaly, which manifests with a spectrum of failed division of the midline structures of the brain. In its most severe form, holoprosencephaly results in cyclopia and complete or partial loss of the hypothalamus, which is not compatible with life. In its more mild forms, holoprosencephaly can manifest with endocrine abnormalities because of defective development of the hypothalamic-pituitary system. After initial patterning by Shh - mediated induction, hypothalamic precursor cells proliferate before exiting the cell cycle and undergo terminal differentiation into the many cells types that comprise the hypothalamus' compact, yet complex structure. Finally, the developing neurons express unique combinations of transcription factors, such as Nkx and Lhx family members, and Sim1, and Six3. Deletions of individual transcription factors have profound effects upon development of specific hypothalamic nuclei.

Terminal differentiation of the hypothalamic nuclei requires the combined action of “codes” of transcription factors that, when expressed with anatomically restricted and developmentally timed precision, give rise to the regional complexity of the hypothalamus. Although still poorly understood, rare genetic mutations have been identified in humans and tested in animal models that demonstrate that dysfunction of specific genes results in loss of specific hypothalamic neurons and corresponding phenotypes. For example, the Prader-Willi syndrome, which manifests as morbid obesity, hypersomnolence, hypogonadism, and intellectual disability, is caused by a deletion of the paternally inherited chromosome 15q11. This genomic region contains several genes implicated in the normal development of the paraventricular nucleus, a cell group with critical integrative functions in feeding and responses to stress (see later).

The relationship of the hypothalamus and pituitary gland has its embryologic origins as an anatomic juxtaposition between the anterior diencephalon and the ectodermally derived Rathke's pouch, from which portions of the ventral pituitary are derived. Thus both the hypothalamus and pituitary are patterned by similar signaling pathways, and dysfunction in these systems may disrupt the development and function of both structures. Craniopharyngiomas are the most common non-neural intracranial tumors in childhood and derive from the remnants of Rathke's pouch. Clinical presentation includes optic, pituitary, and/or hypothalamic symptoms, including obesity, hypopituitarism, and sleep and circadian rhythm dysfunction.

Blood Supply of the Hypothalamus and Pituitary Gland

The hypothalamus is what the circle of Willis encircles. The internal carotid artery runs through the cavernous sinus, which is just below the hypothalamus, and the site of its venous drainage. As the internal carotid artery emerges from the cavernous sinus, it ends in the middle cerebral artery laterally, the posterior communicating artery caudally, and the anterior cerebral artery rostrally. The anterior cerebral artery runs above the optic nerve, crosses the olfactory tract, and meets the anterior communicating artery in the midline before turning upward and back. The posterior communicating artery runs back to meet the posterior cerebral artery shortly after it emerges from the basilar artery. As a result, the hypothalamus is fed by small penetrating arteries that originate directly from the tributaries of the circle of Willis.

The anterior part of the hypothalamus, above the optic chiasm, is supplied by arterial feeding vessels from the anterior cerebral artery. These vessels densely penetrate the basal forebrain just in front of the optic chiasm, giving it the name the “anterior perforated substance.” The tuberal, or midlevel of the hypothalamus, is fed mainly by small branches directly from the internal carotid artery and the posterior communicating artery. Posteriorly, small penetrating vessels from the posterior cerebral arteries running through the interpeduncular fossa give it the name “posterior perforated substance.” Many of these small blood vessels supply the posterior part of the thalamus, but some also provide blood to the posterior hypothalamus. The cell groups within the hypothalamus are not uniformly supplied with blood vessels. The paraventricular and supraoptic nuclei, which contain neurons that make the vasoactive hormones oxytocin and vasopressin, have particularly rich capillary networks.

The superior hypophyseal artery is one of the branches derived from the internal carotid artery. It supplies the pituitary stalk, where it breaks up into a series of looplike capillaries in the median eminence and pituitary stalk. The hypothalamic neurons that make pituitary releasing (and release-inhibiting) hormones send axons that terminate on these loops, which, unlike most brain capillaries, have fenestrations to permit easy penetration by these small peptide hormones (see Plate 5-6 ). These capillaries drain into the hypophyseal portal veins, which along with some branches of the inferior hypophyseal artery, provide blood flow to the adenohypophysis or anterior pituitary gland. The posterior pituitary gland is supplied almost entirely by the inferior hypophyseal artery. Because most of the blood flow to the anterior pituitary gland is from the portal system, it is possible, on occasions, for the gland to outgrow its blood supply. This occurs mainly during pregnancy or can occur when a pituitary adenoma, an otherwise benign tumor, becomes larger than can be accommodated by the blood supply. At this point, there is infarction of the pituitary, often with bleeding, which may become life threatening (pituitary apoplexy). The typical presentation is sudden onset of dysfunction of cranial nerve II, III, IV, or VI, with a severe headache that is generally localized between the eyes, and often impaired consciousness.

Finally, the fenestrated capillary loops in the median eminence not only allow egress of hypothalamic-releasing hormones to the anterior pituitary gland, but also permit blood-borne substances to enter the brain. The hormone leptin, which is made by white adipose tissue during times of plenty, is believed to enter the brain via the median eminence to signal satiety to cell groups in the basal medial hypothalamus. There is another area of fenestrated capillaries along the anterior wall of the third ventricle, called the organum vasculosum of the lamina terminalis, which may allow entry of other hormones, such as angiotensin, which may be involved in thirst and water balance, and perhaps some cytokines that may play a role in the fever response. These regions are called circumventricular organs because they are around the edges of the ventricles. Another circumventricular organ, the area postrema, is found at the outflow of the fourth ventricle in the medulla and is probably involved in emetic reflexes based on blood-borne toxins or hormones, such as glucagon-like protein 1.

Overview of Hypothalamic Cell Groups

The hypothalamus consists of a complex assemblage of cell groups. The borders of these cell groups often are not quite as distinct as those shown in the drawings, but the different cell groups are also distinguished based upon their neurotransmitters, functions, and connections.

In general, the hypothalamus can be divided into three tiers of nuclei. Most medially, along the wall of the third ventricle, is the periventricular nucleus, shown here in green. Along the base of the periventricular nucleus is an expansion laterally along the edge of the median eminence, known as the arcuate or infundibular nucleus. The periventricular stratum contains many neurons that make releasing or release-inhibiting hormones (see Plate 5-6 ) and whose axons end on the capillary loops of the hypophysial portal vessels in the median eminence. Many axons from the brainstem run through the periventricular gray matter, in the posterior longitudinal fasciculus, and into the periventricular region of the hypothalamus.

The next tier of nuclei is sometimes called the medial tier. These nuclei are generally involved in intrinsic connections within the hypothalamus that allow integration of various functions. The most rostral of the medial nuclei is the medial preoptic region (orange), which sits along the wall of the third ventricle as it opens. Along the anterior wall of the third ventricle is the median preoptic nucleus (not shown here). These two cell groups are involved in integrating control of body temperature with fluid and electrolyte balance, wake-sleep cycles, and reproductive function.

The next most caudal region is called the anterior hypothalamic area (purple). At the base of the anterior hypothalamic area, just above the optic chiasm, is the suprachiasmatic nucleus (see Plate 5-5 ). These structures are involved in regulating circadian rhythms. The suprachiasmatic nucleus is the body's main biologic clock, and it sets the timing of rhythms of sleep, feeding, body temperature, and reproduction. These functions are controlled by means of outputs to the portion of the anterior hypothalamic area between the suprachiasmatic nucleus and the paraventricular nucleus (blue), called the subparaventricular zone.

The supraoptic and paraventricular nuclei are also at this anterior level in the medial tier. Both nuclei contain large numbers of oxytocin and vasopressin neurons, whose axons travel through the pituitary stalk in the tuberohypophysial tract, to the posterior pituitary gland, where they release their hormones into the circulation. The paraventricular nucleus also contains neurons that make releasing hormones (especially corticotrophic-releasing hormone) and project to the median eminence. A third population of neurons in the paraventricular nucleus sends axons through the medial forebrain bundle in the lateral hypothalamus to the brainstem and spinal cord, to control both the sympathetic and parasympathetic nervous systems. Many of these neurons use either oxytocin or vasopressin as a central neurotransmitter in this autonomic pathway, but they are an entirely separate set of neurons from those that send axons to the posterior pituitary gland.

Just caudal to the anterior hypothalamic area, in the tuberal level of the hypothalamus, the medial tier contains three cell groups. The ventromedial nucleus (tan) sits just above the median eminence and is mainly involved in feeding, aggression, and sexual behavior. The dorsomedial nucleus (yellow), which is just dorsal to it, has extensive outputs to much of the rest of the hypothalamus. The subparaventricular zone sends circadian outputs to both the dorsomedial and ventromedial nuclei, and the dorsomedial nucleus uses this input to organize circadian cycles of wake-sleep, corticosteroid secretion, feeding, and other behaviors. The dorsal hypothalamic area, just above the dorsomedial nucleus, contains neurons that are involved in regulating body temperature.

At the most posterior end of the hypothalamus, the mammillary bodies form a prominent pair of protuberances along the base of the brain. Despite having very clear-cut, heavily myelinated connections, the function of the mammillary nuclei remains mysterious. They receive a major brainstem input from the mammillary peduncle and a large bundle of efferents from the hippocampal formation through the fornix. The large fiber bundle that emerges from the mammillary body splits into a mammillotegmental tract to the brainstem and a mammillothalamic tract to the anterior thalamic nucleus. Neurons in the mammillary body appear to be concerned with head position in space, and may be related to hippocampal circuits that remember the positions of objects in space (so-called place cells). However, lesions of the mammillary bodies in primates have relatively subtle effects on memory.

The lateral tier of the hypothalamus includes the lateral preoptic and lateral hypothalamic areas. These regions are traversed by the medial forebrain bundle, which connects the brainstem below with the hypothalamus and the forebrain above. Many neurons in the lateral hypothalamic area project through the medial forebrain bundle, either to the basal forebrain or cerebral cortex, or to the brainstem or spinal cord. Among these are the neurons that contain the peptides orexins (also known as hypocretins) or melanin-concentrating hormone (MCH). These neurons are involved in regulating wake-sleep cycles as well as metabolism, feeding, and other types of motivated behaviors. Loss of the orexin neurons causes the disorder known as narcolepsy (see Plate 5-22 ).

At the posterior hypothalamic level, there is also a cluster of histaminergic neurons, called the tuberomammillary nucleus, in the lateral hypothalamus adjacent to the mammillary body. These neurons play a role in regulation of wakefulness and body temperature and have projections from the cerebral cortex to the spinal cord. The posterior hypothalamic area sits just above the mammillary body. In humans, many of the orexin, MCH, and histaminergic neurons are found in this region.

Hypothalamic Control of the Pituitary Gland

The hypothalamus contains two sets of neuroendocrine neurons, the magnocellular neurons, which send axons to the posterior pituitary gland, and the parvicellular neurons, which secrete releasing or release-inhibiting hormones into the pituitary portal circulation.

The magnocellular neurons consist of two clusters: the supraoptic and paraventricular nuclei. Each cell group contains both oxytocin (OXY) and vasopressin (VP) neurons. These cells secrete the hormones from their terminals in the posterior pituitary gland into the general circulation. Vasopressin controls urinary water and sodium excretion, as well as having direct vasoconstrictor effects on blood vessels. Oxytocin has some vasoconstrictor properties and causes uterine contractions but also is involved in the milk let-down reflex during suckling. Cutting the pituitary stalk causes loss of secretion of both hormones, but the predominant symptom is diabetes insipidus, due to lack of vasopressin. Such individuals have excess loss of water in the urine, requiring the ingestion of up to 20 liters of water per day to maintain blood osmolality in the normal range, unless the hormone is replaced.

The parvicellular neurons are located along the wall of the third ventricle in the periventricular, paraventricular, and arcuate nuclei. Different populations of parvicellular endocrine neurons, secreting specific pituitary releasing or release-inhibiting hormones, have characteristic locations within this region. The corticotropin-releasing hormone neurons, which cause secretion of adrenocorticotrophic hormone (ACTH), and ultimately adrenal corticosteroids, are mainly located in the paraventricular nucleus. Many neurons that secrete thyrotropin-releasing hormone neurons, which cause secretion of thyroid-stimulating hormone (TSH), or somatostatin, which inhibits secretion of growth hormone (GH), are also in the paraventricular nucleus, but some are found rostral to it in the periventricular nucleus. Neurons that secrete gonadotropin-releasing hormone neurons (which cause secretion of luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) are found in the most rostral part of the periventricular nucleus and dorsal arcuate nucleus. The rostral part of the arcuate nucleus also contains growth hormone–releasing hormone neurons. Neurons secreting dopamine (a prolactin release–inhibiting hormone) are found widely distributed along the wall of the third ventricle in the periventricular, paraventricular, and arcuate nuclei. The arcuate nucleus also contains neurons that express pro-opiomelanocortin (POMC), a precursor protein that can be differentially processed to produce ACTH (e.g., in the pituitary gland), but that is processed into α-melanocyte–stimulating hormone (α-MSH) and β-endorphin in the arcuate nucleus, which uses them as neurotransmitters.

The anterior pituitary gland contains a mixed population of pituitary cells, each of which secretes a different hormone: TSH, ACTH/α-MSH, FSH/LH, prolactin, or GH. These hormones as well as their releasing and release-inhibiting factors can feed back upon the parvicellular endocrine neurons, providing short loop feedback. Prolactin is the only pituitary hormone that is primarily under inhibitory tone from the hypothalamus. Hence, when the pituitary stalk is damaged, the secretion of other anterior pituitary hormones is diminished, but prolactin increases.

Endocrine disorders may ensue from either excess secretion or lack of secretion of either an anterior pituitary hormone or its hypothalamic-releasing or release-inhibiting hormones. Thus precocious puberty is sometimes seen with hypothalamic hamartomas that secrete gonadotropin-secreting factor. On the other hand, amenorrhea may occur from increased secretion of prolactin. Cushing syndrome—the oversecretion of adrenal corticosteroids—may result from a steroid-secreting adrenal tumor, a pituitary tumor (or sometimes a lung or other tumor) that secretes ACTH, or hypersecretion of corticotropin-releasing hormone.

Hypothalamic Control of the Autonomic Nervous System

Other than a relatively modest projection to the preganglionic neurons from the infralimbic cortex, the hypothalamus is the highest level of the neuraxis that provides substantial input to the autonomic nervous system. It regulates virtually all autonomic functions and coordinates them with each other, and with ongoing behavioral, metabolic, and emotional activity. The hypothalamus contains several sets of neurons, using different neurotransmitters, that provide innervation to the sympathetic and parasympathetic preganglionic neurons, as well as brainstem areas that regulate the autonomic nervous system. Many of these neurons are in the paraventricular nucleus of the hypothalamus. These form populations of small neurons that are typically dorsal or ventral to the main endocrine groups, and most of the paraventricular-autonomic neurons contain messenger ribonucleic acid (mRNA) for either oxytocin or vasopressin. The descending pathways also stain immunohistochemically for these peptides and are probably involved in stress responses.

A second set of hypothalamic-autonomic neurons is found in the lateral hypothalamic area. These consist mainly of neurons containing orexin or melanin-concentrating hormone (MCH) neurons, and sometimes the peptide cocaine- and amphetamine-regulated transcript (CART), which is thought to be involved in regulation of feeding and metabolism as well as wake-sleep and locomotor activity. A third population of hypothalamic-autonomic cells is found in the arcuate nucleus and adjacent retrochiasmatic area. These neurons contain α-melanocyte–stimulating hormone and CART and may also be involved in feeding and metabolic regulation.

All three sets of neurons send axons to the brainstem, where they innervate the nucleus of the solitary tract (which receives visceral afferent input from the glossopharyngeal and vagus nerves), as well as the regions that coordinate autonomic and respiratory reflexes in the ventrolateral medulla. Other axons innervate the parasympathetic preganglionic neurons in the Edinger-Westphal nucleus (pupillary constriction), the superior salivatory nucleus (associated with the facial nerve, which supplies the submandibular and sublingual salivary glands as well as the cerebral vasculature), the inferior salivatory nucleus (associated with the rostral tip of the nucleus of the solitary tract, supplying the parotid gland), the dorsal motor vagal nucleus (which supplies the abdominal organs), and the nucleus ambiguus (which is the main source of vagal input to the thoracic organs, including the esophagus, heart, and lungs).

Finally, there are descending axons from the hypothalamus that innervate the sympathetic preganglionic neurons in the thoracic spinal cord. Different populations of hypothalamospinal neurons contact distinct targets. For example, the main projection from the orexin neurons is to the upper thoracic spinal cord, which may be important for autonomic functions associated with ingestion. The oxytocin neurons innervate specific clusters of sympathetic preganglionic neurons at multiple spinal cord levels.

In addition, there is a major input to the medullary raphe nuclei from the preoptic area and dorsomedial nucleus of the hypothalamus. The medullary raphe nuclei contain both serotoninergic and glutamatergic neurons that innervate the sympathetic preganglionic column at multiple levels and regulate populations of neurons involved in thermoregulation. This pathway is thought to be a major mechanism for regulating body temperature.

Damage to the descending hypothalamic-autonomic pathway, in the lateral medulla or spinal cord, causes an ipsilateral central Horner syndrome. Such patients not only have a small pupil and ptosis on that side but lack sweating on the affected side of the face and body.

Olfactory Inputs to the Hypothalamus

There are about 1,000 olfactory receptor genes, each of which recognizes a different class of chemical olfactory stimulus. Each olfactory receptor cell expresses a single olfactory receptor type, and each gene is expressed in several hundred cells, spread across the olfactory mucosa. The axons from olfactory receptor cells then run through openings in the cribriform plate, which forms the base of the skull over the olfactory mucosa, and axons from individual cells, which express a single receptor gene, then converge in the olfactory bulb on one or a few individual olfactory glomeruli.

The glomeruli are on the surface of the olfactory bulb and are spherical areas, each about one third millimeter across. The outside of the glomerulus is lined with tiny periglomerular cells, which are interneurons. Just deep to the glomerular layer are mitral and tufted cells, which send their apical dendrites up into the glomeruli, where they receive olfactory sensory information. These excite granule cells, which, in turn, inhibit the other mitral and tufted cells, as well as receiving centrifugal axons, which allow them to modulate the perception of the sensory stimulus. Only the mitral and tufted cells send their axons into the brain via the olfactory tract. In humans, this is a long white matter bundle that runs the length of the frontal lobe and is sometimes erroneously called the “olfactory nerve.”

The olfactory tract supplies information about smell to a variety of targets in the brain. It bifurcates as it approaches the temporal lobe into one branch that runs medially into the basal forebrain and another that runs laterally to supply olfactory inputs to cortical structures. The basal forebrain branch provides inputs to the anterior olfactory nucleus, which sends axons through the anterior commissure to the opposite hemisphere, and the olfactory tubercle, which is the part of the striatum that receives olfactory inputs. The lateral olfactory branch provides inputs to the primary olfactory cortex, which appears to be necessary for processing the conscious appreciation of odors, as well as the entorhinal cortex, which is a point of convergence of information from multiple sensory systems and a major relay into the hippocampal formation. There is also input to the amygdala, which may be important for relaying olfactory signals related to food acquisition and sexual behavior to the hypothalamus.

In many mammals, there is an accessory olfactory system. A small pit in the nasal mucosa, called the vomeronasal organ, contains olfactory sensory neurons that are important for sensing pheromones. These olfactory neurons synapse in a specialized region called the accessory olfactory bulb and relay information concerned with social behaviors into the amygdala and hypothalamus. Such a system has never been clearly identified in humans, and its very existence remains controversial.

Visual Inputs to the Hypothalamus

The hypothalamus is largely framed by the optic chiasm, which underlies its most rostral part (the preoptic area) and provides the lateral boundary for its middle, tuberal part. Despite this close relationship, it remained a mystery for many years how the hypothalamus used visual input to synchronize its biologic clock with the external world. In 1972, two groups of scientists demonstrated that some axons leave the optic chiasm as it passes by the hypothalamus and provide an input that is now called the retinohypothalamic tract.

The retinohypothalamic tract originates from about 1,000 scattered retinal ganglion cells in each retina. In 2001, it was discovered that these retinal ganglion cells have the peculiar property of making their own light-sensing pigment, called melanopsin. So, although other retinal ganglion cells that are concerned with patterned vision are “blind” and depend upon input from rods and cones to signal to them the presence of light in their receptive fields, the melanopsin-containing retinal ganglion cells are intrinsically photosensitive. These neurons act essentially as light level detectors and relay this information both to the hypothalamus as well as to the olivary pretectal nucleus, which is a critical relay in the pupillary light reflex pathway.

By replacing the melanopsin gene with one for β-galactosidase, one can then stain the melanopsin-containing retinal ganglion cells blue and follow their axons into the brain. The densest site of retinohypothalamic input is to the suprachiasmatic nucleus, although other axons, in smaller numbers, enter other parts of the hypothalamus. The suprachiasmatic nucleus is the brain's biologic clock; damage to this cell group causes animals and humans to lose their 24-hour patterns of activity in wake-sleep, feeding, body temperature, corticosteroid secretion, and other important physiologic and behavioral functions. Although the neurons in the suprachiasmatic nucleus maintain an approximately 24-hour rhythm of activity even when placed into tissue culture, retinal input is necessary to reset their clock rhythm to maintain synchrony with the external world. In the absence of light cues, circadian rhythms in both people and animals show a free-running cycle that is generally just a bit different from 24 hours and may vary among individual (humans average about 24.1 hours). Although this may seem like a small difference from 24 hours, without a mechanism for synchronization, someone with a 24.1-hour cycle would be 3 hours off-cycle from the rest of the world by the end of 1 month. Some blind individuals, with total loss of retinal input to the brain, show this type of shift of their circadian rhythms over time so that they go through periods every few months where their cycles go out of phase with the rest of the world. Other blind people, such as those with rod and cone degeneration, who retain intrinsically photosensitive melanopsin-containing retinal ganglion cells, remain in synchrony with the world that they cannot see.

Melatonin is one of the hormones whose 24-hour cycle of secretion is driven by the suprachiasmatic nucleus. Suprachiasmatic axons directly contact neurons in the paraventricular nucleus, which, in turn, innervates the sympathetic preganglionic neurons in the upper thoracic spinal cord. The latter project to the superior cervical ganglion, which sends axons along the internal carotid artery intracranially to innervate the pineal gland, causing secretion of melatonin. The hormone is mainly secreted at the onset of the dark period and in humans may promote sleepiness. One of the major targets in the brain for melatonin is the suprachiasmatic nucleus itself, which stands out when the brain is stained for melatonin receptors.

Other retinal axons to the hypothalamus may be important in providing visual inputs to neurons concerned with a variety of diverse functions. For example, retinal inputs to a sleep-promoting cell group, the ventrolateral preoptic nucleus, may explain why people turn out the lights and close their eyes when falling asleep. Other inputs to the lateral hypothalamus may contact neurons involved in regulating arousal and feeding. In rodents, who might be recognized as potential prey when they venture into a lighted area, an important response to light is immobility. This reduced locomotion in light appears to be regulated by retinal inputs to the subparaventricular zone.

Somatosensory Inputs to the Hypothalamus

The somatosensory system provides a major source of direct inputs to the hypothalamus. For many years it was thought that the somatosensory system primarily fed through the thalamus to the cerebral cortex and that sensory inputs to the hypothalamus must be relayed from the cortex. However, in 1980, it was discovered that some axons from the ascending somatosensory pathways directly reach the hypothalamus. These inputs originate from somatosensory neurons in the spinal and trigeminal dorsal horn. Many of these neurons are concerned with painful stimuli. These may be used in orchestrating emotional responses, such as anger, fight, or flight in response to a physical injury. On the other hand, they may be important stimuli for the underlying autonomic and endocrine responses associated with pain, such as elevation of blood pressure and heart rate, or secretion of cortisol.

Somatosensory inputs are also important in sexual behavior. Neurons in the preoptic area promote erection in males, and nerve cells in the ventromedial nucleus of the hypothalamus can potently drive sexual behaviors, including mounting postures in males and receptive postures in females. The neurons that produce these responses are, in turn, driven by a range of visual, olfactory, and tactile stimuli. In some species, ovulation is also triggered by sexual somatosensory stimuli (such as vaginal stimulation).

Another hypothalamically mediated response that is dependent upon somatosensory input is the milk let-down reflex during breastfeeding. Breast milk production is stimulated by prolactin, but the release of the milk requires somatosensory stimulation as well. The infant suckling at the breast causes sensory input that reaches the oxytocin neurons in the paraventricular and supraoptic nuclei in the hypothalamus. These neurons fire in bursts, which causes them to release oxytocin into the circulation from their axon terminals in the posterior pituitary gland. The oxytocin, in turn, causes milk to flow from the breast.

In each of these examples, autonomic, endocrine, and behavioral responses must be coordinated, the hallmark of a hypothalamically mediated behavior. The integration of these responses in each case depends upon somatosensory input that is delivered directly to the hypothalamus.

Taste and Other Visceral Sensory Inputs to the Hypothalamus

A special class of visceral sensory pathway provides taste information to the hypothalamus and other areas of the brain. Taste receptor cells are found in taste buds, located in clusters along the surface of the tongue. Different classes of taste receptors respond to different classes of chemicals in food, including acids (sour), sugars (sweet), sodium (salty), glutamate (an important amino acid component of proteins, whose taste is said to be “beefy” or “umame” in Japanese), and complex plant alkaloids that often warn of poisonous compounds (bitter). The taste receptor cells are innervated by sensory neurons from the facial (VII nerve, to the anterior two thirds of the tongue), glossopharyngeal (IX nerve, to the posterior tongue and tonsillar arches), and vagus (X nerve, to the posterior tongue and oropharynx) cranial nerves. Much like other somatosensory systems, the gustatory sensory neurons are located in ganglia (geniculate for the facial nerve, petrosal for the glossopharyngeal nerve, and nodose for the vagus nerve) and consist of pseudounipolar cells, with a single axon that bifurcates in the ganglion into a central and a peripheral branch. The central branches terminate in the rostral third of the nucleus of the solitary tract in the medulla. The axons end in a roughly topographic order with respect to the surface of the tongue (axons from the anterior two thirds of the tongue ending most rostrally). The nucleus of the solitary tract gives off local connections in the brainstem to reflex pathways for salivation and for regulation of biting, chewing, and swallowing activity.

Ascending axons from the nucleus of the solitary tract travel through the brainstem, and a large proportion of them synapse in the parabrachial nucleus. From there, axons continue on to the thalamus (for conscious appreciation of taste), amygdala (for taste associations), and hypothalamus (presumably for regulation of feeding). The inputs to the hypothalamus and amygdala are augmented by a smaller number of axons that reach these sites directly from the nucleus of the solitary tract. In primates, there is evidence that some axons from the taste portion of the nucleus of the solitary tract may reach the thalamus directly, without requiring a relay in the parabrachial nucleus. Taste neurons in the thalamus are located adjacent to the tongue somatosensory area, and they innervate the insular cortex, which is the primary taste cortex.

The posterior two thirds of the nucleus of the solitary tract receives inputs from other internal organs via the glossopharyngeal and vagus nerves. These terminate in a roughly topographic order, with gastrointestinal inputs in the middle part of the nucleus and cardiorespiratory in the caudal part. The nucleus of the solitary tract provides local inputs to cell groups in the medulla that control gastrointestinal functions, including gastric acid secretion and gut motility as well as cardiovascular and respiratory reflexes (e.g., the baroreceptor reflex that stabilizes blood pressure when moving from a lying to a standing position, and the increase in both respiratory rate and blood pressure when there is a high level of carbon dioxide in the blood).

Other axons from the posterior two thirds of the nucleus of the solitary tract terminate in the parabrachial nucleus. Parabrachial neurons then contact the visceral sensory thalamus, which, in turn, projects to the insular cortex, where sensations such as gastric fullness or air hunger reach conscious appreciation. Other parabrachial outputs are joined by smaller numbers of axons from the nucleus of the solitary tract itself in projecting to the amygdala, where they may be involved in visceral conditioned reflexes. Parabrachial inputs to the hypothalamus may play a role in a wide range of functions, from regulation of behaviors such as feeding and drinking to control of secretion of hormones such as vasopressin (during hypovolemia) and oxytocin (during emesis).

Limbic and Cortical Inputs to the Hypothalamus

In addition to having direct sensory inputs, the hypothalamus receives highly processed information from the cerebral cortex, which is relayed via the limbic system. The limbic lobe of the brain was first defined by Paul Broca, in 1878, as the cortex surrounding the medial edge of the cerebral hemisphere, as shown in orange in the upper figure. Broca's limbic lobe includes the cingulate gyrus (the infralimbic, prelimbic, anterior cingulate, and retrosplenial areas), the hippocampal formation (including the entorhinal area, subiculum, hippocampal CA fields, and dentate gyrus), and the amygdala. These limbic regions all receive highly processed sensory information from the association regions of the cerebral cortex, process that information for its emotional content, and then project back to the association cortical areas to provide emotional coloring to cognition.

Each of the limbic areas also sends descending inputs to the hypothalamus. The inputs from the cingulate gyrus mainly originate in the infralimbic and prelimbic regions (around and just beneath the splenium of the corpus callosum). These areas mainly send axons to the lateral hypothalamus, as well as to components of the autonomic system in the brainstem and the spinal cord, and are believed to provide much of the autonomic component of emotional response.

Neurons in the hippocampal formation, particularly the CA1 field and the subiculum, send axons to the hypothalamus through the fornix. This long looping pathway, shown in yellow in the figure, curves just under the corpus callosum, and then dives into the diencephalon at the foramen of Monro. Many axons leave the fornix in the hypothalamus and provide inputs to the ventromedial nucleus. However, a dense column of fornix axons reach the mammillary body, where they terminate. These structures are shown in blue in the upper figure and red in the lower one. Although the hippocampus appears to be very important in memory consolidation, isolated damage to the fornix or mammillary bodies has more limited and inconsistent effects on memory, so the function of this pathway remains enigmatic.

The mammillary nuclei provide another salient bundle of axons to the anterior nucleus of the thalamus. This mammillothalamic tract is heavily myelinated and easily seen, but its contribution to memory formation is more subtle, like that of the mammillary body itself. Lesions of the mammillothalamic tract have been reported to prevent the generalization of limbic seizures, however, and this pathway has been suggested as a target for deep brain stimulation to prevent generalization of seizures. The anterior thalamic nucleus projects to the cingulate gyrus, and, in 1937, James Papez hypothesized that perhaps the momentum of emotions could be explained by a “reverberating circuit,” completed by a projection from the cingulate cortex back to the hippocampus, to neurons that contribute to the fornix. Although there is no credible evidence for this last link in the “circuit” actually existing or for the proposed circuit actually playing a role in emotion, the theory has achieved great attention.

The amygdala provides the hypothalamus with inputs via two pathways. Some axons leave the amygdala in parallel to the fornix, running along the lateral edge of the lateral ventricle just below the tail and body of the caudate nucleus in the stria terminalis, shown in blue in the lower figure. Other amygdaloid inputs to the hypothalamus take a much more direct anterior route, running over the optic tract into the lateral hypothalamus. Many hypothalamic cell groups receive inputs from the amygdala, which are thought to be important for the visceral components of conditioned emotional responses.

Overview of Hypothalamic Function and Dysfunction

The hypothalamus works to integrate autonomic, endocrine, and behavioral functions of the brain that subserve basic life functions, such as maintaining fluid and electrolyte balance, feeding and metabolism, body temperature and energy expenditure, cycles of sleep and wakefulness, and a wide range of emergency responses. As a result, the range of disorders that occur when the hypothalamus malfunctions is also very great.

Because the hypothalamus is very small, injuries often involve multiple systems. Hence, a patient with a pituitary tumor or craniopharyngioma impinging on the hypothalamus may have disorders extending into many functions. Such patients are often quite somnolent because an important branch of the ascending arousal system runs through the lateral hypothalamic area. There may also be loss of circadian (24-hour) rhythms of behavior so that the relatively limited waking time may occur during the night rather than in the day.

Alfred Froehlich in 1901 described the patients with such lesions as having an “adiposogenital syndrome” because they became obese and had failure of sexual maturation. Research in the last decade has identified the reason for this association. Feeding in humans (and other animals) is controlled in part by the hormone leptin, which is made by white adipose tissue during times of plenty. In the absence of leptin or its receptors, both humans and animals are ravenous and become quite obese. Leptin is now known to act on the hypothalamus in the region just above the pituitary stalk, to decrease activity in circuits that promote eating. When tumors in the region of the pituitary gland damage this part of the hypothalamus, feeding circuits become disinhibited and the patient becomes obese. An adequate nutritional state is also required for the brain to trigger the hormonal changes that accompany puberty. These circuits are also dependent upon leptin to provide a signal that there are sufficient energy stores to make reproduction possible. Patients whose pituitary tumors develop before puberty may fail to go through the transition. Adults who are severely underweight may have regression of sexual organs, accompanied by amenorrhea in women.

The hypothalamic-releasing hormones, in general, are required by the anterior pituitary gland to secrete adequate amounts of growth, thyroid, corticotrophic, and gonadal hormones. In the presence of a pituitary tumor that damages the hypophysial portal bed in the pituitary stalk, secretion of all of these hormones is diminished. On the other hand, prolactin is mainly under inhibitory control by the hypothalamus, primarily through release of dopamine into the portal circulation. Damage to the pituitary stalk thus causes hyperprolactinemia, with galactorrhea (breast milk production) and amenorrhea in women.

Pituitary stalk lesions also sever the axons from the paraventricular and supraoptic nuclei, which release the hormones oxytocin and vasopressin from the posterior pituitary gland. Such patients have diabetes insipidus, with excessive urination, requiring compensatory drinking to avoid volume depletion.

Smaller, focal hypothalamic lesions can sometimes have different results. For example, bilateral lateral hypothalamic lesions, such as multiple sclerosis plaques, have been reported to cause emaciation. Lesions of the preoptic area can cause loss of thirst and loss of ability to increase vasopressin secretion during dehydration. On hot days, such patients may have substantial volume depletion without becoming thirsty.

Hypothalamic lesions in children may also have somewhat different clinical presentations than in adults. Hypothalamic hamartomas can cause gelastic epilepsy, in which the child laughs uncontrollably but mirthlessly, and sometimes precocious puberty (if the hamartoma includes gonadotropic-releasing hormone neurons). On the other hand, a large hypothalamic lesion in an infant is more likely to present with wasting and emaciation than with obesity, but such children may be quite happy and playful, rather than somnolent.