Hypothalamus

The hypothalamus is a part of the vertebrate brain that is located below the thalamus. In humans, it lies directly above the soft patate in the roof of the mouth. The hypothalamus is an very important area, and damage to even a small part of it can have very severe consequences, including death. The hypothalamus links the nervous system to the endocrine system by synthesizing and secreting neurohormones, often called releasing hormones, that control the secretion of hormones from the anterior pituitary gland. The hypothalamus also controls body temperature, appetite, thirst, metabolism, circadian rhythms, physiological responses to stress, and several important behaviors, including aggression, maternal behavior and pair bonding.

The hypothalamus consists of many small populations of neurons that are specialised for particular functions, some of which are aggregated into discrete nuclei within the hypothalamus. These populations differ not only functionally but also anatomically and biochemically, by the chemical messengers that they produce and by the receptor molecules that they express. For example, the supraoptic nucleus contains just oxytocin and vasopressin-producing cells, and is a relatively homogeneous nucleus; all of these neurons are neuroendocrine cells that project to the posterior pituitary gland, but the functions of oxytocin and vasopressin are very different - oxytocin regulates milk-let down and uterine contractions, while vasopressin regulates water reabsorption by the kidneys. The arcuate nucleus also contains two populations of neuroendocrine cells - one makes growth-hormone releasing hormone to regulate the secretion of growth hormone, the other makes dopamine and regulates prolactin secretion. However, the arcuate nucleus also contains two populations of neurones that regulate appetite - one of these makes both neuropeptide Y and agouti-related peptide and stimulates feeding, while another makes alpha-melanocyte stimulating hormone which potently suppresses appetite. Another population of arcuate neurones make kisspeptin, and indirectly regulate the secretion of luteinizing hormone. Yet other cells make somatostatin, and their function is unknown.

Inputs to the hypothalamus

The hypothalamus is a complex region, and even small nuclei within it can have many different functions. The paraventricular nucleus, for instance, contains oxytocin and vasopressin neurons which project to the posterior pituitary, but also contains other neurons that regulate ACTH and TSH secretion from the anterior pituitary, gastric reflexes, maternal behavior, blood pressure, feeding, immune responses, penile erection, and body temperature. The hypothalamus co-ordinates many seasonal and circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms, and many important stereotyped behaviours. It must therefore respond to many different signals, some of which are generated externally and some internally. The hypothalamus is richly connected with many parts of the central nervous system, including the caudal brainstem, the limbic forebrain and the olfactory bulbs.

The hypothalamus is responsive to:

• Light: daylength and photoperiod for generating circadian rhythms
• Melatonin secreted from the pineal gland, which regulates seasonal rhythms
• Olfactory stimuli, including those arising from the detection of pheromones
• Steroids, including gonadal steroids and corticosteroids
• Neurally transmitted information arising especially from the heart, the stomach, and the reproductive tract, but also from peripheral pain receptors and temperature receptors
• Autonomic inputs
• Blood-borne stimuli, including many peptide hormones secreted by peripheral endocrine tissues, such as leptin, ghrelin, angiotensin and insulin. Also pituitary hormones, cytokines, glucose and plasma osmolarity.
• Stress
• Temperature - both skin temperature and core temperature.
• Invading microorganisms, by increasing body temperature, resetting the body's thermostat.

Olfactory stimuli

Olfactory stimuli are essential for reproduction and neuroendocrine function in many species. For instance, if a pregnant mouse is exposed to the urine of a 'strange' male during a critical period after coitus then the pregnancy fails (the Bruce effect). Thus during coitus, a female mouse forms a precise 'olfactory memory' of her partner which persists for several days. Pregnancy is maintained by neuroendocrine signals controlled by the hypothalamus, and it is the disruption of these that underlies pregnancy failure in this case. Pheromonal cues aid synchronisation of oestrus in many species; in women, synchronised menstruation may also arise from pheromonal cues.

Blood-borne stimuli

Peptide hormones have important influences upon the hypothalamus, and to do so they must evade the blood-brain barrier. The hypothalamus is bounded in part by specialized brain regions that lack an effective blood-brain barrier. Some of these sites are the sites of neurosecretion - the neurohypophysis and the median eminence, but others are sites at which the brain samples the composition of the blood. Two of these sites, the subfornical organ and the organum vasculosum of the lamina terminalis (OVLT) are "circumventricular organs", where neurons are in intimate contact with both blood and CSF. These structures are densely vascularized, and contain osmoreceptive and sodium-receptive neurons which control drinking, vasopressin release, sodium excretion, and sodium appetite. They also contain neurons with receptors for angiotensin, atrial natriuretic factor, endothelin and relaxin, each of which is important in the regulation of fluid and electrolyte balance. The circumventricular organs may also be the site of action of interleukins and other cytokines to elicit both fever and ACTH secretion, via effects on hypothalamic neurons.

Two hormones with particularly important actions on the hypothalamus are leptin, secreted by (fat cells), and ghrelin, secreted from the stomach. These have important effects on appetite; leptin normally acts to suppress appetite, whereas ghrelin, which is secreted from the stomach when it is empty, stimulates hunger. These two hormones both act at the arcuate nucleus and also at the ventromedial nucleus of the hypothalamus; these two sites contain neurons specifically involved in the regulation of feeding behaviour and in the control of energy expenditure (metabolism). Other hypothalamic regions with important roles in appetite are the lateral hypothalamus - known as a "hunger center", and the dorsomedial hypothalamus.

Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus to inhibit further growth hormone secretion (negative feedback); how it enters the brain is not clear, but some neurons in the hypothalamus express receptors for growth hormone. There is also evidence for central feedback actions of prolactin and TSH.

It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of leptin, there is evidence of active uptake at the choroid plexus from blood into CSF. In the case of peptides like ghrelin that act at the arcuate nucleus, it is possible that some arcuate neurons have processes that lie outside the blood-brain barrier.

Steroids

The hypothalamus contains many neurons that are sensitive to gonadal steroids (estrogen, progesterone and testosterone) and others that are sensitive to glucocorticoids – (the steroid hormones of the adrenal gland, released in response to ACTH). The adrenal gland is regulated by the 'hypothalamo-pituitary-adrenal axis' (the "HPA axis"), and glucocorticoid actions in the hypothalamus are involved in negative feedback regulation of this axis.

Specialized senses

The hypothalamus contains several populations of neurons with highly specialized properties that enable them to signal the status of the body. These include osmoreceptors and sodium receptors in the anterior hypothalamus, and specialised glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area contains thermosensitive neurons; these are important for TRH secretion.

Neural inputs

The hypothalamus receives many inputs from the caudal brainstem; notably from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla. Oxytocin secretion in response to suckling or vagino-cervical stimulation is mediated by some of these pathways; vasopressin secretion in response to cardiovascular stimuli arising from chemoreceptors in the carotid sinus and aortic arch, and from low-pressure atrial volume receptors, is mediated by others. In the rat, stimulation of the vagina also causes prolactin secretion, and this results in pseudo-pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of high levels of estrogen can induce maternal behaviour in a virgin ewe. These effects are all mediated by the hypothalamus, and the information is carried mainly by spinal pathways that relay in the brainstem. Stimulation of the nipples stimulates release of oxytocin and prolactin and suppresses the release of luteinising hormone and follicle stimulating hormone.

Cardiovascular stimuli are carried by the vagus nerve, but the vagus also conveys a variety of visceral information, including for instance signals arising from gastric distension to suppress feeding. Again this information reaches the hypothalamus via relays in the caudal brainstem.

Projections

Most fiber systems of the hypothalamus run in two ways (bidirectional). Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and the dorsal longitudinal fasciculus. Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and stria terminalis. There are two exceptions on this bidirectional rule: Projections to the pituitary gland are one-way only (from the hypothalamus to the pituitary), and the suprachiasmatic nucleus of the hypothalamus receives connections from the retina.

Sexual dimorphism

The hypothalamus is sexually dimorphic, i.e. there are many differences in both structure and function between males and females. Some differences are apparent even in gross neuroanatomy: most notably, the sexually-dimorphic nucleus within the preoptic area, is more than twice as large in males as in females. However most differences are more subtle changes in the connectivity and chemical sensitivity of particular sets of neurons. The importance of these changes can be recognised by functional differences between males and females. For instance, the pattern of secretion of growth hormone is sexually dimorphic, and this is one reason why in many species, adult males are much larger than females. Other striking functional dimorphisms are in the behavioral responses to ovarian steroids of the adult. Males and females respond differently to ovarian steroids, partly because estrogen receptors are expressed in different sets of neurons in males and females.

Estrogen and progesterone act by influencing gene expression in their target cells. To influence gene expression, estrogen binds to an intracellular receptor, and this complex is then translocated to the cell nucleus where it interacts with regions of the DNA known as 'estrogen regulatory elements' (EREs). Increased protein synthesis can follow as early as 30 min later. Thus, for estrogen to directly influence the expression of a particular gene in a particular cell, the following must occur:

• the cell must be exposed to estrogen
• the cell must express estrogen receptors
• the gene must be one that is regulated by an ERE.

Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly in neurons in the anterior and mediobasal hypothalamus, notably:

• the preoptic area (where LHRH neurons are located)
• the periventricular nucleus (where somatostatin neurons are located)
• the ventromedial hypothalamus, (which is important for sexual behavior).

In a "critical period" at around the time of birth, gonadal steroids influence the development of the hypothalamus. They determine the ability of females to exhibit a normal reproductive cycle, and of males and females to display appropriate reproductive behaviors in adult life. Thus, if a female rat is injected just once with testosterone in the first few days of postnatal life (during the "critical period" ), the hypothalamus is irreversibly masculinized; the adult rat will not be able to generate an LH surge in response to estrogen (a characteristic of females), but will be able to display male sexual behaviors (mounting a sexually-receptive female). By contrast, a male rat castrated just after birth will be feminized, and the adult will show female sexual behavior in response to estrogen (sexual receptivity, lordosis}.

In primates, the developmental influence of androgens is less clear. 'Tomboyism' in girls might reflect the effects of androgens on the fetal brain, but many think that the sex of rearing during the first 2-3 years is usually more important for gender identity.

Paradoxically, the masculinizing effects of testosterone are mediated by estrogen. Within the brain, testosterone is converted to (estradiol), which is the main active hormone for developmental influences. The human testis secretes large amounts of testosterone from about week 8 of fetal life until 5-6 months after birth (a similar perinatal surge in testosterone is observed in many species), a process that appears to underlie the male phenotype. Estrogen from the maternal circulation is relatively ineffective, partly because of the high circulating levels of steroid-binding proteins in pregnancy.

Sex steroids are not the only important influences upon hypothalamic development; stress in early life can affect the capacity of the adult hypothalamus to respond to an acute stressor, by the effects of early exposure to glucocorticoids - steroid hormones that are secreted from the adrenal gland in response to stress. Glucocorticoid receptors are very widespread throughout the brain; in the paraventricular nucleus they mediate negative feedback control of CRF synthesis and secretion, but elsewhere their role is not well understood.

Boundaries

The anatomical boundaries of the hypothalamus are:

• rostral, the lamina terminalis.
• caudal, the posterior margin of the mamillary bodies.
• dorsal, the hypothalamic sulcus.
• medial, the third ventricle.
• lateral, the subthalamus and internal capsule.
• ventral, the optic chiasm, median eminence, tuber cinereum, mammillary bodies, and posterior pituitary