The hypothalamus, which serves autonomic, appetitive, and regulatory functions, lies below and in front of the thalamus; it forms the floor and lower walls of the third ventricle (see Fig 9–1). External landmarks of the hypothalamus are the optic chiasm; the tuber cinereum, with its infundibulum extending to the posterior lobe of the hypophysis; and the mammillary bodies lying between the cerebral peduncles (Fig 9–6).
Diencephalon from below, with adjacent structures.
The hypothalamus can be divided into an anterior portion, the chiasmatic region, including the lamina terminalis; the central hypothalamus, including the tuber cinereum and the infundibulum (the stalk connecting the pituitary to the hypothalamus); and the posterior portion, the mammillary area (Fig 9–7).
Coronal sections through the diencephalon and adjacent structures. A: Section through the optic chiasm and the anterior commissure. B: Section through the tuber cinereum and the anterior portion of the thalamus. C: Section through the mammillary bodies and middle thalamus. D: Key to the section levels.
The right and left sides of the hypothalamus each have a medial hypothalamic area that contains many nuclei and a lateral hypothalamic area that contains fiber systems (eg, the medial forebrain bundle) and diffuse lateral nuclei.
Medial Hypothalamic Nuclei
Each half of the medial hypothalamus can be divided into three parts (Fig 9–8): the supraoptic portion, which is farthest anterior and contains the supraoptic, suprachiasmatic, and paraventricular nuclei; the tuberal portion, which lies behind the supraoptic portion and contains the ventromedial, dorsomedial, and arcuate nuclei in addition to the median eminence; and the mammillary portion, which is the farthest posterior and contains the posterior nucleus and several mammillary nuclei. The preoptic area lies anterior to the hypothalamus, between the optic chiasm and the anterior commissure.
The human hypothalamus, with a superimposed diagrammatic representation of the portal-hypophyseal vessels. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology. 22nd ed. McGraw-Hill, 2005.)
The thalamic syndrome is characterized by immediate hemianesthesia, with the threshold of sensitivity to pinprick, heat, and cold rising later. When a sensation, sometimes referred to as thalamic hyperpathia, is felt, it can be disagreeable and unpleasant. The syndrome usually appears during recovery from a thalamic infarct; rarely, persistent burning or boring pain can occur (thalamic pain).
Consistent with its autonomic and regulatory functions, the hypothalamus receives inputs from limbic structures, thalamus and cortex, visceral and somatic afferents, and sensors such as osmoreceptors, which permit it to monitor the circulation.
Afferent connections to the hypothalamus include part of the medial forebrain bundle, which sends fibers to the hypothalamus from nuclei in the septal region, parolfactory area, and corpus striatum; thalamohypothalamic fibers from the medial and midline thalamic nuclei; and the fornix, which brings fibers from the hippocampus to the mammillary bodies. These connections include the stria terminalis, which brings fibers from the amygdala; pallidohypothalamic fibers, which lead from the lentiform nucleus to the ventromedial hypothalamic nucleus; and the inferior mammillary peduncle, which sends fibers from the tegmentum of the midbrain. A small number of ganglion cells from throughout the retina (less than 1%) send axons that provide visual input to the suprachiasmatic nucleus via the retinohypothalamic tract. These and other connections are shown in Table 9–2.
TABLE 9–2Principal Pathways to and from the Hypothalamus. ||Download (.pdf) TABLE 9–2 Principal Pathways to and from the Hypothalamus.
|Tract ||Type* ||Description |
|Medial forebrain bundle ||A, E ||Connects limbic lobe and midbrain via lateral hypothalamus, where fibers enter and leave it; includes direct amygdalohypothalamic fibers, which are sometimes referred to as a separate pathway |
|Fornix ||A, E ||Connects hippocampus to hypothalamus; mostly mammillary bodies |
|Stria terminalis ||A ||Connects amygdala to hypothalamus, especially ventromedial region |
|Mammillary peduncle ||A ||Connects brain stem to lateral mammillary nuclei |
|Ventral noradrenergic bundle ||A ||Axons of noradrenergic neurons projecting from nucleus of tractus solitarius and ventrolateral medulla to paraventricular nuclei and other parts of hypothalamus |
|Dorsal noradrenergic bundle ||A ||Axons of noradrenergic neurons projecting from locus ceruleus to dorsal hypothalamus |
|Serotonergic neurons ||A ||Axons of serotonin-secreting neurons projecting from dorsal and other raphe nuclei to hypothalamus |
|Adrenergic neurons ||A ||Axons of epinephrine-secreting neurons from medulla to ventral hypothalamus |
|Retinohypothalamic fibers ||A ||Optic nerve fibers to suprachiasmatic nuclei from optic chiasm |
|Thalamohypothalamic and pallidohypothalamic fibers ||A ||Connects thalamus and lenticular nucleus to hypothalamus |
|Periventricular system (including dorsal longitudinal fasciculus of Schütz) ||A, E ||Interconnects hypothalamus and midbrain; efferent projections to spinal cord, afferent from sensory pathways |
|Mamillothalamic tract of Vicq d'Azyr ||E ||Connects mammillary nuclei to anterior thalamic nuclei |
|Mamillotegmental tract ||E ||Connects hypothalamus with reticular portions of midbrain |
|Hypothalamohypophyseal tract (supraopticohypophyseal and paraventriculohypophyseal tracts) ||E ||Axons of neurons in supraoptic and paraventricular nuclei that end in median eminence, pituitary stalk, and posterior pituitary |
|Neurons containing vasopressin, oxytocin ||E ||Run from paraventricular nucleus to nucleus of tractus solitarius, other brain stem nuclei, intermediolateral column of spinal cord; also from paraventricular nucleus to central nucleus of amygdala |
|Neurons containing hypophyseotropic hormones ||E ||Run from various hypothalamic nuclei to median eminence |
Affective and emotional inputs from the prefrontal cortex reach the hypothalamus via a polysynaptic pathway that passes through the dorsomedial nuclei of the thalamus. In addition, visceral information from the vagal sensory nuclei, gustatory messages from the nucleus solitarius, and somatic afferent messages from the genitalia and nipples are relayed to the hypothalamus.
Efferent tracts from the hypothalamus include the hypothalamohypophyseal tract, which runs from the supraoptic and paraventricular nuclei to the neurohypophysis (see the next paragraph); the mamillotegmental tract (part of the medial forebrain bundle) going to the tegmentum; and the mamillothalamic tract (tract of Vicq d'Azyr), from the mammillary nuclei to the anterior thalamic nuclei. There are also the periventricular system, including the dorsal fasciculus to the lower brain levels; the tuberohypophyseal tract, which goes from the tuberal portion of the hypothalamus to the posterior pituitary; and fibers from the septal region, by way of the fornix, to the hippocampus (see Chapter 19).
There are rich connections between the hypothalamus and the pituitary gland. The pituitary has two major lobes: the posterior pituitary (neurohypophysis) and anterior pituitary (adenohypophysis). Neurons in the supraoptic and paraventricular nuclei send axons, via the hypothalamohypophyseal tract, to the neurohypophysis. These axons transport Herring bodies, which contain precursors of the hormones oxytocin and vasopressin (also known as antidiuretic hormones, or ADHs) to the posterior pituitary. Oxytocin and vasopressin are released from axon endings in the posterior pituitary and are then taken up by a rich network of vessels that transports them to the general circulation (Figs 9–8 and 9–9).
Schematic view of the pituitary portal system of vessels and neurohypophyseal pathways. The portal hypophyseal vessels serve as a vascular conduit that carries various hypophyseotropic hormones from their sites of release from hypothalamic neurons, in the median eminence on the pituitary stalk, to the anterior pituitary. In contrast, the axons of supraoptic and paraventricular neurons run all the way to the posterior pituitary, where they release vasopressin and oxytocin.
Neurons in other hypothalamic nuclei regulate the adenohypophysis via the production of a group of hypophyseotropic hormones that control the secretion of anterior pituitary hormones (Fig 9–10). The hypophyseotropic hormones include releasing factors and inhibitory hormones, which, respectively, stimulate or inhibit the release of various anterior pituitary hormones.
Effects of hypophyseotropic hormones on the secretion of anterior pituitary hormones. CRH, corticotropin-releasing hormone; TRH, thyrotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; GRH, growth hormone-releasing hormone; GIH, growth hormone-inhibiting hormone; PRH, prolactin-releasing hormone; PIH, prolactin-inhibiting hormone. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology. 22nd ed. McGraw-Hill, 2005.)
Communication between the hypothalamus and adenohypophysis involves a vascular circuit (the portal hypophyseal system) that carries hypophyseotropic hormones from the hypothalamus to the adenohypophysis. After their synthesis in the cell bodies of neurons located in the hypothalamic nuclei, these hormones are transported along relatively short axons that terminate in the median eminence and pituitary stalk. Here they are released and taken up by capillaries of the portal hypophyseal circulation. The portal hypophyseal vessels form a plexus of capillaries and veins that carries the hypophyseotropic hormones from the hypothalamus to the anterior pituitary. After delivery from the portal hypophyseal vessels to sinusoids in the anterior pituitary, the hypophyseotropic hormones bathe the pituitary cells and control the release of pituitary hormones. These pituitary hormones, in turn, play important regulatory roles throughout the body (Fig 9–11).
Anterior pituitary hormones. ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; b-LPH, beta-lipotropin (function unknown). In women, FSH and LH act in sequence on the ovary to produce growth of the ovarian follicle, ovulation, and formation and maintenance of the corpus luteum. In men, FSH and LH control the functions of the testes. Prolactin stimulates lactation. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology. 22nd ed. McGraw-Hill, 2005.)
Although the hypothalamus is small (weighing 4 g, or about 0.3% of the total brain weight), it has important regulatory functions, as outlined in Table 9–3.
TABLE 9–3Principal Hypothalamic Regulatory Mechanisms. ||Download (.pdf) TABLE 9–3 Principal Hypothalamic Regulatory Mechanisms.
|Function ||Afferents from ||Integrating Areas |
|Temperature regulation ||Cutaneous cold receptors; temperature-sensitive cells in hypothalamus ||Anterior hypothalamus (response to heat), posterior hypothalamus (response to cold) |
|Neuroendocrine control of catecholamines ||Emotional stimuli, probably via limbic system ||Dorsomedial and posterior hypothalamus |
|Vasopressin ||Osmoreceptors, volume receptors, others ||Supraoptic and paraventricular nuclei |
|Oxytocin ||Touch receptors in breast, uterus, genitalia ||Supraoptic and paraventricular nuclei |
|Thyroid-stimulating hormone (thyrotropin, TSH) via thyrotropin-stimulating hormone (TRH) ||Temperature receptors, perhaps others ||Dorsomedial nuclei and neighboring areas |
|Adrenocorticotropic hormone (ACTH) and b-lipotropin (b-LPH) via corticotropin-releasing hormone (CRH) ||Limbic system (emotional stimuli); reticular formation ("systemic" stimuli); hypothalamic or anterior pituitary cells sensitive to circulating blood cortisol level; suprachiasmatic nuclei (diurnal rhythm) ||Paraventricular nuclei |
|Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via luteinizing-hormone-releasing hormone (LHRH) ||Hypothalamic cells sensitive to estrogens; eyes, touch receptors in skin and genitalia ||Preoptic area, other areas |
|Prolactin via prolactin-inhibiting hormone (PIH) and prolactin-releasing hormone (PRH) ||Touch receptors in breasts, other unknown receptors ||Arcuate nucleus, other areas (hypothalamus inhibits secretion) |
|Growth hormone via somatostatin and growth-hormone-releasing hormone (GRH) ||Unknown receptors ||Periventricular nucleus, arcuate nucleus |
|"Appetitive" behavior Thirst ||Osmoreceptors, subfornical organ ||Lateral superior hypothalamus |
|Hunger ||"Glucostat" cells sensitive to rate of glucose utilization ||Ventromedial satiety center, lateral hunger center; also limbic components |
|Sexual behavior ||Cells sensitive to circulating estrogen and androgen, others ||Anterior ventral hypothalamus plus (in the male) piriform cortex |
|Defensive reactions Fear, rage ||Sense organs and neocortex, paths unknown ||In limbic system and hypothalamus |
|Control of various endocrine and activity rhythms ||Retina via retinohypothalamic fibers ||Suprachiasmatic nuclei |
A tonically active feeding center in the lateral hypothalamus evokes eating behavior. A satiety center in the ventromedial nucleus stops hunger and inhibits the feeding center when a high blood glucose level is reached after food intake. Damage to the feeding center leads to anorexia (loss of appetite) and severe loss of body weight; lesions of the satiety center lead to hyperphagia (overeating) and obesity.
Although anatomically discrete centers have not been identified, the posterolateral and dorsomedial areas of the hypothalamus function as a sympathetic (catecholamine) activating region, whereas an anterior area functions as a parasympathetic activating region.
When some regions of the hypothalamus are appropriately stimulated, they evoke autonomic responses that result in loss, conservation, or production of body heat. A fall in body temperature, for example, causes vasoconstriction, which conserves heat, and shivering, which produces heat. A rise in body temperature results in sweating and cutaneous vasodilation. Normally, the hypothalamic set point, or thermostat, lies just below 37°C of body temperature. A higher temperature, or fever, is the result of a change in the set point, for example, by pyrogens in the blood.
Hypothalamic influence on vasopressin secretion within the posterior pituitary is activated by osmoreceptors within the hypothalamus, particularly in neurons within a "thirst center" located near the supraoptic nucleus. The osmoreceptors are stimulated by changes in blood osmolarity. Their activation results in the generation of bursts of action potentials in neurons of the supraoptic nucleus; these action potentials travel along the axons of these neurons, to their terminals within the neurohypophysis, where they trigger the release of vasopressin. Pain, stress, and certain emotional states also stimulate vasopressin secretion. Lack of secretion of vasopressin caused by hypothalamic or pituitary lesions can result in diabetes insipidus, which is characterized by polyuria (increased urine excretion) and polydipsia (increased thirst).
E. Anterior Pituitary Function
The hypothalamus exerts a direct influence on secretions of the anterior pituitary and an indirect influence on secretions of other endocrine glands by releasing or inhibiting hormones carried by the pituitary portal vessels (see Fig 9–9). It thus regulates many endocrine functions, including reproduction, sexual behavior, thyroid and adrenal cortex secretions, and growth.
Many body functions (eg, temperature, corticosteroid levels, oxygen consumption) are cyclically influenced by light intensity changes that have a circadian (day-to-day) rhythm. Within the hypothalamus, a specific cell group, the suprachiasmatic nucleus, functions as an intrinsic clock. Within these cells, there are "clock genes," including two genes called clock and per, that turn on and off with a circadian, once-per-day, rhythm (Fig 9–12). Thus, cells within the suprachiasmatic nucleus show circadian rhythms in metabolic and electrical activity, and in neurotransmitter synthesis, and appear to keep the rest of the brain on a day–night cycle. A retinosuprachiasmatic pathway carries information about the light intensity and can "entrain" the suprachiasmatic clock in order to synchronize its activity with environmental events (eg, the light–dark day–night cycle). In the absence of any sensory input, the suprachiasmatic nucleus itself can function as an independent clock with a period of about 25 hours per cycle; lesions in this nucleus cause the loss of all circadian cycles.
Clock genes turn on and off, once per daily cycle, within neurons of the suprachiasmatic nucleus. Top panels: Transcription of the Per1 gene peaks at about mid-day (Per1 mRNA within suprachiasmatic neurons appears black). Bottom panels: Per1 protein, which is produced after a delay of about 6 hours, peaking in the early evening. Per1 protein appears light. (Reproduced, with permission, from Mendoza J, Challet E: Neuroscientist 2009;5:480.)
The hypothalamus is involved in the expression of rage, fear, aversion, sexual behavior, and pleasure. Patterns of expression and behavior are subject to limbic system influence and, in part, to changes in visceral system function (see Chapters 19 and 20).