View source for Hypothalamus

{{Infobox Brain|
  Name            = Hypothalamus |
  Latin           = hypothalamus |
  GraySubject     = 189 |
  GrayPage        = 812 |
  Image           = LocationOfHypothalamus.jpg |
  Caption         = Location of the human hypothalamus |
  Image2          = Illu diencephalon .jpg|
  Caption2        = Dienchephalon |
  IsPartOf        = | 
  Components      = |
  Artery          = |
  Vein            = |
  BrainInfoType   = hier |
  BrainInfoNumber = 358 |
  MeshName        = Hypothalamus |
  MeshNumber      = A08.186.211.730.385.357 |
}}
{{SI}}
__NOTOC__
{{GS}}




The '''hypothalamus''' links the [[nervous system]] to the [[endocrine system]] via the [[pituitary gland]] (hypophysis). The hypothalamus, (from Greek ὑποθαλαμος = under the thalamus) is located below the [[thalamus]], just above the [[brain stem]]. This gland occupies the major portion of the ventral region of the [[diencephalon]]. It is found in all [[mammal]]ian [[brain]]s. In humans, it is roughly the size of an almond.

The hypothalamus regulates certain [[metabolic]] processes and other activities of the [[Autonomic Nervous System]] activities. It synthesizes and secretes [[hormones|neurohormones]], often called hypothalamic-releasing hormones, and these in turn stimulate or inhibit the secretion of pituitary [[hormones]].

The hypothalamus controls [[body temperature]], [[hunger]], [[thirst]],<ref>http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46359</ref> and [[Circadian rhythm|circadian cycles]].   

==Inputs==

The hypothalamus is a very complex region, and even small nuclei within the hypothalamus are involved in many different functions. The [[paraventricular nucleus]] for instance contains [[oxytocin]] and [[vasopressin]] neurons which project to the [[posterior pituitary]], but also contains neurons that regulate [[ACTH]] and [[Thyroid-stimulating hormone|TSH]] secretion (which project to the [[anterior pituitary]]), gastric reflexes, maternal behavior, [[blood pressure]], [[feeding]], [[immune responses]], and temperature.

The hypothalamus co-ordinates many seasonal and circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms,<ref>http://www.sci.uidaho.edu/med532/hypothal.htm</ref> and many important stereotyped behaviours. The hypothalamus must therefore respond to many different signals, some of which are generated externally and some internally. It is thus richly connected with many parts of the CNS, including the brainstem [[reticular formation]] and autonomic zones, the limbic forebrain (particularly the [[amygdala]], [[septum]], [[diagonal band of Broca]], and the [[olfactory bulb]]s, and the [[cerebral cortex]]). 

The hypothalamus is responsive to:

*Light: daylength and photoperiod for generating [[circadian]] and seasonal rhythms
*Olfactory stimuli, including pheromones
*Steroids, including gonadal steroids and corticosteroids
*Neurally transmitted information arising in particular from the heart, the stomach, and the reproductive tract
*[[Autonomic Nervous System|Autonomic]] inputs
*Blood-borne stimuli, including [[leptin]], [[ghrelin]], [[angiotensin]], [[insulin]], pituitary hormones, [[cytokines]], plasma concentrations of glucose and osmolarity etc
*[[Stress (medicine)|Stress]]
*Invading microorganisms by increasing body temperature, resetting the body's thermostat upward.

===Olfactory stimuli===

Olfactory stimuli are important 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.
Pheromonal cues aid synchronisation of oestrus in many species; in women, synchronised [[menstruation]] may also arise from pheromonal cues, although the role of pheromones in humans is doubted by some.

===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; the capillary endothelium at these sites is fenestrated to allow free passage of even large proteins and other molecules.  Some of these sites are the sites of neurosecretion - the [[neurohypophysis]] and the [[median eminence]]. However others are sites at which the brain samples the composition of the blood. Two of these sites, the [[subfornical organ]] and the OVLT ([[organum vasculosum of the lamina terminalis]]) are so-called [[circumventricular organs]], where neurons are in intimate contact with both blood and [[Cerebrospinal fluid|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. Neurons in the OVLT and SFO project to the [[supraoptic nucleus]] and [[paraventricular nucleus]], and also to preoptic hypothalamic areas. The circumventricular organs may also be the site of action of [[interleukins]] to elicit both fever and ACTH secretion, via effects on paraventricular neurons. 

It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of [[prolactin]] and [[leptin]], there is evidence of active uptake at the [[choroid plexus]] from blood into CSF. Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, [[growth hormone]] feeds back on the hypothalamus, but how it enters the brain is not clear. There is also evidence for central actions of [[prolactin]] and [[Thyroid-stimulating hormone|TSH]].

===Steroids===

The hypothalamus contains neurons that are sensitive to gonadal steroids and [[glucocorticoids]] – (the steroid hormones of the [[adrenal gland]], released in response to [[ACTH]]). It also contains 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 [[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 behavior 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 [[Luteinizing hormone|LH]] and [[Follicle-stimulating hormone|FSH]].

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 brainstem.

==Nuclei==

The hypothalamic nuclei include the following:<ref>[http://www.psycheducation.org/emotion/pics/big%20hypothalamus.htm Diagram of Nuclei (psycheducation.org)]</ref><ref>[http://universe-review.ca/I10-80-nuclei.jpg Diagram of Nuclei (universe-review.ca)]</ref><ref>[http://www.utdallas.edu/~tres/integ/hom3/display13_04.html Diagram of Nuclei (utdallas.edu)]</ref>

[[Image:HypothalamicNuclei.png|thumb|left|350px|Hypothalamic nuclei]]
{| class="wikitable" 
|-
|'''Region'''
|'''Medial Area'''
|'''Lateral Area'''
|-
|Anterior
|
[[Medial preoptic nucleus]]<br>
[[Supraoptic nucleus]]<br>
[[Paraventricular nucleus]]<br>
[[Anterior hypothalamic nucleus]]<br>
[[Suprachiasmatic nucleus]]
|
[[Lateral preoptic nucleus]]<br>
[[Lateral hypothalamus|Lateral nucleus]]<br>
Part of supraoptic nucleus
|-
|Tuberal
|
[[Dorsomedial hypothalamic nucleus]]<br>
[[Ventromedial nucleus]]<br>
[[Lateral hypothalamus|Arcuate nucleus]]
|
[[Lateral hypothalamus|Lateral nucleus]]<br>
Lateral tuberal nuclei
|-
|Posterior
|
Mammillary nuclei (part of [[mammillary body|mammillary bodies]])<br>
[[Posterior nucleus (hypothalamus)|Posterior nucleus]]
|[[Lateral hypothalamus|Lateral nucleus]]
|}
:''See also:'' [[ventrolateral preoptic nucleus]]

==Outputs==

The outputs balsphemy of the hypothalamus can be divided into two categories: neural projections, and endocrine hormones.<ref>http://thalamus.wustl.edu/course/hypoANS.html</ref>

===Neural projections===

Most fiber systems of the hypothalamus run in two ways (bidirectional). 
*Projections to areas [[Anatomical terms of location|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 of brain|fornix]] and [[terminal stria]].

===Endocrine hormones===

Most of the hypothalamic hormones generated are distributed to the pituitary via the [[hypophyseal portal system]].<ref>http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/overview.html</ref>

The primary hypothalamic hormones are:

{| class="wikitable"
! Name || Other Names || Abbreviations || Location || Function
 |- 
 | [[Corticotropin-releasing hormone]] || Corticotropin-releasing factor, Corticoliberin || CRH, CRF || [[Parvocellular part|parvocellular]] neuroendocrine neurons in the [[paraventricular nucleus]] || with [[vasopressin]], stimulates [[anterior pituitary]] to secrete [[Adrenocorticotropic hormone|ACTH]]
 |- 
 | [[Dopamine]] || Prolactin-inhibiting hormone || DA, PIH || neuroendocrine neurons of the [[arcuate nucleus]] || inhibits secretion of [[prolactin]] from the [[anterior pituitary]]
 |- 
 | [[Gonadotropin-releasing hormone]] || Luteinising-hormone releasing hormone || GnRH, LHRH || neuroendocrine neurons in the [[medial preoptic nucleus|medial preoptic]] and [[arcuate nucleus|arcuate nuclei]] || stimulates [[anterior pituitary]] to secrete [[Luteinizing hormone|LH]] and [[Follicle-stimulating hormone|FSH]]
 |- 
 | [[Growth hormone-releasing hormone]] || Growth-hormone-releasing factor, somatocrinin || GHRH, GHRF, GRF || [[arcuate nucleus]] [[neuroendocrine]] neurons || stimulates [[anterior pituitary]] to secrete [[growth hormone]]
 |- 
 | [[Melatonin]] ||  ||  || [[suprachiasmatic nucleus]] ||
 |- 
 
 | [[Somatostatin]] || Growth hormone-inhibiting hormone, Somatotropin release-inhibiting factor || SS, GHIH, SRIF || neuroendocrine neurons of the [[periventricular nucleus]] || inhibits secretion of [[growth hormone]] from the [[anterior pituitary]]
 |- 
 | [[Thyrotropin-releasing hormone]] || Thyrotropin-releasing factor, Thyroliberin, Protirelin || TRH, TRF || [[Parvocellular part|parvocellular]] neuroendocrine neurons in the [[paraventricular nucleus|paraventricular]] and [[anterior hypothalamic nucleus|anterior hypothalamic nuclei]] || stimulates [[anterior pituitary]] to secrete [[Thyroid-stimulating hormone|TSH]]
 |- 
 

See also: [[Hypocretin]]

==Control of food intake==

The extreme [[Anatomical terms of location|lateral]] part of the [[ventromedial nucleus]] of the hypothalamus is responsible for the control of food intake. Stimulation of this area causes increased food intake. Bilateral [[lesion]] of this area causes complete cessation of food intake. Medial parts of the nucleus have a controlling effect on the lateral part. Bilateral lesion of the medial part of the ventromedial nucleus causes [[hyperphagia]] and obesity of the animal. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake.

There are different hypotheses related to this regulation:<ref>{{cite journal |author=Theologides A |title=Anorexia-producing intermediary metabolites |journal=Am J Clin Nutr |volume=29 |issue=5 |pages=552-8 |year=1976 |pmid=178168}}</ref>

#Lipostatic hypothesis - this hypothesis holds that [[adipose]] [[biological tissue|tissue]] produces a [[Humoral immunity|humoral]] signal that is proportionate to the amount of fat and acts on the hypothalamus to decrease food intake and increase energy output. It has been evident that a [[hormone]] [[leptin]] acts on the hypothalamus to decrease food intake and increase energy output.
#Gutpeptide hypothesis - [[Gastrointestinal tract|gastrointestinal]] hormones like Grp, [[glucagon]]s, [[Cholecystokinin|CCK]] and others claimed to inhibit food intake. The food entering the gastrointestinal tract triggers the release of these hormones which acts on the brain to produce satiety. The brain contains both CCK-A and CCK-B receptors.
#Glucostatic hypothesis - the activity of the satiety center in the ventromedial nuclei is probably governed by the [[glucose]] utilization in the neurons. It has been postulated that when their glucose utilization is low and consequently when the arteriovenous blood glucose difference across them is low, the activity across the neurons decrease. Under these conditions, the activity of the feeding center is unchecked and the individual feels hungry. Food intake is rapidly increased by intraventricular administration of [[2-Deoxy-D-glucose|2-deoxyglucose]] therefore decreasing glucose utilization in cells.
#Thermostatic hypothesis - according to this hypothesis, a decrease in body temperature below a given set point stimulates appetite, while an increase above the set point inhibits appetite.

==Sexual dimorphism==

Several hypothalamic nuclei are [[sexually dimorphic]], i.e. there are clear differences in both structure and function between males and females. 

Some differences are apparent even in gross neuroanatomy: most notable is the [[sexually dimorphic nucleus]] within the [[preoptic area]], which is present only in males. However most of the differences are 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. 

===Responses to ovarian steroids===

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 the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic, i.e. estrogen receptors are expressed in different sets of neurons.

[[Estrogen]] and [[progesterone]] act by influencing gene expression in particular neurons. To influence gene expression, estrogen binds to an intracellular receptor, and this complex is translocated to the cell nucleus where it interacts with regions of the DNA known as [[estrogen regulatory element]]s (EREs). Increased protein synthesis may follow as soon as 30 min later. 
Thus, for estrogen to 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). 

===Gonadal steroids in neonatal life of rats===

In neonatal life, gonadal steroids influence the development of the neuroendocrine hypothalamus. For instance, 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. 

*If a ''female rat'' is injected once with testosterone in the first few days of postnatal life (during the "critical period" of sex-steroid influence), the hypothalamus is irreversibly masculinized; the adult rat will be incapable of generating an LH surge in response to estrogen (a characteristic of females), but will be capable of exhibiting ''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]]}. 

===Androgens in primates===

In primates, the developmental influence of [[androgens]] is less clear, and the consequences are less complete. 'Tomboyism' in girls might reflect the effects of androgens on the fetal brain, but the sex of rearing during the first 2-3 years is believed by many to be the most important determinant of gender identity, because during this phase either estrogen or testosterone will have permanent effects on either a female or male brain, influencing both heterosexuality and homosexuality.<ref>[[John Money]], 'The concept of gender identity disorder in childhood and adolescence after 39 years', Journal of Sex and Marital Therapy 20 (1994): 163-77.</ref>

The paradox is that the masculinizing effects of [[testosterone]] are mediated by estrogen. Within the brain, testosterone is aromatized to ([[estradiol]]), which is the principal active hormone for developmental influences. The human [[testis]] secretes high levels 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.

===Other influences upon hypothalamic development===

Sex steroids are not the only important influences upon hypothalamic development; in particular, [[Puberty|pre-pubertal]] stress in early life determines the capacity of the adult hypothalamus to respond to an acute stressor.<ref>{{cite journal | last = Romeo | first = Russell D | coauthors = Rudy Bellani, Ilia N. Karatsoreos, Nara Chhua, Mary Vernov, Cheryl D. Conrad and Bruce S. McEwen | title = Stress History and Pubertal Development Interact to Shape Hypothalamic-Pituitary-Adrenal Axis Plasticity | journal = Endocrinology | volume = 147 | issue = 4 | pages = 1664-1674 | publisher = The Endocrine Society  | date = 2005 | url = http://endo.endojournals.org/cgi/content/short/147/4/1664 | doi = 10.1210/en.2005-1432 | accessdate = 2007-10-16 }}</ref> Unlike gonadal steroid receptors, [[glucocorticoid]] receptors are very widespread throughout the brain; in the [[paraventricular nucleus]], they mediate negative feedback control of [[Corticotropin-releasing hormone|CRF]] synthesis and secretion, but elsewhere their role is not well understood.

==Effects of aging on the hypothalamus==

Studies in female mice have shown that both [[Supraoptic nucleus]] (SON) and [[Paraventricular nucleus]] (PVN)  lose approximately one-third of IGF-1R immunoreactive cells with normal aging. Also, Old caloricly restricted (CR) mice lost higher numbers of IGF-1R non-immunoreactive cells while maintaining similar counts of IGF-1R immunoreactive cells in comparison to Old-Al mice.  Consequently, Old-CR mice show a higher percentage of IGF-1R immunoreactive cells reflecting increased hypothalamic sensitivity to IGF-1 in comparison to normally aging mice. <ref>{{cite journal |author=Saeed O,Yaghmaie F,Garan SA,Gouw AM,Voelker MA,Sternberg H, Timiras PS. |title=Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice|journal=Int J Dev Neurosci |volume=25 |issue=1 |pages=23-8 |year=2007  |pmid=17194562}}</ref> <ref>{{cite journal |author=Yaghmaie F, Saeed O, Garan SA, Voelker MA, Gouw AM, Freitag W, Sternberg H, Timiras PS|title=Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice |journal=Int J Dev Neurosci |volume=24 |issue=7 |pages=431-6 |year=2006 |pmid=17034982}}</ref>
<ref>{{cite journal |author=F. Yaghmaie, O. Saeed, S.A. Garan, A.M. Gouw, P. Jafar, J. Kaur, S. Nijjar, P.S. Timiras, H. Sternberg, M.A. Voelker |title=Tracking changes in hypothalamic IGF-1 sensitivity with aging and caloric restriction |journal=Experimental Gerontology |volume=42 |issue=1-2 |pages=148-149 |year=2007 }}
[http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T6J-4KGG1P4-10&_user=10&_handle=C-WA-A-VD-VD-MsSAYWB-UUW-U-U-VD-U-U-AADUEEDBAV-AAZYCDYAAV-WUBCCYBZA-VD-U&_fmt=full&_coverDate=02%2F28%2F2007&_rdoc=45&_orig=browse&_srch=%23toc%235032%232007%23999579998%23639966!&_cdi=5032&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d5741475a812c1d5a283114bba5379a8]</ref>

==See also==
*[[HPA axis]]
*[[Neuroendocrinology]]

==Additional images==
<gallery>Image:Gray654.png|Median sagittal section of brain of human embryo of three months.</gallery>

==References==
{{reflist|2}}

==External links==
*{{BrainMaps|Hypothalamus}}
*[http://www.endotext.org/neuroendo/neuroendo3b/neuroendo3b.htm The Hypothalamus and Pituitary at endotexts.org]

{{Diencephalon}}
{{Endocrine system}}
{{Limbic system}}
{{Pituitary and hypothalamic hormones and analogues}}

[[Category:Endocrine system]]
[[Category:Limbic system]]
[[Category:Cerebrum]]
[[Category:Neuroanatomy]]
[[Category:Neuroendocrinology]]
[[Category:Endocrinology]]

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[[ca:Hipotàlem]]
[[cs:Hypothalamus]]
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[[es:Hipotálamo]]
[[fi:Hypotalamus]]
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[[he:היפותלמוס]]
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[[it:Ipotalamo]]
[[ja:視床下部]]
[[la:Hypothalamus]]
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[[pl:Podwzgórze]]
[[pt:Hipotálamo]]
[[ru:Гипоталамус]]
[[sk:Podlôžko]]
[[sv:Hypotalamus]]
[[tr:Hipotalamus]]

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