The median preoptic nucleus is located dorsal to the other three nuclei of the preoptic area of the anterior

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

. The hypothalamus is located just beneath the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...

, the main sensory relay station of the

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

, and is considered part of the

limbic system The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...

, which also includes structures such as the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...

and the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex ver ...

. The hypothalamus is highly involved in maintaining

homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...

of the body, and the median preoptic nucleus is no exception, contributing to regulation of blood composition,

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...

, and non-REM sleep. The median preoptic nucleus is highly involved in three main areas. These include osmoregulation,

thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...

, and sleep

. Within each area are many functions. The role that the median preoptic nucleus plays in osmoregulation is in blood composition and volume, including fluid and salt balance, and produces responses ranging from behavioral to

endocrine The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...

Thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...

includes both responses to

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...

and to decreased core temperature upon cutaneous exposure to cold, both of which involve the median preoptic nucleus as an important mediator of sensory input and regulatory output. Sleep homeostasis is involved in both the onset and maintenance of

sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...

. The median preoptic nucleus has excitatory and inhibitory projections to many areas of the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

. It has inhibitory influences through

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...

projections to the areas of the brain involved in the

stimulation Stimulation is the encouragement of development or the cause of activity generally. For example, "The press provides stimulation of political discourse." An interesting or fun activity can be described as "stimulating", regardless of its physic ...

of thermogenesis, as well as on wake-active areas of the brain to induce sleep. Microinjection of ethanol, triazolam, and

propofol Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation f ...

into this area induces sleep in rodents, suggesting that it is involved in their pharmacologic effects on sleep. Glutamatergic and noradrenergic, as well as other neurotransmitters, have excitatory influences on other areas of the brain. The median preoptic nucleus is highly involved in cardiovascular regulation, including the release of atrial natriuretic peptide by the

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

in response to high

blood volume Blood volume (volemia) is the volume of blood (blood cells and plasma) in the circulatory system of any individual. Humans A typical adult has a blood volume of approximately 5 liters, with females and males having approximately the same blood ...

. It also is involved in controlling febrile response to

and stimulation of

thirst Thirst is the craving for potable fluids, resulting in the basic instinct of animals to drinking, drink. It is an essential mechanism involved in fluid balance. It arises from a lack of fluids or an increase in the concentration of certain osmol ...

, among other functions. Both the connectivity and anatomical position of the median preoptic nucleus allow it to be both a relay station and mediator for sensory and regulatory information, and produce

neural In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

and

behavioral Behavior (American English) or behaviour (British English) is the range of actions and mannerisms made by individuals, organisms, systems or artificial entities in some environment. These systems can include other systems or organisms as we ...

responses to maintain

Location

The median preoptic nucleus is located in the preoptic area of the

. Forming a critical part of the anteroventral

third ventricle The third ventricle is one of the four connected ventricles of the ventricular system within the mammalian brain. It is a slit-like cavity formed in the diencephalon between the two thalami, in the midline between the right and left lateral ...

and the midline of the lamina terminalis, the median preoptic nucleus occupies an anatomical position that allows it to play an important role in many aspects of

homeostatic In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism an ...

regulation. This region is important in cardiovascular,

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...

, and blood composition regulation, and receives inputs from the subfornical organ (SFO) and the

vascular organ of lamina terminalis The vascular organ of lamina terminalis (VOLT), organum vasculosum of the lamina terminalis (OVLT), or supraoptic crest is one of the four sensory circumventricular organs of the brain, the others being the subfornical organ, the median eminence, ...

(VOLT), which lie outside the

blood brain barrier Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the ...

and relay information concerning blood osmolality and levels of

signals such as atrial natriuretic peptide (ANP).Kolaj, M., & Renaud, L. P. (2010). Metabotropic Glutamate Receptors in Median Preoptic Neurons modulate Neuronal Excitability and Glutamatergic and GAGAergic Inputs From the Subfornical Organ (vol 103, pg 1104, 2010). Journal of Neurophysiology, 104(1), 579-579

Connectivity

Connectivity with other regions of the

, such as the

ventrolateral preoptic area The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain ...

(VLPO) and with regions of the brain stem also allow the median preoptic nucleus to be involved in other aspects of

. These include sleep-waking behaviors as well as

and drinking behavior, as well as

. Parallel pathways in the preoptic area are involved in regulation of body temperature and

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

response. One pathway originates in the median preoptic nucleus while the other originates in the dorsolateral preoptic area (DLPO). Both are inhibitory to areas in the

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...

which activate non-shivering thermogenesis via brown adipose tissue (BAT) in response to cutaneous cold or

prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...

.Yoshida, K., Li, X. D., Cano, G., Lazarus, M., & Saper, C. B. (2009). Parallel Preoptic Pathways for Thermoregulation. Journal of Neuroscience, 29(38)

Role in thermoregulation

It's known that mammals have a circadian rhythm in body temperature (Tb) that depend on the integrity of the suprachiasmatic nucleus (SCN), However, fasting also influences the Tb in the resting period and the presence of the SCN is essential for this process. Although not only the SCN but also the arcuate nucleus (ARC), are involved in the Tb setting through afferents to the thermoregulatory median preoptic nucleus (MnPO). After studies performed by Guzmán-Ruiz et al. it's known that the vasopressin release from the SCN decreases the temperature just before light onset, whereas a-melanocyte stimulating hormone release, especially at the end of the dark period, maintains high temperature. Both peptides have opposite effects on the brown adipose tissue activity through thermoregulatory nuclei such as the dorsomedial nucleus of the hypothalamus and the dorsal raphe nucleus. Coordination between circadian and metabolic signaling within the hypothalamus is essential for an adequate temperature control. The balance between the releases of neuropeptides derived from the biological clock and from a metabolic sensory organ as the arcuate nucleus, are essential for an adequate temperature control. These observations show that brain areas involved in circadian and metabolic functions of the body need to interact to produce a coherent arrangement of physiological processes associated with temperature control. 1 The neural activation mechanisms involved in the regulation of

are largely undefined. It is known that sympathetic pathways are involved in increasing heat production and reducing heat loss and are activated by

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

in the rostral medullary raphe (RMR). These neurons were identified as playing an important role in the elevation of body temperature during both cold exposure and induced fever by observation that hyperpolarization prior to exposure to these conditions inhibits the elevation of

in response.

Febrile response

Inputs to the RMR from the median preoptic nucleus are

, and therefore inhibitory in nature. Lesions on the median preoptic nucleus produce diminished

responses, as the projections from the MnPn to the RMR contain

prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deriv ...

EP3 receptors, which are essential for fever response. Prostaglandin E2 binds to E3 receptors in the median preoptic nucleus to inhibit their activity and cause

. This means that the median preoptic nucleus is responsible for inhibiting mechanisms which elevate

. This is not the only area of the

involved, and elimination of the activity of the median preoptic nucleus will not in and of itself cause elevated body temperature. When combined with lesions on other preoptic hypothalamic nuclei, however, damage to the median preoptic nucleus causes an elevated baseline body temperature.

Menopause

Other receptors, neurokinin 3 receptors, which are expressed in the median preoptic nucleus, are also involved in

. Activation of these receptors in rats causes decrease in

core temperature Normal human body-temperature (normothermia, euthermia) is the typical temperature range found in humans. The normal human body temperature range is typically stated as . Human body temperature varies. It depends on sex, age, time of day, exer ...

. These receptors are highly expressed in the median preoptic area in response to decreased

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

levels in menopausal women, and are thought to play a role in the generation of hot flashes during

menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

.Dacks, P. A., Krajewski, S. J., & Rance, N. E. (2011). Activation of Neurokinin 3 Receptors in the Median Preoptic Nucleus Decreases Core Temperature in the Rat. Endocrinology, 152(12), 4894-4905.

Environmental cold exposure

Responses to cold are produced by cutaneous cold sensitive pathways through the

Parabrachial area The parabrachial nuclei, also known as the parabrachial complex, are a group of nuclei in the dorsolateral pons that surrounds the superior cerebellar peduncle as it enters the brainstem from the cerebellum. They are named from the Latin term for ...

. Thermoreceptors in the skin detect temperature in the environment relative to body temperature. These afferent neurons project up the spinal cord to the parabrachial area, which innervates several areas of the preoptic area, including the median preoptic nucleus. Exposure to cold leads to disinhibition of the RMR and other regions, which leads to brown adipose thermogenesis. This is also known as non-shivering thermogenesis, which metabolizes fat but dissipates heat from the proton motive force in mitochondria rather than using

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...

to produce ATP.Nakamura, K. (2011). Central circuitries for body temperature regulation and fever. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 301(5), R1207-R1228.

Role in osmoregulation

The region of the brain which includes the ventral portion of the median preoptic nucleus, the anteroventral third ventricle (AV3V), is highly involved in the maintenance of fluid, electrolyte, and cardiovascular

.Pedrino, G. R., Monaco, L. R., & Cravo, S. L. (2009). Renal vasodilation induced by hypernatraemia Role of alpha-adrenoceptors in the median preoptic nucleus. Clinical and Experimental Pharmacology and Physiology, 36(12) The median preoptic nucleus, along with the

(VOLT) and the subfornical organ (SFO) respond to changes in blood composition as well as neural input from receptors in blood vessels. Stretch receptors in the aorta and other vessels send sensory input to this region, relaying information about

and

Response to changes in blood osmolality

The importance of the median preoptic nucleus in fluid composition and homeostasis can be seen anatomically, as it contains connections between several regions highly involved in body fluid balance and cardiovascular function, such as the paraventricular nucleus and the supraoptic nucleus. Functionally, its importance can be understood because

lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

to the median preoptic nucleus generally cause inappropriate fluid composition, water intake and release of atrial natriuretic peptide (ANP). The responses to the changes in fluid composition mediated by the median preoptic nucleus result from noradrenergic innervation from regions of the caudal ventrolateral medulla. Responses can be

, autonomic or

, and responses to spikes in blood sodium levels include the release of atrial natriuretic peptide and oxytocin. Atrial natriuretic peptide is released by the heart in response to high

and high salinity of the blood. It is an important and potent vasodilator, and also reduces the reuptake of sodium in the kidneys. In addition, it inhibits pathways such as the renin-aldostrone-angiotensin pathway which raise

. Activation of the median preoptic nucleus leads to

of the paraventricular nucleus (PVN). The afferents to this area are glutamatergic, or use glutamate as their primary neurotransmitter, although

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...

produces a similar response, and result in sympathoexcitation of the PVN.Henry, M., Grob, M., & Mouginot, D. (2009). Endogenous angiotensin II facilitates GABAergicneurotransmission afferent to the Na+-responsive neurons of the rat median preoptic nucleus. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 297(3), R783-R792. This was confirmed by the use of a

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

receptor antagonist in the PVN, which inhibited this response as a result of the activation of the MnPn. Thus, glutamate bound to receptors is necessary for the

activation Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical o ...

of these neurons in the median preoptic nucleus and the activation of the paraventricular nucleus. The activation of the PVN via this glutamatergic mechanism results in increased activity of renal sympathetic nerve pathways as well as heart rate and

mean arterial pressure In medicine, the mean arterial pressure (MAP) is an average blood pressure in an individual during a single cardiac cycle. MAP is altered by cardiac output and systemic vascular resistance. Testing Mean arterial pressure can be measured direc ...

.Llewellyn, T., Zheng, H., Liu, X. F., Xu, B., & Patel, K. P. (2012). Median preoptic nucleus and subfornical organ drive renal sympathetic nerve activity via a glutamatergic mechanism within the paraventricular nucleus. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 302(4), R424-R432.

Role in homeostatic regulation of sleep

Anatomical and electrophysiological experiments on adult rats show an important role is for the median preoptic nucleus in the production of sleep. The first evidence of this was an observation that damage to this area caused

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

in human patients.Luppi, P. H., & Fort, P. (2011). What are the mechanisms activating the sleep-active neurons located in the preoptic area? Sleep and Biological Rhythms, 9, 59-64. Current experiments using

c-Fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jink ...

expression as a marker for activation of neurons during sleep shows a

dichotomy A dichotomy is a partition of a whole (or a set) into two parts (subsets). In other words, this couple of parts must be * jointly exhaustive: everything must belong to one part or the other, and * mutually exclusive: nothing can belong simul ...

of function in sleep promotion and maintenance between the ventrolateral preoptic nucleus and the median preoptic nucleus. Evidence suggests that

neurons in the median preoptic nucleus play a role in the promotion of the onset of sleep, while neurons in the ventrolateral preoptic nucleus play a role in the maintenance of sleep.Gvilia, I., Suntsova, N., Angara, B., McGinty, D., & Szymusiak, R. (2011). Maturation of sleep homeostasis in developing rats: a role for preoptic area neurons. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 300(4), R885-R894 While the idea of a complete separation of function between these two nuclei is an attractive one, it is more likely a question of degree of involvement of these two nuclei in the onset and maintenance of sleep, rather than playing completely separate roles. It is likely that the MnPn plays an important, but not exclusive, role in the onset of sleep, while the VLPO plays a more important role in the maintenance of sleep. Both areas project to wake-active areas of the brain. There is also a dense, bidirectional neuronal projection between the median preoptic nucleus and the ventrolateral preoptic nucleus. These existence of inhibitory projections between the ventrolaternal preoptic nucleus and the median preoptic nucleus suggests shared function and a regulatory relationship between the two nuclei.

Non-REM sleep

The promotion of sleep by GABAergic neurons in the median preoptic area is most closely associated with NREM, or quiet sleep.Benedetto, L., Chase, M. H., & Torterolo, P. (2012). GABAergic processes within the median preoptic nucleus promote NREM sleep. Behavioural Brain Research, 232(1), 60-65. The amount of time spent in NREM sleep increases with the number of activated GABA receptors in the median preoptic area, as demonstrated by increased time in NREM sleep in response to microinjections of GABA agonists into the median preoptic area of cats. Time spent in REM sleep did not increase, and control injections decreased time spent in both NREM and REM sleep.

Relationship with the VLPO

The ventrolateral (VLPO) and median preoptic (MnPn) nuclei promote sleep through

neuronal projections to wake-active areas of the brain. Activation of the neurons in the VLPO and MnPn leads to increased concentrations of the primary inhibitory neurotransmitter, GABA, in wakefulness areas of the brain, such as the tuberomammillary nucleus and the

locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system. The locus coer ...

. This leads to the inhibition of cholinergic, noradrenergic and serotonergic activity in these areas. Noradrenergic projections from wake-promoting areas inhibit sleep-promoting areas, establishing a "reciprocal inhibitory interaction" between sleep and wakefulness areas which leads to the regulation of sleep patterns. The mechanism for the activation of the sleep-promoting neurons in the VLPO and MnPn has not been well defined, however, it has been suggested that the suprachiasmic nucleus may play a role, as well as simply decreased sensory input at the onset of sleepiness.

References

1uzmán-Ruiz, M. A., Ramirez-Corona, A., Guerrero-Vargas, N. N., Sabath, E., Ramirez-Plascencia, O. D., Fuentes-Romero, R., ... & Buijs, R. M. (2015). Role of the suprachiasmatic and arcuate nuclei in diurnal temperature regulation in the rat. The Journal of Neuroscience, 35(46), 15419-15429. {{Authority control Hypothalamus