Suprachiasmatic nucleus
Encyclopedia
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm
. It is responsible for controlling circadian rhythm
s. The neuronal and hormonal activities it generates regulate many different body functions in a 24-hour cycle, using around 20,000 neuron
s.
The SCN, pine cone-shaped and the size of a grain of rice, interacts with many other regions of the brain. It contains several cell types and several different peptide
s (including vasopressin
and vasoactive intestinal peptide
) and neurotransmitter
s.
immediately dorsal and superior (hence supra) to the optic chiasm
(CHO) bilateral to (on either side of) the third ventricle
.
Many aspects of mammalian behavior and physiology show circadian rhythmicity, including sleep, physical activity, alertness, hormone levels, body temperature, immune function, and digestive activity. Remarkably, all of these diverse rhythms are controlled by a single tiny brain area, the SCN, and are lost if the SCN is destroyed. In the case of sleep, for example, the total amount is maintained in rats with SCN damage, but the length and timing of sleep episodes become erratic. The importance of entraining organisms, including humans, to exogenous cues such as the light/dark cycle, is reflected by several circadian rhythm sleep disorders, where this process does not function normally.
The SCN also controls "slave oscillators" in the peripheral tissues, which exhibit their own ~24-hour rhythms, but are kept in synchrony by the SCN.
The SCN receives inputs from specialized photoreceptive retinal ganglion cells, via the retinohypothalamic tract
.
Neurons in the ventrolateral SCN (vlSCN) have the ability for light-induced gene expression. Melanopsin
-containing ganglion cell
s in the retina
have a direct connection to the ventrolateral SCN via the retinohypothalamic tract. If light is turned on at night, the vlSCN relays this information throughout the SCN, in a process called entrainment
.
Neurons in the dorsomedial SCN (dmSCN) are believed to have an endogenous 24-hour rhythm that can persist under constant darkness (in humans averaging about 24 hours 11 min). A GABAergic mechanism couples the ventral and dorsal regions of the SCN.
The SCN sends information to other hypothalamic nuclei and the pineal gland
to modulate body temperature and production of hormones such as cortisol
and melatonin
.
Some of the others are the lateral geniculate nucleus
(LGN), the superior colliculus
, the basal optic system, and the pretectum
:
cycle in individual SCN neurons. This cycle has been well conserved through evolution, and is essentially similar in cells from many widely different organisms that show circadian rhythms.
, the cellular circadian rhythm in neurons is controlled by two interlocked feedback loops.
These genes encode various transcription factors that trigger expression of other proteins. The products of clock and cycle, called CLK and CYC, belong to the PAS-containing subfamily of the basic-helix-loop-helix
(bHLH) family of transcription factors, and form a heterodimer. This heterodimer (CLK-CYC) initiates the transcription of PER and TIM, whose protein products dimerize and then inhibit their own expression by disrupting CLK-CYC-mediated transcription. This negative feedback mechanism gives a 24-hour rhythm in the expression of the clock genes. Many genes are suspected to be linked to circadian control by "E-box elements" in their promoters, as CLK-CYC and its homologs
bind to these elements.
The 24-hr rhythm could be reset by light via the protein cryptochrome
(CRY), which is involved in the circadian photoreception in Drosophila. CRY associates with TIM in a light-dependent manner that leads to the destruction of TIM. Without the presence of TIM for stabilization, PER is eventually destroyed during the day. As a result, the repression of CLK-CYC is reduced and the whole cycle reinitiates again.
In mammals, circadian clock genes behave in a manner similar to that of flies.
CLOCK
(circadian locomotor output cycles kaput) was first cloned in mouse and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1
) is the primary homolog of Drosophila CYC.
Three homologs of PER (PER1
, PER2
, and PER3
) and two CRY
homologs (CRY1 and CRY2) have been identified.
TIM
has been identified in mammals, however, its function is still not determined. Mutations in TIM result in an inability to respond to zeitgebers, which is essential for resetting the biological clock.
Recent research suggests that, outside the SCN, clock genes may have other important roles as well, including their influence on the effects of drugs of abuse such as cocaine
.
s in a 24-hour rhythm. At mid-day, the firing rate reaches a maximum, and, during the night, it falls again. How the gene expression cycle (so-called the core clock) connects to the neural firing remains unknown.
Many SCN neurons are sensitive to light stimulation via the retina, and sustainedly firing action potentials during a light pulse (~30 seconds) in rodents. The photic response is likely linked to effects of light on circadian rhythms. In addition, focal application of melatonin can decrease firing activity of these neurons, suggesting that melatonin receptors present in the SCN mediate phase-shifting effects through the SCN.
Professor Swaab conducted a follow-on study in rats. Male rats were treated with ATD, an aromatase inhibitor, which prevents testosterone from converting to estradiol. The experiment compared three different populations, an untreated control group, a prenatally treated group, and a pre- and postnatally treated group. Adult rats that were treated with ATD prenatally showed no difference from the control group. Adult rats treated with ATD both pre- and postnatally, however, had significantly more neurons in the SCN than the controls. These male rats also exhibited bisexual behavior. According to the authors, "This observation supports the hypothesis that the increased number of vasopressin neurons found earlier in the SCN of adult homosexual men might reflect differences that took place in the interaction between sex hormones and the brain early in development."
However, Swaab's research was "criticized on both methodological and conceptual grounds" in a 2003 review by Karori Mbugua. Among the issues Mbugua raises are:
1. sexual orientation was assessed by health care professionals by unknown means, rather than being self-reported.
2. While subjects "died of opportunistic infections resulting from AIDS, they were not matched for clinical diagnosis". Thus the diseases which actually killed the subjects were not controlled for.
Optic chiasm
The optic chiasm or optic chiasma is the part of the brain where the optic nerves partially cross...
. It is responsible for controlling circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
s. The neuronal and hormonal activities it generates regulate many different body functions in a 24-hour cycle, using around 20,000 neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s.
The SCN, pine cone-shaped and the size of a grain of rice, interacts with many other regions of the brain. It contains several cell types and several different peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s (including vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
and vasoactive intestinal peptide
Vasoactive intestinal peptide
Vasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...
) and neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s.
Location
The SCN is situated in the anterior part of the hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
immediately dorsal and superior (hence supra) to the optic chiasm
Optic chiasm
The optic chiasm or optic chiasma is the part of the brain where the optic nerves partially cross...
(CHO) bilateral to (on either side of) the third ventricle
Third ventricle
The third ventricle is one of four connected fluid-filled cavities comprising the ventricular system within the human brain. It is a median cleft between the two thalami, and is filled with cerebrospinal fluid ....
.
Circadian effects
Organisms in every kingdom of life—bacteria, plants, fungi, and animals—show genetically-based 24-hour rhythms. Although all of these clocks appear to be based on a similar type of genetic feedback loop, the specific genes involved are thought to have evolved independently in each kingdom. Within the animal kingdom, however, a related set of genes are used by a wide variety of animals: the circadian genes in fruit flies, for example, are closely related to those in mammals.Many aspects of mammalian behavior and physiology show circadian rhythmicity, including sleep, physical activity, alertness, hormone levels, body temperature, immune function, and digestive activity. Remarkably, all of these diverse rhythms are controlled by a single tiny brain area, the SCN, and are lost if the SCN is destroyed. In the case of sleep, for example, the total amount is maintained in rats with SCN damage, but the length and timing of sleep episodes become erratic. The importance of entraining organisms, including humans, to exogenous cues such as the light/dark cycle, is reflected by several circadian rhythm sleep disorders, where this process does not function normally.
The SCN also controls "slave oscillators" in the peripheral tissues, which exhibit their own ~24-hour rhythms, but are kept in synchrony by the SCN.
The SCN receives inputs from specialized photoreceptive retinal ganglion cells, via the retinohypothalamic tract
Retinohypothalamic tract
The retinohypothalamic tract is a photic input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells , which contain the photopigment melanopsin...
.
Neurons in the ventrolateral SCN (vlSCN) have the ability for light-induced gene expression. Melanopsin
Melanopsin
Melanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of...
-containing ganglion cell
Ganglion cell
A retinal ganglion cell is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and amacrine cells...
s in the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
have a direct connection to the ventrolateral SCN via the retinohypothalamic tract. If light is turned on at night, the vlSCN relays this information throughout the SCN, in a process called entrainment
Entrainment (chronobiology)
Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...
.
Neurons in the dorsomedial SCN (dmSCN) are believed to have an endogenous 24-hour rhythm that can persist under constant darkness (in humans averaging about 24 hours 11 min). A GABAergic mechanism couples the ventral and dorsal regions of the SCN.
The SCN sends information to other hypothalamic nuclei and the pineal gland
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
to modulate body temperature and production of hormones such as cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
and melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
.
Other signals from the retina
The SCN is one of many nuclei that receive nerve signals directly from the retina.Some of the others are the lateral geniculate nucleus
Lateral geniculate nucleus
The lateral geniculate nucleus is the primary relay center for visual information received from the retina of the eye. The LGN is found inside the thalamus of the brain....
(LGN), the superior colliculus
Superior colliculus
The optic tectum or simply tectum is a paired structure that forms a major component of the vertebrate midbrain. In mammals this structure is more commonly called the superior colliculus , but, even in mammals, the adjective tectal is commonly used. The tectum is a layered structure, with a...
, the basal optic system, and the pretectum
Pretectum
The pretectum, also known as the pretectal area, is a region of neurons found between the thalamus and midbrain. It receives binocular sensory input from retinal ganglion cells of the eyes, and is the region responsible for maintaining the pupillary light reflex.-Outputs:The pretectum, after...
:
- The LGN passes information about color, contrast, shape, and movement on to the visual cortexVisual cortexThe visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
and itself signals to the SCN. - The superior colliculus controls the movement and orientation of the eye.
- The basal optic system also controls eye movements.
- The pretectum controls the size of the pupilPupilThe pupil is a hole located in the center of the iris of the eye that allows light to enter the retina. It appears black because most of the light entering the pupil is absorbed by the tissues inside the eye. In humans the pupil is round, but other species, such as some cats, have slit pupils. In...
.
Gene expression
The circadian rhythm in the SCN is generated by a gene expressionGene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
cycle in individual SCN neurons. This cycle has been well conserved through evolution, and is essentially similar in cells from many widely different organisms that show circadian rhythms.
Fruitfly
For example, in the fruitfly DrosophilaDrosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
, the cellular circadian rhythm in neurons is controlled by two interlocked feedback loops.
- In the first loop, the bHLH transcription factors clock (CLK) and cycle (CYC) drive the transcription of their own repressors period (PER) and timeless (TIM). PER and TIM proteins then accumulate in the cytoplasm, translocate into the nucleus at night, and turn off their own transcription, thereby setting up a 24-hour oscillation of transcription and translation.
- In the second loop, the transcription factors vrille (VRI) and Pdp1 are initiated by CLK/CYC. PDP1 acts positively on CLK transcription and negatively on VRI.
These genes encode various transcription factors that trigger expression of other proteins. The products of clock and cycle, called CLK and CYC, belong to the PAS-containing subfamily of the basic-helix-loop-helix
Basic-helix-loop-helix
A basic helix-loop-helix is a protein structural motif that characterizes a family of transcription factors.- Structure :The motif is characterized by two α-helices connected by a loop. In general, transcription factors including this domain are dimeric, each with one helix containing basic amino...
(bHLH) family of transcription factors, and form a heterodimer. This heterodimer (CLK-CYC) initiates the transcription of PER and TIM, whose protein products dimerize and then inhibit their own expression by disrupting CLK-CYC-mediated transcription. This negative feedback mechanism gives a 24-hour rhythm in the expression of the clock genes. Many genes are suspected to be linked to circadian control by "E-box elements" in their promoters, as CLK-CYC and its homologs
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
bind to these elements.
The 24-hr rhythm could be reset by light via the protein cryptochrome
Cryptochrome
Cryptochromes are a class of blue light-sensitive flavoproteins found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and in the sensing of magnetic fields in a number of species...
(CRY), which is involved in the circadian photoreception in Drosophila. CRY associates with TIM in a light-dependent manner that leads to the destruction of TIM. Without the presence of TIM for stabilization, PER is eventually destroyed during the day. As a result, the repression of CLK-CYC is reduced and the whole cycle reinitiates again.
Mammals
CLOCK
CLOCK
Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...
(circadian locomotor output cycles kaput) was first cloned in mouse and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1
ARNTL
Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene which is associated with susceptibility to hypertension and type 2 diabetes.-Function:...
) is the primary homolog of Drosophila CYC.
Three homologs of PER (PER1
PER1
Period circadian protein homolog 1 is a protein that in humans is encoded by the PER1 gene....
, PER2
PER2
Period circadian protein homolog 2 is a protein that in humans is encoded by the PER2 gene.PER2 contains glucocorticoid response elements and a GRE within the core clock gene Per2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo...
, and PER3
PER3
Period circadian protein homolog 3 is a protein that in humans is encoded by the PER3 gene....
) and two CRY
Cryptochrome
Cryptochromes are a class of blue light-sensitive flavoproteins found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and in the sensing of magnetic fields in a number of species...
homologs (CRY1 and CRY2) have been identified.
TIM
Timeless (gene)
Timeless is a gene in Drosophila which encodes TIM, an essential protein that regulates circadian rhythms. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation [negative feedback] loop involving the period gene and its protein.-Discovery:Timeless was...
has been identified in mammals, however, its function is still not determined. Mutations in TIM result in an inability to respond to zeitgebers, which is essential for resetting the biological clock.
Recent research suggests that, outside the SCN, clock genes may have other important roles as well, including their influence on the effects of drugs of abuse such as cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
.
Electrophysiology
Neurons in the SCN fire action potentialAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s in a 24-hour rhythm. At mid-day, the firing rate reaches a maximum, and, during the night, it falls again. How the gene expression cycle (so-called the core clock) connects to the neural firing remains unknown.
Many SCN neurons are sensitive to light stimulation via the retina, and sustainedly firing action potentials during a light pulse (~30 seconds) in rodents. The photic response is likely linked to effects of light on circadian rhythms. In addition, focal application of melatonin can decrease firing activity of these neurons, suggesting that melatonin receptors present in the SCN mediate phase-shifting effects through the SCN.
Sexual orientation and the SCN
In 1990, Professor D.F. Swaab carried out research into this part of hypothalamus searching for an organic basis for homosexuality in humans. He found the suprachiasmatic nucleus to be nearly twice the size in homosexual men as heterosexual men. This research was further confirmed by Laura S. Allen, who found the midsagittal plane of the anterior commissure of the hypothalamus to be one third larger in male homosexual subjects than in male heterosexuals.Professor Swaab conducted a follow-on study in rats. Male rats were treated with ATD, an aromatase inhibitor, which prevents testosterone from converting to estradiol. The experiment compared three different populations, an untreated control group, a prenatally treated group, and a pre- and postnatally treated group. Adult rats that were treated with ATD prenatally showed no difference from the control group. Adult rats treated with ATD both pre- and postnatally, however, had significantly more neurons in the SCN than the controls. These male rats also exhibited bisexual behavior. According to the authors, "This observation supports the hypothesis that the increased number of vasopressin neurons found earlier in the SCN of adult homosexual men might reflect differences that took place in the interaction between sex hormones and the brain early in development."
However, Swaab's research was "criticized on both methodological and conceptual grounds" in a 2003 review by Karori Mbugua. Among the issues Mbugua raises are:
1. sexual orientation was assessed by health care professionals by unknown means, rather than being self-reported.
2. While subjects "died of opportunistic infections resulting from AIDS, they were not matched for clinical diagnosis". Thus the diseases which actually killed the subjects were not controlled for.