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The '''ventrolateral preoptic nucleus''' ('''VLPO'''), also known as the '''intermediate nucleus of the preoptic area''' ('''IPA'''), is a small cluster of [[neuron]]s situated in the anterior [[hypothalamus]], sitting just above and to the side of the [[optic chiasm]] in the brain of humans and other animals.<ref name="NHM sleep-narcolepsy">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 294–296 | edition = 2nd | chapter = Chapter 12: Sleep and Arousal | quote = <br />NEURAL SUBSTRATES OF SLEEP<br />Several neural systems mediate the switching between wakefulness and sleep and between the different stages of sleep 12–3. These systems include the ascending reticular activating system (ARAS), the ventrolateral pre-optic (VLPO) area, and the orexin/hypocretin system (Chapters 6 and 7).&nbsp;... The VLPO area of the anterior hypothalamus consists mainly of inhibitory neurons that release γ-aminobutyric acid (GABA) and the neuropeptide galanin. The VLPO neurons are likely to have reciprocal interactions with the ARAS and orexin neurons. The VLPO neurons inhibit and are inhibited by the TMN histamine neurons and REM-off monoamine neurons. Orexin neurons are located in the lateral hypothalamus. They are organized in a widely projecting manner, much like the monoamines (Chapter 6), and innervate all of the components of the ARAS. They excite the REM-off monoaminergic neurons during wakefulness and the PT cholinergic neurons during REM sleep. They are inhibited by the VLPO neurons during NREM sleep.&nbsp;... During NREM sleep, the VLPO area neurons start inhibiting the orexin neurons of the lateral hypothalamus. Consequently, the norepinephrine and serotonin REM-off cells, which are excited by orexin neurons during wakefulness, start to wane in activity, which gradually releases the cholinergic REM-on cells from their inhibitory effect. At the end of NREM sleep, the VLPO area neurons directly inhibit the REM-off cells, which completely disinhibits the REM-on cholinergic neurons and initiates REM sleep. Consistent with the inhibition of REMon cells by serotonergic and noradrenergic inputs, antidepressant drugs, which increase the availability of synaptic serotonin or norepinephrine (Chapter 14), reduce REM sleep.}}</ref><ref>{{Cite journal|last=Saper|first=Clifford B.|last2=Fuller|first2=Patrick M.|last3=Pedersen|first3=Nigel P.|last4=Lu|first4=Jun|last5=Scammell|first5=Thomas E.|date=2010|title=Sleep State Switching|url=https://linkinghub.elsevier.com/retrieve/pii/S0896627310009748|journal=Neuron|language=en|volume=68|issue=6|pages=1023–1042|doi=10.1016/j.neuron.2010.11.032|via=}}</ref> The brain's sleep-promoting nuclei (e.g., the VLPO, [[parafacial zone]], [[nucleus accumbens core]], and [[lateral hypothalamic]] [[melanin-concentrating hormone|MCH]] neurons),<ref>{{Cite journal|last=Saper|first=Clifford B.|last2=Fuller|first2=Patrick M.|last3=Pedersen|first3=Nigel P.|last4=Lu|first4=Jun|last5=Scammell|first5=Thomas E.|date=2010|title=Sleep State Switching|url=https://linkinghub.elsevier.com/retrieve/pii/S0896627310009748|journal=Neuron|language=en|volume=68|issue=6|pages=1023–1042|doi=10.1016/j.neuron.2010.11.032|via=}}</ref><ref name="PZ primary source">{{cite journal | vauthors = Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, Fuller PM | title = The GABAergic parafacial zone is a medullary slow wave sleep-promoting center | journal = Nat. Neurosci. | volume = 17 | issue = 9 | pages = 1217–1224 | date = September 2014 | pmid = 25129078 | pmc = 4214681 | doi = 10.1038/nn.3789 | quote = In the present study we show, for the first time, that activation of a delimited node of GABAergic neurons located in the medullary PZ can potently initiate SWS and cortical SWA in behaving animals.&nbsp;... For now however it remains unclear if the PZ is interconnected with other sleep– and wake–promoting nodes beyond the wake–promoting PB.&nbsp;... The intensity of cortical slow–wave–activity (SWA: 0.5–4Hz) during SWS is also widely accepted as a reliable indicator of sleep need&nbsp;... In conclusion, in the present study we demonstrated that all polygraphic and neurobehavioral manifestation of SWS, including SWA, can be initiated in behaving animals by the selective activation of a delimited node of GABAergic medullary neurons.| url = https://dash.harvard.edu/bitstream/handle/1/14351306/4214681.pdf?sequence=1 }}</ref><ref name="ARAS, sleep, and the parafacial zone review">{{cite journal | vauthors = Schwartz MD, Kilduff TS | title = The Neurobiology of Sleep and Wakefulness | journal = The Psychiatric Clinics of North America | volume = 38 | issue = 4 | pages = 615–644 | date = December 2015 | pmid = 26600100 | pmc = 4660253 | doi = 10.1016/j.psc.2015.07.002 | quote = More recently, the medullary parafacial zone (PZ) adjacent to the facial nerve was identified as a sleep-promoting center on the basis of anatomical, electrophysiological and chemo- and optogenetic studies.<sup>23, 24</sup> GABAergic PZ neurons inhibit glutamatergic parabrachial (PB) neurons that project to the BF,<sup>25</sup> thereby promoting NREM sleep at the expense of wakefulness and REM sleep.&nbsp;... Sleep is regulated by GABAergic populations in both the preoptic area and the brainstem; increasing evidence suggests a role for the melanin-concentrating hormone cells of the lateral hypothalamus and the parafacial zone of the brainstem}}</ref><ref name="GABAergic neurons review">{{cite journal | vauthors = Brown RE, McKenna JT | title = Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal | journal = Front. Neurol. | volume = 6 | issue = | pages = 135 | date = June 2015 | pmid = 26124745 | pmc = 4463930 | doi = 10.3389/fneur.2015.00135 | quote = The sleep-promoting action of GABAergic neurons located in the preoptic hypothalamus (6–8) is now well-known and accepted (9). More recently, other groups of sleep-promoting GABAergic neurons in the lateral hypothalamus (melanin-concentrating hormone neurons) and brainstem [parafacial zone; (10)] have been identified.}}</ref><ref name="Nucleus accumbens - Slow-wave sleep">{{cite journal | vauthors = Valencia Garcia S, Fort P | title = Nucleus Accumbens, a new sleep-regulating area through the integration of motivational stimuli | journal = Acta Pharmacologica Sinica | volume = | issue = | pages = | date = December 2017 | pmid = 29283174 | doi = 10.1038/aps.2017.168 | quote = The nucleus accumbens comprises a contingent of neurons specifically expressing the post-synaptic A2A-receptor (A2AR) subtype making them excitable by adenosine, its natural agonist endowed with powerful sleep-promoting properties[4].&nbsp;... In both cases, large activation of A2AR-expressing neurons in NAc promotes slow wave sleep (SWS) by increasing the number and duration of episodes.&nbsp;... After optogenetic activation of the core, a similar promotion of SWS was observed, whereas no significant effects were induced when activating A2AR-expressing neurons within the shell.}}</ref><ref name="Slow-wave sleep and NAcc core A2AR neurons - Sept 2017 primary source">{{cite journal | vauthors = Oishi Y, Xu Q, Wang L, Zhang BJ, Takahashi K, Takata Y, Luo YJ, Cherasse Y, Schiffmann SN, de Kerchove d'Exaerde A, Urade Y, Qu WM, Huang ZL, Lazarus M | title = Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice | journal = Nature Communications | volume = 8 | issue = 1 | pages = 734 | date = September 2017 | pmid = 28963505 | pmc = 5622037 | doi = 10.1038/s41467-017-00781-4 | quote = Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound.}}</ref> together with the [[ascending reticular activating system|ascending arousal system]] which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states.<ref name="NHM sleep-narcolepsy" /><ref name="ARAS, sleep, and the parafacial zone review" /><ref name="GABAergic neurons review" /> The VLPO is active during [[sleep]], particularly during [[non-rapid eye movement sleep]] (NREM sleep), and releases inhibitory [[neurotransmitter]]s, mainly [[gamma-Aminobutyric acid|GABA]] and [[galanin]], which inhibit neurons of the [[ascending reticular activating system|ascending arousal system]] that are involved in [[wakefulness]] and arousal.<ref name="NHM sleep-narcolepsy" /> The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the sleep-promoting substance [[adenosine]]<ref name = "Gallopin2005"/> and the endosomnogen [[Prostaglandin D2]].<ref name="Scammell1998">
The '''ventrolateral preoptic nucleus''' ('''VLPO'''), also known as the '''intermediate nucleus of the preoptic area''' ('''IPA'''), is a small cluster of [[neuron]]s situated in the anterior [[hypothalamus]], sitting just above and to the side of the [[optic chiasm]] in the brain of humans and other animals.<ref name=":0">{{Cite journal|last=Saper|first=Clifford B.|last2=Fuller|first2=Patrick M.|last3=Pedersen|first3=Nigel P.|last4=Lu|first4=Jun|last5=Scammell|first5=Thomas E.|date=2010|title=Sleep State Switching|url=https://linkinghub.elsevier.com/retrieve/pii/S0896627310009748|journal=Neuron|language=en|volume=68|issue=6|pages=1023–1042|doi=10.1016/j.neuron.2010.11.032|via=}}</ref><ref name=":1">{{Cite journal|last=Saper|first=Clifford B.|last2=Scammell|first2=Thomas E.|last3=Lu|first3=Jun|date=2005|title=Hypothalamic regulation of sleep and circadian rhythms|url=http://www.nature.com/articles/nature04284|journal=Nature|language=en|volume=437|issue=7063|pages=1257–1263|doi=10.1038/nature04284|issn=0028-0836|via=}}</ref> The brain's sleep-promoting nuclei (e.g., the VLPO, [[parafacial zone]], [[nucleus accumbens core]], and [[lateral hypothalamic]] [[melanin-concentrating hormone|MCH]] neurons),<ref name="PZ primary source">{{cite journal | vauthors = Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, Fuller PM | title = The GABAergic parafacial zone is a medullary slow wave sleep-promoting center | journal = Nat. Neurosci. | volume = 17 | issue = 9 | pages = 1217–1224 | date = September 2014 | pmid = 25129078 | pmc = 4214681 | doi = 10.1038/nn.3789 | quote = In the present study we show, for the first time, that activation of a delimited node of GABAergic neurons located in the medullary PZ can potently initiate SWS and cortical SWA in behaving animals.&nbsp;... For now however it remains unclear if the PZ is interconnected with other sleep– and wake–promoting nodes beyond the wake–promoting PB.&nbsp;... The intensity of cortical slow–wave–activity (SWA: 0.5–4Hz) during SWS is also widely accepted as a reliable indicator of sleep need&nbsp;... In conclusion, in the present study we demonstrated that all polygraphic and neurobehavioral manifestation of SWS, including SWA, can be initiated in behaving animals by the selective activation of a delimited node of GABAergic medullary neurons.| url = https://dash.harvard.edu/bitstream/handle/1/14351306/4214681.pdf?sequence=1 }}</ref><ref name="ARAS, sleep, and the parafacial zone review">{{cite journal | vauthors = Schwartz MD, Kilduff TS | title = The Neurobiology of Sleep and Wakefulness | journal = The Psychiatric Clinics of North America | volume = 38 | issue = 4 | pages = 615–644 | date = December 2015 | pmid = 26600100 | pmc = 4660253 | doi = 10.1016/j.psc.2015.07.002 | quote = More recently, the medullary parafacial zone (PZ) adjacent to the facial nerve was identified as a sleep-promoting center on the basis of anatomical, electrophysiological and chemo- and optogenetic studies.<sup>23, 24</sup> GABAergic PZ neurons inhibit glutamatergic parabrachial (PB) neurons that project to the BF,<sup>25</sup> thereby promoting NREM sleep at the expense of wakefulness and REM sleep.&nbsp;... Sleep is regulated by GABAergic populations in both the preoptic area and the brainstem; increasing evidence suggests a role for the melanin-concentrating hormone cells of the lateral hypothalamus and the parafacial zone of the brainstem}}</ref><ref name="GABAergic neurons review">{{cite journal | vauthors = Brown RE, McKenna JT | title = Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal | journal = Front. Neurol. | volume = 6 | issue = | pages = 135 | date = June 2015 | pmid = 26124745 | pmc = 4463930 | doi = 10.3389/fneur.2015.00135 | quote = The sleep-promoting action of GABAergic neurons located in the preoptic hypothalamus (6–8) is now well-known and accepted (9). More recently, other groups of sleep-promoting GABAergic neurons in the lateral hypothalamus (melanin-concentrating hormone neurons) and brainstem [parafacial zone; (10)] have been identified.}}</ref><ref name="Slow-wave sleep and NAcc core A2AR neurons - Sept 2017 primary source">{{cite journal | vauthors = Oishi Y, Xu Q, Wang L, Zhang BJ, Takahashi K, Takata Y, Luo YJ, Cherasse Y, Schiffmann SN, de Kerchove d'Exaerde A, Urade Y, Qu WM, Huang ZL, Lazarus M | title = Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice | journal = Nature Communications | volume = 8 | issue = 1 | pages = 734 | date = September 2017 | pmid = 28963505 | pmc = 5622037 | doi = 10.1038/s41467-017-00781-4 | quote = Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound.}}</ref> together with the [[ascending reticular activating system|ascending arousal system]] which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states.<ref name=":0" /><ref name="ARAS, sleep, and the parafacial zone review" /><ref name="GABAergic neurons review" /> The VLPO is active during [[sleep]], particularly during [[non-rapid eye movement sleep]] (NREM sleep),<ref name=":2">{{Cite journal|last=Sherin|first=J. E.|last2=Shiromani|first2=P. J.|last3=McCarley|first3=R. W.|last4=Saper|first4=C. B.|date=1996-01-12|title=Activation of Ventrolateral Preoptic Neurons During Sleep|url=http://www.sciencemag.org/cgi/doi/10.1126/science.271.5246.216|journal=Science|language=en|volume=271|issue=5246|pages=216–219|doi=10.1126/science.271.5246.216|issn=0036-8075}}</ref> and releases inhibitory [[neurotransmitter]]s, mainly [[gamma-Aminobutyric acid|GABA]] and [[galanin]], which inhibit neurons of the [[ascending reticular activating system|ascending arousal system]] that are involved in [[wakefulness]] and arousal.<ref name=":0" /><ref>{{Cite journal|last=Brown|first=Ritchie E.|last2=Basheer|first2=Radhika|last3=McKenna|first3=James T.|last4=Strecker|first4=Robert E.|last5=McCarley|first5=Robert W.|date=2012|title=Control of Sleep and Wakefulness|url=http://www.physiology.org/doi/10.1152/physrev.00032.2011|journal=Physiological Reviews|language=en|volume=92|issue=3|pages=1087–1187|doi=10.1152/physrev.00032.2011|issn=0031-9333|via=}}</ref> The VLPO is in turn innervated by neurons from several components of the ascending arousal system.<ref name=":3">{{Cite journal|last=Gallopin|first=Thierry|last2=Fort|first2=Patrice|last3=Eggermann|first3=Emmanuel|last4=Cauli|first4=Bruno|last5=Luppi|first5=Pierre-Hervé|last6=Rossier|first6=Jean|last7=Audinat|first7=Etienne|last8=Mühlethaler|first8=Michel|last9=Serafin|first9=Mauro|date=2000|title=Identification of sleep-promoting neurons in vitro|url=http://www.nature.com/articles/35010109|journal=Nature|language=en|volume=404|issue=6781|pages=992–995|doi=10.1038/35010109|issn=0028-0836|via=}}</ref> The VLPO is activated by the endogenous sleep-promoting substances [[adenosine]]<ref>{{Cite journal|last=Scammell|first=T.E|last2=Gerashchenko|first2=D.Y|last3=Mochizuki|first3=T|last4=McCarthy|first4=M.T|last5=Estabrooke|first5=I.V|last6=Sears|first6=C.A|last7=Saper|first7=C.B|last8=Urade|first8=Y|last9=Hayaishi|first9=O|date=2001|title=An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons|url=http://dx.doi.org/10.1016/s0306-4522(01)00383-9|journal=Neuroscience|volume=107|issue=4|pages=653–663|doi=10.1016/s0306-4522(01)00383-9|issn=0306-4522|via=}}</ref><ref name = "Gallopin2005"/> and [[prostaglandin D2]].<ref name="Scammell1998">
{{Cite journal | author=Scammell T| title=Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2 | journal=[[PNAS]] | volume=95 | year=1998 | pages= 7754–7759| doi=10.1073/pnas.95.13.7754| pmc=22747}}
{{Cite journal | author=Scammell T| title=Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2 | journal=[[PNAS]] | volume=95 | year=1998 | pages= 7754–7759| doi=10.1073/pnas.95.13.7754| pmc=22747}}
</ref> The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters [[norepinephrine]] and [[acetylcholine]].<ref name="Chou2002">
</ref> The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters [[norepinephrine]] and [[acetylcholine]].<ref name=":3" /> The role of the VLPO in sleep and wakefulness, and its association with [[sleep disorder]]s – particularly [[insomnia]] and [[narcolepsy]] – is a growing area of neuroscience research.
{{Cite journal | author=Chou T | title= Afferents to the Ventrolateral Preoptic Nucleus| journal=[[The Journal of Neuroscience]] | volume=22 | year=2002 | pages=977–990}}
</ref> The role of the VLPO in sleep and wakefulness, and its association with [[sleep disorder]]s – particularly [[insomnia]] and [[narcolepsy]] – is a growing area of neuroscience research.


==Structure==
==Structure==
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{{Cite journal | author=Sherin J | title=Innervation of Histaminergic Tuberomammillary Neurons by GABAergic and Galaninergic Neurons in the Ventrolateral Preoptic Nucleus of the Rat | journal=[[The Journal of Neuroscience]] | volume=18 | issue = 12 | year=1998 | pages=4705–4721 }}
{{Cite journal | author=Sherin J | title=Innervation of Histaminergic Tuberomammillary Neurons by GABAergic and Galaninergic Neurons in the Ventrolateral Preoptic Nucleus of the Rat | journal=[[The Journal of Neuroscience]] | volume=18 | issue = 12 | year=1998 | pages=4705–4721 }}
</ref>
</ref>
''In vitro'' studies in rats have shown that many neurons in the VLPO that are inhibited by norepinephrine or acetylcholine are multipolar triangular shaped cells with low threshold spikes.<ref name="Gallopin2000">
''In vitro'' studies in rats have shown that many neurons in the VLPO that are inhibited by norepinephrine or acetylcholine are multipolar triangular shaped cells with low threshold spikes.<ref name=":3" /> These triangular multipolar neurons exist in two sub-populations in the VLPO:
{{Cite journal | author=Gallopin T | title=Identification of sleep-promoting neurons ''in vitro'' | journal=[[Nature (journal)|Nature]] | volume=404 | year=2000 | pages=992–995 | doi=10.1038/35010109 }}
</ref> However, in the past few years it has become clear that these triangular multipolar neurons exist in two sub-populations in the VLPO:
*Type 1 – inhibited by serotonin.
*Type 1 – inhibited by serotonin.
*Type 2 – excited by serotonin and adenosine.
*Type 2 – excited by serotonin and adenosine.
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===Sleep/wakefulness===
===Sleep/wakefulness===
[[File:VLPO Flip-Flop Switch Hypothesis.png|thumb|400px|Schematic representation of the Flip-Flop Switch Hypothesis]]
[[File:VLPO Flip-Flop Switch Hypothesis.png|thumb|400px|Schematic representation of the Flip-Flop Switch Hypothesis]]
In the early 20th century, von Economo noted that humans who had encephalitis with lesions in the anterior hypothalamus had insomnia, and proposed a sleep-promoting influence from that area. Animal studies in the mid-20th century in rats and cats confirmed that very large lesions in the preoptic area and basal forebrain resulted in insomnia<ref name="Nauta1946">
In the early 20th century, von Economo noted that humans who had encephalitis with lesions in the anterior hypothalamus had insomnia, and proposed a sleep-promoting influence from that area.<ref name=":1" /> Animal studies in the mid-20th century in rats and cats confirmed that very large lesions in the preoptic area and basal forebrain resulted in insomnia<ref name="Nauta1946">
{{Cite journal | author=Nauta W | title=Hypothalamic regulation of sleep in rats | journal=[[Journal of Neurophysiology]] | volume=9 | year=1946 | pages=285–314}}
{{Cite journal | author=Nauta W | title=Hypothalamic regulation of sleep in rats | journal=[[Journal of Neurophysiology]] | volume=9 | year=1946 | pages=285–314}}
</ref><ref name="McGinty1968">
</ref><ref name="McGinty1968">
{{Cite journal | author=McGinty D | title=Sleep Suppression after Basal Forebrain Lesions in the Cat | journal=[[Science (journal)|Science]] | volume=160 | year=1968 | pages=1253–1255 | doi=10.1126/science.160.3833.1253 | issue=3833}}
{{Cite journal | author=McGinty D | title=Sleep Suppression after Basal Forebrain Lesions in the Cat | journal=[[Science (journal)|Science]] | volume=160 | year=1968 | pages=1253–1255 | doi=10.1126/science.160.3833.1253 | issue=3833}}
</ref> but did not identify the cell group that was responsible. In 1996, Sherin and colleagues reported the presence of a cell group in the VLPO that expresses cFos (a protein often found in neurons that have recently been active) during sleep, and that these neurons contain the inhibitory neurotransmitters GABA and galanin, and that they innervate components of the ascending arousal system, including the [[tuberomammillary nucleus]] (TMN) and other components of the lateral hypothalamus; the [[Raphe nuclei|raphe nuclei;]], the [[locus coeruleus]] (LC); the [[Pedunculopontine nucleus|pedunculopontine]] (PPT) and [[laterodorsal tegmental nucleus|laterodorsal tegmental nuclei]] (LDT); and the parabrachial nucleus (PB).
</ref> but did not identify the cell group that was responsible. In 1996, Sherin and colleagues reported the presence of a cell group in the VLPO that expresses cFos (a protein often found in neurons that have recently been active) during sleep, and that these neurons contain the inhibitory neurotransmitters GABA and galanin.<ref name="Sherin 1998" /><ref name=":2" /> . These same neurons were found to innervate components of the ascending arousal system, including the [[tuberomammillary nucleus]] (TMN) and other components of the lateral hypothalamus; the [[Raphe nuclei|raphe nuclei;]] the [[locus coeruleus]] (LC); the [[Pedunculopontine nucleus|pedunculopontine]] (PPT) and [[laterodorsal tegmental nucleus|laterodorsal tegmental nuclei]] (LDT); and the parabrachial nucleus (PB). More recent studies using opto- or chemogenetic activation of VLPO neurons have confirmed that they promote sleep.<ref>{{Cite journal|last=Kroeger|first=Daniel|last2=Absi|first2=Gianna|last3=Gagliardi|first3=Celia|last4=Bandaru|first4=Sathyajit S.|last5=Madara|first5=Joseph C.|last6=Ferrari|first6=Loris L.|last7=Arrigoni|first7=Elda|last8=Münzberg|first8=Heike|last9=Scammell|first9=Thomas E.|date=2018|title=Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice|url=http://www.nature.com/articles/s41467-018-06590-7|journal=Nature Communications|language=en|volume=9|issue=1|pages=|doi=10.1038/s41467-018-06590-7|issn=2041-1723|via=}}</ref>


The sleep-promoting effects of the VLPO neurons is thought to be due to release of GABA and possibly galanin that suppresses firing of arousal system neurons. As the VLPO is also inhibited by neurotransmitters released by components of the arousal systems, such as acetylcholine and norepinephrine,<ref name=":3" /> a current theory has proposed that the VLPO and the arousal system form a "flip-flop" circuit.<ref name=":0" /><ref name=":1" /> This term from electrical engineering denotes a circuit in which mutual inhibition means that each component of the circuit, as it turns on, turns the other off, resulting in rapid transitions from one state (wake or sleep) to the other, with minimal time in transition states. This theory has been used to create mathematical models that explain much of the wake-sleep behavior in animals, including in pathological states and responses to drugs.<ref name=":0" /><ref>{{Cite journal|last=Phillips|first=A.J.K.|last2=Robinson|first2=P.A.|date=2007|title=A Quantitative Model of Sleep-Wake Dynamics Based on the Physiology of the Brainstem Ascending Arousal System|url=http://journals.sagepub.com/doi/10.1177/0748730406297512|journal=Journal of Biological Rhythms|language=en|volume=22|issue=2|pages=167–179|doi=10.1177/0748730406297512|issn=0748-7304|via=}}</ref><ref>{{Cite journal|last=Fulcher|first=Ben D.|last2=Phillips|first2=Andrew J. K.|last3=Postnova|first3=Svetlana|last4=Robinson|first4=Peter A.|date=2014|editor-last=Mistlberger|editor-first=Ralph E.|title=A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake|url=https://dx.plos.org/10.1371/journal.pone.0091982|journal=PLoS ONE|language=en|volume=9|issue=3|pages=e91982|doi=10.1371/journal.pone.0091982|issn=1932-6203|via=}}</ref> [[Orexin]] neurons in the posterior lateral hypothalamus potentiate neurons in the ascending arousal system and help stabilize the brain in the waking state (and consolidated wakefulness, which builds up homeostatic sleep drive, helps stabilize the brain during later sleep). The loss of orexin neurons in the disorder narcolepsy destabilizes the wake-sleep switch, resulting in overwhelming sleep episodes during the waking day, as well as more frequent awakenings from sleep at night.<ref name=":0" />
The release of GABA and possibly galanin by VLPO neurons is thought to suppress the arousal system and result in sleep. As the VLPO is inhibited by neurotransmitters released by components of the arousal systems, such as acetylcholine and norepinephrine, a current theory has proposed that the VLPO and the arousal system form a "flip-flop" circuit.<ref name="Saper2005">
{{Cite journal | author=Saper C | title=Hypothalamic regulation of sleep and circadian rhythms | journal=[[Nature (journal)|Nature]] | volume=437 | year=2005 | pages= 1257–1263 | doi=10.1038/nature04284 | pmid=16251950 | issue=7063}}
</ref> This mutual inhibition means that each component of the circuit turns the other off, resulting in rapid transitions from one state (wake or sleep) to the other, with minimal time in transition states. This theory has been used to create mathematical models that explain much of the wake-sleep behavior in animals, including in pathological states and responses to drugs. [[Orexin]] neurons in the posterior of the hypothalamus potenntial neurons in the ascending arousal system and help stabilize the brain in the waking state (and consolidated wakefulness, which builds up homeostatic sleep drive) helps stabilize the brain during later sleep). The loss of orexin neurons in the disorder narcolepsy destabilizes the wake-sleep switch, resulting in overwhelming sleep episodes during the waking day, as well as more frequent awakenings from sleep at night.


===Circadian rhythm===
===Circadian rhythm===
There is a strong [[circadian rhythm|circadian rhythm of sleep in]] mammals. The “master clock” for circadian rhythms in mammals is the [[suprachiasmatic nucleus]] (SCN). The SCN has little if any projection directly to the VLPO neurons. Instead, they project strongly to the adjacent subparaventricular zone, which in turn contains inhibitory GABAergic neurons that innervate the dorsomedial nucleus of the hypothalamus. Lesions of the dorsomedial nucleus almost completely eliminate the circadian rhythm of sleep. GABAergic neurons in the dorsomedial nucleus innervate the VLPO, and glutamatergic neurons innervate the lateral hypothalamus, suggesting that the dorsomedial nucleus mainly promotes wakefulness during the active period (daytime for humans).<ref name="Saper2005"/>
There is a strong [[circadian rhythm|circadian rhythm of sleep in]] mammals. The “master clock” for circadian rhythms in mammals is the [[suprachiasmatic nucleus]] (SCN). The SCN has little if any projection directly to the VLPO neurons. Instead, they project strongly to the adjacent subparaventricular zone, which in turn contains inhibitory GABAergic neurons that innervate the dorsomedial nucleus of the hypothalamus.<ref name=":4">{{Cite journal|last=Chou|first=Thomas C.|last2=Scammell|first2=Thomas E.|last3=Gooley|first3=Joshua J.|last4=Gaus|first4=Stephanie E.|last5=Saper|first5=Clifford B.|last6=Lu|first6=Jun|date=2003|title=Critical Role of Dorsomedial Hypothalamic Nucleus in a Wide Range of Behavioral Circadian Rhythms|url=http://dx.doi.org/10.1523/jneurosci.23-33-10691.2003|journal=The Journal of Neuroscience|volume=23|issue=33|pages=10691–10702|doi=10.1523/jneurosci.23-33-10691.2003|issn=0270-6474|via=}}</ref><ref>{{Cite journal|last=Vujovic|first=Nina|last2=Gooley|first2=Joshua J.|last3=Jhou|first3=Thomas C.|last4=Saper|first4=Clifford B.|date=2015|title=Projections from the subparaventricular zone define four channels of output from the circadian timing system: Projections from the SPZ|url=http://doi.wiley.com/10.1002/cne.23812|journal=Journal of Comparative Neurology|language=en|volume=523|issue=18|pages=2714–2737|doi=10.1002/cne.23812|via=}}</ref> Lesions of the dorsomedial nucleus almost completely eliminate the circadian rhythm of sleep. GABAergic neurons in the dorsomedial nucleus innervate the VLPO, and glutamatergic neurons innervate the lateral hypothalamus, suggesting that the dorsomedial nucleus mainly promotes wakefulness during the active period (daytime for humans).<ref name=":4" />


==Clinical significance==
==Clinical significance==
Line 53: Line 47:
</ref>
</ref>


Lesions in the VLPO in rats results in 50-60% decrease in NREM sleep time and prolonged [[insomnia]].<ref>{{Cite journal|last=Lu|first=Jun|last2=Greco|first2=Mary Ann|last3=Shiromani|first3=Priyattam|last4=Saper|first4=Clifford B.|date=2000|title=Effect of Lesions of the Ventrolateral Preoptic Nucleus on NREM and REM Sleep|url=http://dx.doi.org/10.1523/jneurosci.20-10-03830.2000|journal=The Journal of Neuroscience|volume=20|issue=10|pages=3830–3842|doi=10.1523/jneurosci.20-10-03830.2000|issn=0270-6474|via=}}</ref> More recent research suggests that stress-induced insomnia could be due to an imbalance of input to arousal system and VLPO neurons.<ref>{{Cite journal|last=Cano|first=G.|last2=Mochizuki|first2=T.|last3=Saper|first3=C. B.|date=2008|title=Neural Circuitry of Stress-Induced Insomnia in Rats|url=http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.1809-08.2008|journal=Journal of Neuroscience|language=en|volume=28|issue=40|pages=10167–10184|doi=10.1523/JNEUROSCI.1809-08.2008|issn=0270-6474|via=}}</ref>
Lesions in the VLPO in rats results in 50-60% decrease in NREM sleep time and prolonged [[insomnia]].<ref name="Liu2002">
{{Cite journal | author=Liu J | title=Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep | journal=[[The Journal of Neuroscience]] | volume=22 | year=2002 | pages= 4568–4576}}
</ref> More recent research suggests insomnia could be due to an imbalance of input to arousal system and VLPO neurons, including orexin neuron signalling. Orexin-receptor [[antagonist]]s such as suvorexant are currently being used for the treatment of insomnia.<ref name="Winrow 2014">
{{Cite journal | author=Winrow C | title=Discovery and development of orexin receptor antagonists as therapeutics for insomnia | journal=[[British Journal of Pharmacology]] | volume=171 | year=2014 | pages=283–293| doi=10.1111/bph.12261| pmc=3904252}}
</ref>


===Anaesthetics===
===Sedative/hypnotic drugs===
Many sedative/hypnotic drugs act by binding to and potentiating GABA-A receptors. These include older drugs such as ethanol, chloral hydrate and barbiturates, as well as newer benzodiazepines and "non-benzodiazepine" drugs (such as zolpidem, which bind to the same receptor but have a different chemical configuration), and even anesthetics such as propofol and isoflurane. As the VLPO inputs to the arousal system use this same receptor, these drugs at low doses essentially act by potentiating the VLPO, producing a sleepy state. Animal studies show that VLPO neurons show cFos activation after sedative doses of these drugs,<ref>{{Cite journal|last=Lu|first=Jun|last2=Nelson|first2=Laura E.|last3=Franks|first3=Nick|last4=Maze|first4=Mervyn|last5=Chamberlin|first5=Nancy L.|last6=Saper|first6=Clifford B.|date=2008|title=Role of endogenous sleep-wake and analgesic systems in anesthesia|url=http://doi.wiley.com/10.1002/cne.21685|journal=The Journal of Comparative Neurology|language=en|volume=508|issue=4|pages=648–662|doi=10.1002/cne.21685|via=}}</ref> and that VLPO lesions produce resistance to their sedative effects. <ref>{{Cite journal|last=Moore|first=Jason T.|last2=Chen|first2=Jingqiu|last3=Han|first3=Bo|last4=Meng|first4=Qing Cheng|last5=Veasey|first5=Sigrid C.|last6=Beck|first6=Sheryl G.|last7=Kelz|first7=Max B.|date=2012|title=Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis|url=https://linkinghub.elsevier.com/retrieve/pii/S096098221201007X|journal=Current Biology|language=en|volume=22|issue=21|pages=2008–2016|doi=10.1016/j.cub.2012.08.042|via=}}</ref> However, at high doses that produce a surgical plane of anesthesia, these drugs have much more widespread inhibitory effects, that do not depend upon the VLPO.<ref>{{Cite journal|last=Eikermann|first=Matthias|last2=Vetrivelan|first2=Ramalingam|last3=Grosse-Sundrup|first3=Martina|last4=Henry|first4=Mark E.|last5=Hoffmann|first5=Ulrike|last6=Yokota|first6=Shigefumi|last7=Saper|first7=Clifford B.|last8=Chamberlin|first8=Nancy L.|date=2011|title=The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia|url=https://linkinghub.elsevier.com/retrieve/pii/S0006899311018993|journal=Brain Research|language=en|volume=1426|pages=30–37|doi=10.1016/j.brainres.2011.10.018|via=}}</ref>
Studies have shown that multiple sedative/hypnotic drugs that act by potentiating GABA-A receptors, including ethanol, chloral hydrate, propofol and gas anesthetics such as [[isoflurane]], at sedative doses increase the activity of the VLPO neurons in mice.<ref name="Moore2012">
<br />{{Reflist}}Studies have shown that multiple sedative/hypnotic drugs that act by potentiating GABA-A receptors, including ethanol, chloral hydrate, propofol and gas anesthetics such as [[isoflurane]], at sedative doses increase the activity of the VLPO neurons in mice.<ref name="Moore2012">
{{Cite journal | author=Moore J | title=Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis | journal=[[Current Biology]] | volume=22 | year=2012 | pages=2008–2016| doi=10.1016/j.cub.2012.08.042| pmc=3628836 }}
{{Cite journal | author=Moore J | title=Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis | journal=[[Current Biology]] | volume=22 | year=2012 | pages=2008–2016| doi=10.1016/j.cub.2012.08.042| pmc=3628836 }}
</ref> This finding suggests that at relatively low sedative doses, these medications may have a common mechanism of action, which includes potentiating the firing of VLPO neurons. High doses used in surgical anesthesia, however, reduce activity of neurons throughout the nervous system.
</ref> This finding suggests that at relatively low sedative doses, these medications may have a common mechanism of action, which includes potentiating the firing of VLPO neurons. High doses used in surgical anesthesia, however, reduce activity of neurons throughout the nervous system.


==References==
==References==

{{Reflist}}


==External links==
==External links==

Revision as of 17:37, 27 June 2019

Ventrolateral Preoptic Nucleus
The VLPO is located at the anterior of the Hypothalamus. It is also called the intermediate nucleus of the preoptic area
Details
Part ofPreoptic nucleus
Identifiers
Acronym(s)VLPO or IPA
NeuroNames3122
Anatomical terms of neuroanatomy

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 of humans and other animals.[1][2] The brain's sleep-promoting nuclei (e.g., the VLPO, parafacial zone, nucleus accumbens core, and lateral hypothalamic MCH neurons),[3][4][5][6] together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states.[1][4][5] The VLPO is active during sleep, particularly during non-rapid eye movement sleep (NREM sleep),[7] and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal.[1][8] The VLPO is in turn innervated by neurons from several components of the ascending arousal system.[9] The VLPO is activated by the endogenous sleep-promoting substances adenosine[10][11] and prostaglandin D2.[12] The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine.[9] The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.

Structure

At least 80% of neurons in the VLPO that project to the ascending arousal system are GABAergic (neurons that produce GABA).[13] In vitro studies in rats have shown that many neurons in the VLPO that are inhibited by norepinephrine or acetylcholine are multipolar triangular shaped cells with low threshold spikes.[9] These triangular multipolar neurons exist in two sub-populations in the VLPO:

  • Type 1 – inhibited by serotonin.
  • Type 2 – excited by serotonin and adenosine.

As adenosine accumulates during wakefulness[11] it is likely that type 2 cells play a role in sleep induction.

The remaining third of neurons in the VLPO are excited by norepinephrine. Their role is unclear.

Function

Sleep/wakefulness

Schematic representation of the Flip-Flop Switch Hypothesis

In the early 20th century, von Economo noted that humans who had encephalitis with lesions in the anterior hypothalamus had insomnia, and proposed a sleep-promoting influence from that area.[2] Animal studies in the mid-20th century in rats and cats confirmed that very large lesions in the preoptic area and basal forebrain resulted in insomnia[14][15] but did not identify the cell group that was responsible. In 1996, Sherin and colleagues reported the presence of a cell group in the VLPO that expresses cFos (a protein often found in neurons that have recently been active) during sleep, and that these neurons contain the inhibitory neurotransmitters GABA and galanin.[13][7] . These same neurons were found to innervate components of the ascending arousal system, including the tuberomammillary nucleus (TMN) and other components of the lateral hypothalamus; the raphe nuclei; the locus coeruleus (LC); the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT); and the parabrachial nucleus (PB). More recent studies using opto- or chemogenetic activation of VLPO neurons have confirmed that they promote sleep.[16]

The sleep-promoting effects of the VLPO neurons is thought to be due to release of GABA and possibly galanin that suppresses firing of arousal system neurons. As the VLPO is also inhibited by neurotransmitters released by components of the arousal systems, such as acetylcholine and norepinephrine,[9] a current theory has proposed that the VLPO and the arousal system form a "flip-flop" circuit.[1][2] This term from electrical engineering denotes a circuit in which mutual inhibition means that each component of the circuit, as it turns on, turns the other off, resulting in rapid transitions from one state (wake or sleep) to the other, with minimal time in transition states. This theory has been used to create mathematical models that explain much of the wake-sleep behavior in animals, including in pathological states and responses to drugs.[1][17][18] Orexin neurons in the posterior lateral hypothalamus potentiate neurons in the ascending arousal system and help stabilize the brain in the waking state (and consolidated wakefulness, which builds up homeostatic sleep drive, helps stabilize the brain during later sleep). The loss of orexin neurons in the disorder narcolepsy destabilizes the wake-sleep switch, resulting in overwhelming sleep episodes during the waking day, as well as more frequent awakenings from sleep at night.[1]

Circadian rhythm

There is a strong circadian rhythm of sleep in mammals. The “master clock” for circadian rhythms in mammals is the suprachiasmatic nucleus (SCN). The SCN has little if any projection directly to the VLPO neurons. Instead, they project strongly to the adjacent subparaventricular zone, which in turn contains inhibitory GABAergic neurons that innervate the dorsomedial nucleus of the hypothalamus.[19][20] Lesions of the dorsomedial nucleus almost completely eliminate the circadian rhythm of sleep. GABAergic neurons in the dorsomedial nucleus innervate the VLPO, and glutamatergic neurons innervate the lateral hypothalamus, suggesting that the dorsomedial nucleus mainly promotes wakefulness during the active period (daytime for humans).[19]

Clinical significance

Insomnia

Elderly human patients with more galanin neurons in their intermediate nucleus (the human equivalent of the VLPO galanin neurons in rodents) have better, more continuous sleep. A reduced number of VLPO neurons is associated with more fragmented sleep (more awakenings throughout the night).[21]

Lesions in the VLPO in rats results in 50-60% decrease in NREM sleep time and prolonged insomnia.[22] More recent research suggests that stress-induced insomnia could be due to an imbalance of input to arousal system and VLPO neurons.[23]

Sedative/hypnotic drugs

Many sedative/hypnotic drugs act by binding to and potentiating GABA-A receptors. These include older drugs such as ethanol, chloral hydrate and barbiturates, as well as newer benzodiazepines and "non-benzodiazepine" drugs (such as zolpidem, which bind to the same receptor but have a different chemical configuration), and even anesthetics such as propofol and isoflurane. As the VLPO inputs to the arousal system use this same receptor, these drugs at low doses essentially act by potentiating the VLPO, producing a sleepy state. Animal studies show that VLPO neurons show cFos activation after sedative doses of these drugs,[24] and that VLPO lesions produce resistance to their sedative effects. [25] However, at high doses that produce a surgical plane of anesthesia, these drugs have much more widespread inhibitory effects, that do not depend upon the VLPO.[26]


  1. ^ a b c d e f Saper, Clifford B.; Fuller, Patrick M.; Pedersen, Nigel P.; Lu, Jun; Scammell, Thomas E. (2010). "Sleep State Switching". Neuron. 68 (6): 1023–1042. doi:10.1016/j.neuron.2010.11.032.
  2. ^ a b c Saper, Clifford B.; Scammell, Thomas E.; Lu, Jun (2005). "Hypothalamic regulation of sleep and circadian rhythms". Nature. 437 (7063): 1257–1263. doi:10.1038/nature04284. ISSN 0028-0836.
  3. ^ Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, Fuller PM (September 2014). "The GABAergic parafacial zone is a medullary slow wave sleep-promoting center" (PDF). Nat. Neurosci. 17 (9): 1217–1224. doi:10.1038/nn.3789. PMC 4214681. PMID 25129078. In the present study we show, for the first time, that activation of a delimited node of GABAergic neurons located in the medullary PZ can potently initiate SWS and cortical SWA in behaving animals. ... For now however it remains unclear if the PZ is interconnected with other sleep– and wake–promoting nodes beyond the wake–promoting PB. ... The intensity of cortical slow–wave–activity (SWA: 0.5–4Hz) during SWS is also widely accepted as a reliable indicator of sleep need ... In conclusion, in the present study we demonstrated that all polygraphic and neurobehavioral manifestation of SWS, including SWA, can be initiated in behaving animals by the selective activation of a delimited node of GABAergic medullary neurons.
  4. ^ a b Schwartz MD, Kilduff TS (December 2015). "The Neurobiology of Sleep and Wakefulness". The Psychiatric Clinics of North America. 38 (4): 615–644. doi:10.1016/j.psc.2015.07.002. PMC 4660253. PMID 26600100. More recently, the medullary parafacial zone (PZ) adjacent to the facial nerve was identified as a sleep-promoting center on the basis of anatomical, electrophysiological and chemo- and optogenetic studies.23, 24 GABAergic PZ neurons inhibit glutamatergic parabrachial (PB) neurons that project to the BF,25 thereby promoting NREM sleep at the expense of wakefulness and REM sleep. ... Sleep is regulated by GABAergic populations in both the preoptic area and the brainstem; increasing evidence suggests a role for the melanin-concentrating hormone cells of the lateral hypothalamus and the parafacial zone of the brainstem
  5. ^ a b Brown RE, McKenna JT (June 2015). "Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal". Front. Neurol. 6: 135. doi:10.3389/fneur.2015.00135. PMC 4463930. PMID 26124745. The sleep-promoting action of GABAergic neurons located in the preoptic hypothalamus (6–8) is now well-known and accepted (9). More recently, other groups of sleep-promoting GABAergic neurons in the lateral hypothalamus (melanin-concentrating hormone neurons) and brainstem [parafacial zone; (10)] have been identified.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Oishi Y, Xu Q, Wang L, Zhang BJ, Takahashi K, Takata Y, Luo YJ, Cherasse Y, Schiffmann SN, de Kerchove d'Exaerde A, Urade Y, Qu WM, Huang ZL, Lazarus M (September 2017). "Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice". Nature Communications. 8 (1): 734. doi:10.1038/s41467-017-00781-4. PMC 5622037. PMID 28963505. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound.
  7. ^ a b Sherin, J. E.; Shiromani, P. J.; McCarley, R. W.; Saper, C. B. (1996-01-12). "Activation of Ventrolateral Preoptic Neurons During Sleep". Science. 271 (5246): 216–219. doi:10.1126/science.271.5246.216. ISSN 0036-8075.
  8. ^ Brown, Ritchie E.; Basheer, Radhika; McKenna, James T.; Strecker, Robert E.; McCarley, Robert W. (2012). "Control of Sleep and Wakefulness". Physiological Reviews. 92 (3): 1087–1187. doi:10.1152/physrev.00032.2011. ISSN 0031-9333.
  9. ^ a b c d Gallopin, Thierry; Fort, Patrice; Eggermann, Emmanuel; Cauli, Bruno; Luppi, Pierre-Hervé; Rossier, Jean; Audinat, Etienne; Mühlethaler, Michel; Serafin, Mauro (2000). "Identification of sleep-promoting neurons in vitro". Nature. 404 (6781): 992–995. doi:10.1038/35010109. ISSN 0028-0836.
  10. ^ Scammell, T.E; Gerashchenko, D.Y; Mochizuki, T; McCarthy, M.T; Estabrooke, I.V; Sears, C.A; Saper, C.B; Urade, Y; Hayaishi, O (2001). "An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons". Neuroscience. 107 (4): 653–663. doi:10.1016/s0306-4522(01)00383-9. ISSN 0306-4522.
  11. ^ a b Gallopin T (2005). "The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus". Neuroscience. 134 (4): 1377–1390. doi:10.1016/j.neuroscience.2005.05.045. PMID 16039802.
  12. ^ Scammell T (1998). "Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2". PNAS. 95: 7754–7759. doi:10.1073/pnas.95.13.7754. PMC 22747.
  13. ^ a b Sherin J (1998). "Innervation of Histaminergic Tuberomammillary Neurons by GABAergic and Galaninergic Neurons in the Ventrolateral Preoptic Nucleus of the Rat". The Journal of Neuroscience. 18 (12): 4705–4721.
  14. ^ Nauta W (1946). "Hypothalamic regulation of sleep in rats". Journal of Neurophysiology. 9: 285–314.
  15. ^ McGinty D (1968). "Sleep Suppression after Basal Forebrain Lesions in the Cat". Science. 160 (3833): 1253–1255. doi:10.1126/science.160.3833.1253.
  16. ^ Kroeger, Daniel; Absi, Gianna; Gagliardi, Celia; Bandaru, Sathyajit S.; Madara, Joseph C.; Ferrari, Loris L.; Arrigoni, Elda; Münzberg, Heike; Scammell, Thomas E. (2018). "Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice". Nature Communications. 9 (1). doi:10.1038/s41467-018-06590-7. ISSN 2041-1723.
  17. ^ Phillips, A.J.K.; Robinson, P.A. (2007). "A Quantitative Model of Sleep-Wake Dynamics Based on the Physiology of the Brainstem Ascending Arousal System". Journal of Biological Rhythms. 22 (2): 167–179. doi:10.1177/0748730406297512. ISSN 0748-7304.
  18. ^ Fulcher, Ben D.; Phillips, Andrew J. K.; Postnova, Svetlana; Robinson, Peter A. (2014). Mistlberger, Ralph E. (ed.). "A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake". PLoS ONE. 9 (3): e91982. doi:10.1371/journal.pone.0091982. ISSN 1932-6203.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ a b Chou, Thomas C.; Scammell, Thomas E.; Gooley, Joshua J.; Gaus, Stephanie E.; Saper, Clifford B.; Lu, Jun (2003). "Critical Role of Dorsomedial Hypothalamic Nucleus in a Wide Range of Behavioral Circadian Rhythms". The Journal of Neuroscience. 23 (33): 10691–10702. doi:10.1523/jneurosci.23-33-10691.2003. ISSN 0270-6474.
  20. ^ Vujovic, Nina; Gooley, Joshua J.; Jhou, Thomas C.; Saper, Clifford B. (2015). "Projections from the subparaventricular zone define four channels of output from the circadian timing system: Projections from the SPZ". Journal of Comparative Neurology. 523 (18): 2714–2737. doi:10.1002/cne.23812.
  21. ^ Lim A (2014). "Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease". Brain. 137: 2847–61.
  22. ^ Lu, Jun; Greco, Mary Ann; Shiromani, Priyattam; Saper, Clifford B. (2000). "Effect of Lesions of the Ventrolateral Preoptic Nucleus on NREM and REM Sleep". The Journal of Neuroscience. 20 (10): 3830–3842. doi:10.1523/jneurosci.20-10-03830.2000. ISSN 0270-6474.
  23. ^ Cano, G.; Mochizuki, T.; Saper, C. B. (2008). "Neural Circuitry of Stress-Induced Insomnia in Rats". Journal of Neuroscience. 28 (40): 10167–10184. doi:10.1523/JNEUROSCI.1809-08.2008. ISSN 0270-6474.
  24. ^ Lu, Jun; Nelson, Laura E.; Franks, Nick; Maze, Mervyn; Chamberlin, Nancy L.; Saper, Clifford B. (2008). "Role of endogenous sleep-wake and analgesic systems in anesthesia". The Journal of Comparative Neurology. 508 (4): 648–662. doi:10.1002/cne.21685.
  25. ^ Moore, Jason T.; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C.; Beck, Sheryl G.; Kelz, Max B. (2012). "Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis". Current Biology. 22 (21): 2008–2016. doi:10.1016/j.cub.2012.08.042. {{cite journal}}: no-break space character in |first4= at position 5 (help); no-break space character in |first5= at position 7 (help); no-break space character in |first6= at position 7 (help); no-break space character in |first7= at position 4 (help); no-break space character in |first= at position 6 (help)
  26. ^ Eikermann, Matthias; Vetrivelan, Ramalingam; Grosse-Sundrup, Martina; Henry, Mark E.; Hoffmann, Ulrike; Yokota, Shigefumi; Saper, Clifford B.; Chamberlin, Nancy L. (2011). "The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia". Brain Research. 1426: 30–37. doi:10.1016/j.brainres.2011.10.018.

Studies have shown that multiple sedative/hypnotic drugs that act by potentiating GABA-A receptors, including ethanol, chloral hydrate, propofol and gas anesthetics such as isoflurane, at sedative doses increase the activity of the VLPO neurons in mice.[1] This finding suggests that at relatively low sedative doses, these medications may have a common mechanism of action, which includes potentiating the firing of VLPO neurons. High doses used in surgical anesthesia, however, reduce activity of neurons throughout the nervous system.

References

Gallopin T, Luppi PH, Cauli B, Urade Y, Rossier J, Hayaishi O, Lambolez B, Fort P (2005). "The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus". Neuroscience. 134 (4): 1377–90. doi:10.1016/j.neuroscience.2005.05.045. PMID 16039802.

  1. ^ Moore J (2012). "Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis". Current Biology. 22: 2008–2016. doi:10.1016/j.cub.2012.08.042. PMC 3628836.
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