A physiologically based model of orexinergic stabilization of sleep and wake
The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well under...
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| description | The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia. |
| doi_str_mv | 10.1371/journal.pone.0091982 |
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Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Fulcher et al 2014 Fulcher et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-22dc94c8c8ec30fb30236e47fce903c0c1c6b879943bea451ee1cb5a0a5fa7483</citedby><cites>FETCH-LOGICAL-c692t-22dc94c8c8ec30fb30236e47fce903c0c1c6b879943bea451ee1cb5a0a5fa7483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961294/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961294/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24651580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fulcher, Ben D</creatorcontrib><creatorcontrib>Phillips, Andrew J K</creatorcontrib><creatorcontrib>Postnova, Svetlana</creatorcontrib><creatorcontrib>Robinson, Peter A</creatorcontrib><title>A physiologically based model of orexinergic stabilization of sleep and wake</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia.</description><subject>Analysis</subject><subject>Animals</subject><subject>Arousal</subject><subject>Biology and Life Sciences</subject><subject>Brain research</subject><subject>Brain stem</subject><subject>Brain Stem - physiology</subject><subject>Circadian rhythms</subject><subject>Computer and Information Sciences</subject><subject>Computer Simulation</subject><subject>Dynamics</subject><subject>Firing pattern</subject><subject>Humans</subject><subject>Hypothalamus</subject><subject>Hypothalamus (lateral)</subject><subject>Hypothalamus - physiology</subject><subject>Inertia</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Mathematical models</subject><subject>Medicine and Health Sciences</subject><subject>Models, Biological</subject><subject>Narcolepsy</subject><subject>Narcolepsy - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fulcher, Ben D</au><au>Phillips, Andrew J K</au><au>Postnova, Svetlana</au><au>Robinson, Peter A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A physiologically based model of orexinergic stabilization of sleep and wake</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-03-20</date><risdate>2014</risdate><volume>9</volume><issue>3</issue><spage>e91982</spage><epage>e91982</epage><pages>e91982-e91982</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24651580</pmid><doi>10.1371/journal.pone.0091982</doi><tpages>e91982</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Animals Arousal Biology and Life Sciences Brain research Brain stem Brain Stem - physiology Circadian rhythms Computer and Information Sciences Computer Simulation Dynamics Firing pattern Humans Hypothalamus Hypothalamus (lateral) Hypothalamus - physiology Inertia Intracellular Signaling Peptides and Proteins - metabolism Mathematical models Medicine and Health Sciences Models, Biological Narcolepsy Narcolepsy - physiopathology Neurons Neurons - physiology Neuropeptides - metabolism Orexins Phenotype Physics Physiological aspects Physiological effects Physiology Preoptic Area - physiology Relaying Rodents Signaling Sleep Sleep - physiology Sleep and wakefulness Sleep deprivation Sleep disorders Stability Wakefulness - physiology |
| title | A physiologically based model of orexinergic stabilization of sleep and wake |
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