{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:53:26Z","timestamp":1790520806363,"version":"4.1.0"},"reference-count":80,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2015,5,22]],"date-time":"2015-05-22T00:00:00Z","timestamp":1432252800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL28785"],"award-info":[{"award-number":["HL28785"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL74011"],"award-info":[{"award-number":["HL74011"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,7]]},"abstract":"\n Key points<\/jats:title>\n \n \n \n This study explores the state dependence of the hypercapnic ventilatory reflex (HCVR). We simulated an instantaneous increase or decrease of central chemoreceptor activity by activating or inhibiting the retrotrapezoid nucleus (RTN) by optogenetics in conscious rats.<\/jats:p>\n <\/jats:list-item>\n \n \n During quiet wake or non\u2010REM sleep, hypercapnia increased both breathing frequency (\n f<\/jats:italic>\n R<\/jats:sub>\n ) and tidal volume (\n V<\/jats:italic>\n T<\/jats:sub>\n ) whereas, in REM sleep, hypercapnia increased\n V<\/jats:italic>\n T<\/jats:sub>\n exclusively.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Optogenetic inhibition of RTN reduced\n V<\/jats:italic>\n T<\/jats:sub>\n in all sleep\u2013wake states, but reduced fR only during quiet wake and non\u2010REM sleep. RTN stimulation always increased\n V<\/jats:italic>\n T<\/jats:sub>\n but raised\n f<\/jats:italic>\n R<\/jats:sub>\n only in quiet wake and non\u2010REM sleep.\n <\/jats:p>\n <\/jats:list-item>\n \n Phasic RTN stimulation produced active expiration and reduced early expiratory airflow (i.e. increased upper airway resistance) only during wake.<\/jats:p>\n <\/jats:list-item>\n \n \n We conclude that the HCVR is highly state\u2010dependent. The HCVR is reduced during REM sleep because\n f<\/jats:italic>\n R<\/jats:sub>\n is no longer under chemoreceptor control and thus could explain why central sleep apnoea is less frequent in REM sleep.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Abstract<\/jats:title>\n \n Breathing has different characteristics during quiet wake, non\u2010REM or REM sleep, including variable dependence on\n \n . We investigated whether the retrotrapezoid nucleus (RTN), a proton\u2010sensitive structure that mediates a large portion of the hypercapnic ventilatory reflex, regulates breathing differently during sleep\n vs<\/jats:italic>\n . wake. Electroencephalogram, neck electromyogram, blood pressure, respiratory frequency (\n f<\/jats:italic>\n R<\/jats:sub>\n ) and tidal volume (\n V<\/jats:italic>\n T<\/jats:sub>\n ) were recorded in 28 conscious adult male Sprague\u2013Dawley rats. Optogenetic stimulation of RTN with channelrhodopsin\u20102, or inhibition with archaerhodopsin, simulated an instantaneous increase or decrease of central chemoreceptor activity. Both opsins were delivered with PRSX8\u2010promoter\u2010containing lentiviral vectors. RTN and catecholaminergic neurons were transduced. During quiet wake or non\u2010REM sleep, hypercapnia (3 or 6%\n \n ) increased both\n f<\/jats:italic>\n R<\/jats:sub>\n and\n V<\/jats:italic>\n T<\/jats:sub>\n whereas, in REM sleep, hypercapnia increased\n V<\/jats:italic>\n T<\/jats:sub>\n exclusively. RTN inhibition always reduced\n V<\/jats:italic>\n T<\/jats:sub>\n but reduced\n f<\/jats:italic>\n R<\/jats:sub>\n only during quiet wake and non\u2010REM sleep. RTN stimulation always increased\n V<\/jats:italic>\n T<\/jats:sub>\n but raised\n f<\/jats:italic>\n R<\/jats:sub>\n only in quiet wake and non\u2010REM sleep. Blood pressure was unaffected by either stimulation or inhibition. Except in REM sleep, phasic RTN stimulation entrained and shortened the breathing cycle by selectively shortening the post\u2010inspiratory phase. Phasic stimulation also produced active expiration and reduced early expiratory airflow but only during wake.\n V<\/jats:italic>\n T<\/jats:sub>\n is always regulated by RTN and CO\n 2<\/jats:sub>\n but\n f<\/jats:italic>\n R<\/jats:sub>\n is regulated by CO\n 2<\/jats:sub>\n and RTN only when the brainstem pattern generator is in autorhythmic mode (anaesthesia, non\u2010REM sleep, quiet wake). The reduced contribution of RTN to breathing during REM sleep could explain why certain central apnoeas are less frequent during this sleep stage.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp270053","type":"journal-article","created":{"date-parts":[[2015,3,27]],"date-time":"2015-03-27T18:13:56Z","timestamp":1427480036000},"page":"2909-2926","source":"Crossref","is-referenced-by-count":87,"title":["State\u2010dependent control of breathing by the retrotrapezoid nucleus"],"prefix":"10.1113","volume":"593","author":[{"given":"Peter G.R.","family":"Burke","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Virginia Charlottesville VA 22908 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Kanbar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Lebanese American University Beyrouth Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler 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