{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:21:36Z","timestamp":1792678896895,"version":"4.5.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"51","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,12,22]]},"abstract":"<jats:p>\n                    In mammals, hypocretin\/orexin (HCRT) neuropeptides are important sleep\u2013wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (\n                    <jats:italic>hcrtr<\/jats:italic>\n                    \u2212\/\u2212). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing\n                    <jats:italic>hcrt:EGFP<\/jats:italic>\n                    revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where\n                    <jats:italic>hcrtr<\/jats:italic>\n                    mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in\n                    <jats:italic>hcrtr<\/jats:italic>\n                    \u2212\/\u2212 pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore,\n                    <jats:italic>hcrtr<\/jats:italic>\n                    \u2212\/\u2212 fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in\n                    <jats:italic>hcrtr<\/jats:italic>\n                    \u2212\/\u2212 fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.906637106","type":"journal-article","created":{"date-parts":[[2009,12,4]],"date-time":"2009-12-04T22:05:25Z","timestamp":1259964325000},"page":"21942-21947","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":178,"title":["Sleep\u2013wake regulation and hypocretin\u2013melatonin interaction in zebrafish"],"prefix":"10.1073","volume":"106","author":[{"given":"Lior","family":"Appelbaum","sequence":"first","affiliation":[{"name":"Center for Narcolepsy, Department of Psychiatry and Behavioral Sciences,"},{"name":"Howard Hughes Medical Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon X.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Beckman Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine S.","family":"Maro","sequence":"additional","affiliation":[{"name":"Department of Biology and Pathology Stanford University, Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotem","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, George S. 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