RRC ID 12113
Author Appelbaum L, Wang GX, Maro GS, Mori R, Tovin A, Marin W, Yokogawa T, Kawakami K, Smith SJ, Gothilf Y, Mignot E, Mourrain P.
Title Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake 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 (hcrtr-/-). 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 hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr 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 hcrtr-/- 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, hcrtr-/- fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr-/- 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.
Volume 106(51)
Pages 21942-7
Published 2009-12-22
DOI 10.1073/pnas.906637106
PII 906637106
PMID 19966231
PMC PMC2799794
MeSH Animals Intracellular Signaling Peptides and Proteins / physiology* Melatonin / biosynthesis Melatonin / physiology* Neuropeptides / physiology* Orexin Receptors Orexins Pineal Gland / metabolism Receptors, G-Protein-Coupled / genetics Receptors, G-Protein-Coupled / metabolism Receptors, G-Protein-Coupled / physiology Receptors, Neuropeptide / genetics Receptors, Neuropeptide / metabolism Receptors, Neuropeptide / physiology Sleep* Wakefulness* Zebrafish / physiology*
IF 9.504
Times Cited 74
Zebrafish tol2 technique?