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Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish.

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.

Pubmed ID: 19966231


  • Appelbaum L
  • Wang GX
  • Maro GS
  • Mori R
  • Tovin A
  • Marin W
  • Yokogawa T
  • Kawakami K
  • Smith SJ
  • Gothilf Y
  • Mignot E
  • Mourrain P


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

December 22, 2009

Associated Grants

  • Agency: NINDS NIH HHS, Id: R01 NS062798
  • Agency: NINDS NIH HHS, Id: R01 NS062798
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Intracellular Signaling Peptides and Proteins
  • Melatonin
  • Neuropeptides
  • Orexin Receptors
  • Pineal Gland
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Sleep
  • Wakefulness
  • Zebrafish