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Neuron. 2014 Apr 2;82(1):151-66. doi: 10.1016/j.neuron.2014.01.040. Epub 2014 Mar 13.

WIDE AWAKE mediates the circadian timing of sleep onset.

Author information

  • 1Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
  • 2Department of Neuroscience and the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • 3Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD 21287, USA.
  • 4Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA.
  • 5Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA.
  • 6Neuroscience Research Institute and Department of Molecular, Cellular, & Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
  • 7Howard Hughes Medical Institute, Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8Department of Neuroscience and the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: kyunghee.koh@jefferson.edu.
  • 9Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: marknwu@jhmi.edu.

Abstract

How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24631345
[PubMed - indexed for MEDLINE]
PMCID:
PMC3982794
Free PMC Article

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