WIDE AWAKE Mediates the Circadian Timing of Sleep Onset

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • Animals
  • Animals, Genetically Modified
  • Brain / cytology
  • CLOCK Proteins / genetics
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology*
  • Circadian Rhythm Signaling Peptides and Proteins / genetics
  • Circadian Rhythm Signaling Peptides and Proteins / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Green Fluorescent Proteins / genetics
  • Hormone Antagonists / pharmacology
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mifepristone / pharmacology
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / physiology*
  • Reaction Time / genetics
  • Sleep / drug effects
  • Sleep / genetics
  • Sleep / physiology*
  • Time Factors

Substances

  • ARNTL Transcription Factors
  • Circadian Rhythm Signaling Peptides and Proteins
  • Clk protein, Drosophila
  • Drosophila Proteins
  • Hormone Antagonists
  • Luminescent Proteins
  • Wake protein, Drosophila
  • cyc protein, Drosophila
  • Green Fluorescent Proteins
  • Mifepristone
  • CLOCK Proteins