WIDE AWAKE mediates the circadian timing of sleep onset

Sha Liu; Angelique Lamaze; Qili Liu; Masashi Tabuchi; Yong Yang; Melissa Fowler; Rajnish Bharadwaj; Julia Zhang; Joseph Bedont; Seth Blackshaw; Thomas E Lloyd; Craig Montell; Amita Sehgal; Kyunghee Koh; Mark N Wu

doi:10.1016/j.neuron.2014.01.040

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.

Authors

Sha Liu¹, Angelique Lamaze², Qili Liu¹, Masashi Tabuchi¹, Yong Yang², Melissa Fowler³, Rajnish Bharadwaj¹, Julia Zhang¹, Joseph Bedont⁴, Seth Blackshaw⁴, Thomas E Lloyd⁵, Craig Montell⁶, Amita Sehgal⁷, Kyunghee Koh⁸, Mark N Wu⁹

Affiliations

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

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding