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Abstract
Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal’s active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.
How the circadian clock generates rhythms of arousal remains unclear. Here, authors show that a clock-output molecule reduces excitability of an arousal circuit during the active phase. These results suggest a multifaceted role for the clock in arousal.
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1 Johns Hopkins University, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
2 Johns Hopkins University, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, McKusick-Nathans Department of Genetic Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
3 Johns Hopkins University, Solomon H. Snyder Department of Neuroscience, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Aarhus University, Danish Research Institute of Translational Neuroscience, Nordic EMBL Partnership for Molecular Medicine, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722); Aarhus University, Department of Biomedicine, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722)
4 University of California, San Francisco, Department of Anatomy, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
5 Johns Hopkins University, Biochemistry, Cellular and Molecular Biology Program, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
6 Johns Hopkins University, Solomon H. Snyder Department of Neuroscience, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
7 Allen Institute for Neural Dynamics, Seattle, USA (GRID:grid.21107.35)
8 Johns Hopkins University, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Solomon H. Snyder Department of Neuroscience, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)