A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus

Qiang Liu, Benjamin J. Bell, Dong Won Kim, Sang Soo Lee, Mehmet F. Keles, Qili Liu, Ian D. Blum, Annette A. Wang, Elijah J. Blank, Jiali Xiong, Joseph L. Bedont, Anna J. Chang, Habon Issa, Jeremiah Y. Cohen, Seth Blackshaw and Mark N. Wu ()
Additional contact information
Qiang Liu: Johns Hopkins University
Benjamin J. Bell: Johns Hopkins University
Dong Won Kim: Johns Hopkins University
Sang Soo Lee: Johns Hopkins University
Mehmet F. Keles: Johns Hopkins University
Qili Liu: University of California, San Francisco
Ian D. Blum: Johns Hopkins University
Annette A. Wang: Johns Hopkins University
Elijah J. Blank: Johns Hopkins University
Jiali Xiong: Johns Hopkins University
Joseph L. Bedont: Johns Hopkins University
Anna J. Chang: Johns Hopkins University
Habon Issa: Johns Hopkins University
Jeremiah Y. Cohen: Allen Institute for Neural Dynamics
Seth Blackshaw: Johns Hopkins University
Mark N. Wu: Johns Hopkins University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41877-4

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