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

Author

Listed:
  • Qiang Liu

    (Johns Hopkins University)

  • Benjamin J. Bell

    (Johns Hopkins University
    Johns Hopkins University)

  • Dong Won Kim

    (Johns Hopkins University
    Aarhus University
    Aarhus 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
    Johns Hopkins University)

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.

Suggested Citation

  • 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 , 2023. "A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41877-4
    DOI: 10.1038/s41467-023-41877-4
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    References listed on IDEAS

    as
    1. Clifford B. Saper & Thomas E. Scammell & Jun Lu, 2005. "Hypothalamic regulation of sleep and circadian rhythms," Nature, Nature, vol. 437(7063), pages 1257-1263, October.
    2. Dong Won Kim & Parris Whitney Washington & Zoe Qianyi Wang & Sonia Hao Lin & Changyu Sun & Basma Taleb Ismail & Hong Wang & Lizhi Jiang & Seth Blackshaw, 2020. "The cellular and molecular landscape of hypothalamic patterning and differentiation from embryonic to late postnatal development," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Franz Weber & Yang Dan, 2016. "Circuit-based interrogation of sleep control," Nature, Nature, vol. 538(7623), pages 51-59, October.
    4. Ed S. Lein & Michael J. Hawrylycz & Nancy Ao & Mikael Ayres & Amy Bensinger & Amy Bernard & Andrew F. Boe & Mark S. Boguski & Kevin S. Brockway & Emi J. Byrnes & Lin Chen & Li Chen & Tsuey-Ming Chen &, 2007. "Genome-wide atlas of gene expression in the adult mouse brain," Nature, Nature, vol. 445(7124), pages 168-176, January.
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