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Chronic sleep fragmentation enhances habenula cholinergic neural activity

Molecular Psychiatry (2019) | Download Citation


Sleep is essential to emotional health. Sleep disturbance, particularly REM sleep disturbance, profoundly impacts emotion regulation, but the underlying neural mechanisms remain elusive. Here we show that chronic REM sleep disturbance, achieved in mice by chronic sleep fragmentation (SF), enhanced neural activity in the medial habenula (mHb), a brain region increasingly implicated in negative affect. Specifically, after a 5-day SF procedure that selectively fragmented REM sleep, cholinergic output neurons (ChNs) in the mHb exhibited increased spontaneous firing rate and enhanced firing regularity in brain slices. The SF-induced firing changes remained intact upon inhibition of glutamate, GABA, acetylcholine, and histamine receptors, suggesting cell-autonomous mechanisms independent of synaptic transmissions. Moreover, the SF-induced hyperactivity was not because of enhanced intrinsic membrane excitability, but was accompanied by depolarized resting membrane potential in mHb ChNs. Furthermore, inhibition of TASK-3 (KCNK9) channels, a subtype of two-pore domain K+ channels, mimicked the SF effects by increasing the firing rate and regularity, as well as depolarizing the resting membrane potential in mHb ChNs in control-sleep mice. These effects of TASK-3 inhibition were absent in SF mice, suggesting reduced TASK-3 activity following SF. By contrast, inhibition of small-conductance Ca2+-activated K+ (SK) channels did not produce similar effects. Thus, SF compromised TASK-3 function in mHb ChNs, which likely led to depolarized resting membrane potential and increased spontaneous firing. These results not only demonstrate that selective REM sleep disturbance leads to hyperactivity of mHb ChNs, but also identify a key molecular substrate through which REM sleep disturbance may alter affect regulation.

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We thank Rachel L. Hines and Fei Wang for assistance with sleep scoring. Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Numbers DA035805 (YH), MH101147 (YH), DA047108 (YH), DA043826 (YH), DA023206 (YD), DA040620 (YD), DA044538 (YD).

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Author notes

    • Feifei Ge

    Present address: Department of Human Anatomy and Histoembryology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 210023, Nanjing, China

    • Ping Mu

    Present address: College of Life Sciences, Ludong University, 186 Hongqi Middle Road, Yantai, 264025, Shandong, China


  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    • Feifei Ge
    • , Ping Mu
    • , Rong Guo
    • , Li Cai
    • , Zheng Liu
    • , Yan Dong
    •  & Yanhua H. Huang
  2. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    • Yan Dong


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Correspondence to Yanhua H. Huang.

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