Chronic sleep fragmentation enhances habenula cholinergic neural activity
Chronic sleep fragmentation enhances habenula cholinergic neural activity
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DOI：
10.1038/s41380-019-0419-z
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发表时间：
2021-03-01
影响因子：
11
通讯作者：
Huang, Yanhua H.
中科院分区：
文献类型：
--
作者：
Ge, Feifei;Mu, Ping;Huang, Yanhua H.
睡眠对情绪健康至关重要。睡眠障碍，特别是REM睡眠障碍，深刻地影响情绪调节，但潜在的神经机制仍然难以捉摸。在这里，我们表明，慢性快速眼动睡眠障碍，在小鼠中实现的慢性睡眠片段（SF），增强神经活动的内侧缰（mHb），大脑区域越来越多地牵连在负面影响。具体而言，经过5天的SF程序，选择性片段REM睡眠，胆碱能输出神经元（ChN）在mHb表现出增加自发放电率和增强的放电规律性的脑切片。SF诱导的放电变化保持完整的谷氨酸，GABA，乙酰胆碱和组胺受体的抑制后，这表明独立于突触传递的细胞自主机制。此外，SF诱导的活动过度不是因为增强的内在膜兴奋性，但伴随着去极化静息膜电位在mHb ChNs。此外，在对照睡眠小鼠中，抑制双孔结构域K+通道的一种亚型，ASK-3（KCNK 9）通道通过增加放电率和规律性以及去极化mHb ChNs的静息膜电位来模拟SF效应。在SF小鼠中不存在这些ASK-3抑制作用，这表明SF后ASK-3活性降低。相比之下，抑制小电导Ca 2+激活的K+（SK）通道没有产生类似的效果。因此，SF损害mHb ChN中的ASK-3功能，这可能导致去极化静息膜电位和增加自发放电。这些结果不仅表明，选择性REM睡眠障碍导致mHb ChNs的过度活跃，但也确定了一个关键的分子底物，通过REM睡眠障碍可能会改变影响调节。
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.