Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice.
Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice.
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DOI：
10.1523/jneurosci.0784-11.2011
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发表时间：
2011-07-20
期刊：
影响因子：
--
通讯作者：
Yamanaka A
中科院分区：
文献类型：
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作者：
Tsunematsu T;Kilduff TS;Boyden ES;Takahashi S;Tominaga M;Yamanaka A
食欲素/下丘脑泌素神经元在睡眠和觉醒的调节中起着至关重要的作用。为了帮助确定这些神经元如何促进觉醒，我们产生了转基因小鼠，其中食欲素神经元表达盐视紫红质（食欲素/Halo小鼠），一种橙子光激活的神经元沉默器。表达盐视紫红质的食欲素神经元的薄片膜片钳记录表明，橙子光照射立即使膜电位超极化，并与光照强度成比例地抑制食欲素神经元放电。在白天（非活动期），食欲素神经元在体内的急性沉默诱导了脑电图的同步和肌电图振幅的降低，这是慢波睡眠（SWS）的特征。与此相反，食欲素神经元光抑制是无效的，在夜间（活跃期）。在食欲素/Halo小鼠中，白天食欲素神经元的急性光抑制也减少了食欲素终末区（中缝背核（DR））神经元的放电。然而，多巴胺能DR神经元在缺乏食欲素神经元的小鼠中表现出正常的放电速率。因此，尽管通常高度依赖于食欲素神经元活性，但在长期缺乏食欲素输入的情况下，多巴胺能DR神经元活性可以被适当地调节。总之，这些结果表明，食欲素神经元的急性抑制导致SWS的一天中的时间依赖性诱导和传出投射部位的神经元的放电率降低，该传出投射部位被认为参与唤醒状态调节。这里提出的结果推进了我们对食欲素神经元在睡眠/觉醒调节中的作用的理解，并且可能与嗜睡症症状进展的机制有关。
Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. To help determine how these neurons promote wakefulness, we generated transgenic mice in which orexin neurons expressed halorhodopsin (orexin/Halo mice), an orange light-activated neuronal silencer. Slice patch-clamp recordings of orexin neurons that expressed halorhodopsin demonstrated that orange light photic illumination immediately hyperpolarized membrane potential and inhibited orexin neuron discharge in proportion to illumination intensity. Acute silencing of orexin neurons in vivo during the day (the inactive period) induced synchronization of the electroencephalogram and a reduction in amplitude of the electromyogram that is characteristic of slow-wave sleep (SWS). In contrast, orexin neuron photoinhibition was ineffective during the night (active period). Acute photoinhibition of orexin neurons during the day in orexin/Halo mice also reduced discharge of neurons in an orexin terminal field, the dorsal raphe (DR) nucleus. However, serotonergic DR neurons exhibited normal discharge rates in mice lacking orexin neurons. Thus, although usually highly dependent on orexin neuronal activity, serotonergic DR neuronal activity can be regulated appropriately in the chronic absence of orexin input. Together, these results demonstrate that acute inhibition of orexin neurons results in time-of-day-dependent induction of SWS and in reduced firing rate of neurons in an efferent projection site thought to be involved in arousal state regulation. The results presented here advance our understanding of the role of orexin neurons in the regulation of sleep/wakefulness and may be relevant to the mechanisms that underlie symptom progression in narcolepsy.