Neural substrates of awakening probed with optogenetic control of hypocretin neurons
Neural substrates of awakening probed with optogenetic control of hypocretin neurons
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DOI：
10.1038/nature06310
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发表时间：
2007-11-15
期刊：
影响因子：
64.8
通讯作者：
De Lecea, Luis
中科院分区：
文献类型：
--
作者：
Adamantidis, Antoine R.;Zhang, Feng;De Lecea, Luis
睡眠的神经基础涉及促进睡眠的区域之间的相互作用，如前下丘脑，以及位于后下丘脑，基底前脑和脑干的唤醒系统（1，2）。下丘脑外侧（5）中的下丘脑泌素（3）（Hcrt，也称为食欲素（4））产生神经元对唤醒稳定性很重要（2），Hcrt功能丧失与嗜睡症有关（6-9）。然而，尚不清楚Hcrt神经元产生的电活动是否足以驱动从睡眠状态唤醒或仅仅与其相关。在这里，我们直接探索了Hcrt神经元活动对体内神经光刺激睡眠状态转换的影响（10-18），将通道视紫红质-2基因靶向Hcrt细胞，并使用光纤将光传递到大脑深处，直接进入自由活动的小鼠的外侧下丘脑。我们发现，Hcrt神经元的直接、选择性、光遗传学光刺激增加了从慢波睡眠或快速眼动睡眠过渡到觉醒的概率。值得注意的是，使用5-30 Hz光脉冲序列的光刺激减少了觉醒的潜伏期，而1 Hz序列则没有。这项研究建立了一个基因定义的神经细胞类型的频率依赖性活动和一个特定的哺乳动物行为的临床条件和神经行为生理学的核心之间的因果关系。
The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem(1,2). Hypocretin(3) (Hcrt, also known as orexin(4))-producing neurons in the lateral hypothalamus(5) are important for arousal stability(2), and loss of Hcrt function has been linked to narcolepsy(6-9). However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation(10-18), genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.