Mechanism for Hypocretin-mediated sleep-to-wake transitions
Mechanism for Hypocretin-mediated sleep-to-wake transitions
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DOI：
10.1073/pnas.1202526109
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发表时间：
2012-09-25
影响因子：
11.1
通讯作者：
de Lecea, Luis
中科院分区：
文献类型：
--
作者：
Carter, Matthew E.;Brill, Julia;de Lecea, Luis
目前的睡眠/觉醒调节模型认为，下丘脑外侧表达下丘脑分泌素（Hcrt）的神经元通过投射到皮层下唤醒中心来促进和稳定觉醒。然而，Hcrt 神经元的关键下游效应器尚不清楚。在这里，我们使用光遗传学、药理学和计算工具来研究非快速眼动 (NREM) 睡眠期间 Hcrt 神经元和蓝斑 (LC) 下游去甲肾上腺素能神经元之间的功能连接。我们发现 Hcrt 刺激期间光抑制 LC 神经元阻断了 Hcrt 介导的睡眠到觉醒的转变。相反，当 LC 神经元受到光刺激以增加膜兴奋性时，与单独的 Hcrt 刺激相比，伴随的 Hcrt 神经元光刺激显着增加了睡眠到觉醒转变的概率。我们还建立了一个基于电导的 Hcrt-LC 电路计算模型，该模型使用 LC 神经元作为 Hcrt 信号传导的主要效应器来概括我们的行为结果。这些结果将 Hcrt-LC 连接确立为关键的积分效应器电路，可调节非活动期间的 NREM 睡眠/唤醒行为。这种不同神经元系统的耦合可以推广到大脑中具有下游效应器/输出群体的其他下丘脑整合核。
Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as the main effectors of Hcrt signaling. These results establish the Hcrt-LC connection as a critical integrator-effector circuit that regulates NREM sleep/wake behavior during the inactive period. This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain.