Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):E2635-44. doi: 10.1073/pnas.1202526109. Epub 2012 Sep 5.
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.
目前的睡眠/觉醒调节模型假设，侧下丘脑表达 Hypocretin（Hcrt）的神经元通过投射到皮质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 神经元和蓝斑核（LC）下游去甲肾上腺素能神经元之间的功能连接。我们发现，在 Hcrt 刺激期间光抑制 LC 神经元会阻断 Hcrt 介导的睡眠到觉醒转变。相比之下，当 LC 神经元被光刺激以增加膜兴奋性时，与单独的 Hcrt 刺激相比，同时对 Hcrt 神经元进行光刺激会显著增加睡眠到觉醒转变的概率。我们还构建了一个基于电导率的 Hcrt-LC 电路计算模型，该模型使用 LC 神经元作为 Hcrt 信号的主要效应器，再现了我们的行为结果。这些结果确立了 Hcrt-LC 连接作为调节非快速眼动睡眠/觉醒行为的关键整合-效应器回路，在非活动期。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。
