REM sleep control by the sublaterodorsal tegmental nucleus glutamatergic neurons

项目摘要/摘要 快速眼动(REM)睡眠的特征类似于去同步脑电(EEG) 到清醒，低肌电(EMG)表明骨骼肌张力，快速眼球运动， 自主神经不稳定，并有生动梦境的报道。快速眼动睡眠障碍会导致许多大脑 疾病包括睡眠障碍、发作性睡病/猝倒和快速眼动睡眠行为障碍(RBD)。快速眼动 睡眠由复杂的神经网络严密控制，其中产生REM睡眠的核心电路是 位于脑干。脑桥背外侧核(SLD)是一种重要的底物。 包含核心电路。SLD谷氨酸能神经元亚群在快速眼动睡眠中主要活跃 并促进向快速眼动睡眠的过渡。然而，这些快速眼动发作的神经元如何执行这些功能仍然存在 知之甚少是因为我们对这些神经元的分子身份缺乏更深入的了解 他们所在的电路图(S)的完整。这在很大程度上是由于 SLD区，包含混合的REM和觉醒活性神经元，以及有限的精确度和特异性 由传统技术提供。这个项目的中心目标是从分子上定义快速眼动的开始 并从功能上评估其在控制快速眼动睡眠中的因果作用。使用两个 无偏高通量测序方法，我们将解剖靶向SLD REM神经元并识别 它们的特异性分子标记(目标1)。使用双向光遗传操作，然后我们将测试 表达这些标记的候选神经元可以促进REM睡眠(目标2)。新药的分子鉴定 SLD中的REM神经元将为REM睡眠产生的核心电路提供遗传通路，从而 加深我们对快速眼动睡眠控制的电路机制的理解。这个项目的成果 应该有助于为发作性睡病/猝倒的基于电路的治疗干预的发展打开大门 和RBD。

PROJECT SUMMARY/ABSTRACT Rapid eye movement (REM) sleep is characterized a desynchronized electroencephalogram (EEG) similar to wakefulness, low electromyogram (EMG) indicative of skeletal muscle atonia, rapid eye movements, autonomic instability, and reports of vivid dreaming. REM sleep disturbances contribute to a number of brain diseases including the sleep disorders narcolepsy/cataplexy and REM sleep behavior disorder (RBD). REM sleep is tightly controlled by a complex neural network in which the core circuits for REM sleep generation are located in the brainstem. The sublaterodorsal nucleus (SLD) of the dorsolateral pons is a critical substrate containing the core circuits. Subsets of SLD glutamatergic neurons are predominantly active during REM sleep and promote the transition to REM sleep. Yet how these REM onset neurons perform these functions remains poorly understood because we lack a deeper understanding of the molecular identities of these neurons and a complete diagram of the circuit(s) in which they are located. This is largely due to the heterogenous nature of the SLD region, which contains intermingled REM and wake-active neurons, and the limited precision and specificity afforded by traditional techniques. The central goal of this project is to molecularly define the REM onset populations within the SLD and to functionally evaluate their causal role in controlling REM sleep. Using two unbiased high-throughput sequencing approaches, we will anatomically target SLD REM neurons and identify their specific molecular markers (Aim 1). Using bidirectional optogenetic manipulation, we will then test whether candidate neurons expressing these markers can promote REM sleep (Aim 2). Molecular identification of novel REM neurons in the SLD will provide genetic access to the core circuits for REM sleep generation and thereby advance our understanding of the circuit mechanisms underlying REM sleep control. The results of this project should help open the door to the development of circuit-based therapeutic interventions for narcolepsy/cataplexy and RBD.