REM sleep control by the sublaterodorsal tegmental nucleus glutamatergic neurons

快速眼动睡眠由背侧被盖核谷氨酸能神经元控制

• 批准号: 10285847
• 负责人: Peng Zhong
• 金额: $ 35.59万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2023-01-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285847
• 关键词: Affinity Chromatography; Anatomy; Brain; Brain Diseases; Brain Stem; Calcium; Candidate Disease Gene; Cataplexy; Cell Nucleus; Cells; Characteristics; Complex; Development; Disease; Dissection; Dreams; Electroencephalogram; Evaluation; FOS gene; Fluorescent in Situ Hybridization; Future; Generations; Genes; Genetic; Glutamates; Goals; High-Throughput Nucleotide Sequencing; Image; Immediate-Early Genes; Investigation; Label; Lead; Link; Maintenance; Mediating; Messenger RNA; Molecular; Mus; Muscle; Narcolepsy; Nature; Neurons; Pathologic; Pattern; Phase; Pontine structure; Population; REM Sleep; REM Sleep Behavior Disorder; REM Sleep Deprivations; Recovery; Reporting; Research; Ribosomes; Role; Skeletal Muscle; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Specificity; Techniques; Testing; Therapeutic Intervention; Tissues; Translating; Validation; Virus; Wakefulness; basal forebrain; base; candidate marker; candidate validation; cell type; experimental study; genetic approach; high reward; high risk; interest; molecular marker; neural circuit; neural network; neuromechanism; non rapid eye movement; novel; novel marker; optogenetics; population movement; postsynaptic; presynaptic; rapid eye movement; sleep onset; sleep regulation; therapeutically effective; transcriptome sequencing

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.

项目摘要/摘要 快速眼动（REM）睡眠的特征是一个去兴奋的脑电图（EEG）类似 对于失眠，指示骨骼肌张力减退的低肌电图（EMG），快速眼球运动， 自主神经不稳定，还有生动梦境的报告快速眼动睡眠障碍会导致一些大脑 疾病，包括睡眠障碍发作性睡病/紧张症和REM睡眠行为障碍（RBD）。REM 睡眠是由一个复杂的神经网络严格控制的，其中产生REM睡眠的核心电路是 位于脑干。脑桥背外侧亚外侧背侧核（SLD）是一个重要的基底 包含核心电路。在REM睡眠期间，SLD神经元的亚群主要活跃 并促进向快速眼动睡眠的过渡。然而，这些快速眼动期神经元如何执行这些功能仍然存在 我们对此知之甚少，因为我们对这些神经元的分子身份缺乏更深入的了解， 它们所在电路的完整示意图。这在很大程度上是由于 SLD区，其中包含混合的REM和唤醒活动神经元，以及有限的精确性和特异性 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发生 SLD内的人群，并从功能上评估其在控制REM睡眠中的因果作用。使用两 无偏见的高通量测序方法，我们将解剖靶向SLD REM神经元，并确定 其特异性分子标记物（Aim 1）。使用双向光遗传学操作，我们将测试是否 表达这些标记物的候选神经元可以促进REM睡眠（Aim 2）。新化合物的分子鉴定 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 推进我们对REM睡眠控制的电路机制的理解。该项目的结果 应该有助于打开大门，以电路为基础的治疗干预发作性睡病/cataepsy的发展 和RBD。