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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要快速眼动 (REM) 睡眠的特点是与脑电图 (EEG) 类似觉醒、低肌电图（EMG）表明骨骼肌无力、快速眼球运动，自主神经不稳定，以及生动的梦的报告。快速眼动睡眠障碍会导致许多大脑功能障碍疾病包括睡眠障碍发作性睡病/猝倒症和快速眼动睡眠行为障碍 (RBD)。快速眼动睡眠睡眠受到复杂的神经网络的严格控制，其中快速眼动睡眠生成的核心电路是位于脑干。脑桥背外侧核（SLD）是一个关键的基质包含核心电路。 SLD 谷氨酸能神经元亚群主要在快速眼动睡眠期间活跃并促进向快速眼动睡眠的过渡。然而，这些 REM 起始神经元如何执行这些功能仍然存在知之甚少，因为我们对这些神经元的分子身份缺乏更深入的了解，而且它们所在电路的完整图。这主要是由于异构性的本质 SLD 区域，包含混合的 REM 和唤醒活动神经元，精度和特异性有限由传统技术提供。该项目的中心目标是从分子水平上定义 REM 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。使用两个通过无偏见的高通量测序方法，我们将在解剖学上靶向 SLD REM 神经元并识别他们的特定分子标记（目标 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快速眼动睡眠（目标 2）。新型分子鉴定 SLD 中的 REM 神经元将为 REM 睡眠生成的核心回路提供遗传通路，从而增进我们对快速眼动睡眠控制背后的电路机制的理解。该项目的成果应该有助于为开发基于回路的发作性睡病/猝倒症治疗干预措施打开大门和RBD。