Mechanisms of Cataplexy

猝倒的机制

基本信息

批准号：
10476056
负责人：
THOMAS E SCAMMELL
金额：
$ 4.71万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476056
关键词：
Amygdaloid structure Anxiety Brain Brain Stem Brain region Calcium Canis familiaris Cataplexy Cell Nucleus Clinical Data Disease Dreams Emotions Event Family Friends Fright Hypothalamic structure Image Injury Lead Light Maps Mediating Modeling Motor Mus Muscle Muscle Tonus Myopathy Narcolepsy Neural Pathways Neurons Oxytocin Oxytocin Receptor Paralysed Pathway interactions Photometry REM Sleep REM Sleep Behavior Disorder Rabies Regulation Research Rewards Role Signal Transduction Sleep Sleep Disorders Sleep Paralysis Slice Social Interaction Stimulus Synapses System Testing behavioral response brain circuitry experimental study fighting hypocretin improved midbrain central gray substance mouse model multidisciplinary neuromechanism optogenetics paraventricular nucleus photoactivation positive emotional state relating to nervous system response social

项目摘要

Muscle paralysis is a normal aspect of REM sleep, but dysfunction in the paralysis system gives rise to cataplexy, sudden episodes of paralysis in people with narcolepsy. Just the opposite occurs in REM sleep behavior disorder (RBD) in which people act out their dreams, often resulting in injury. With both cataplexy and RBD, the events are frequently brought on by strong emotions: cataplexy is often triggered when laughing at a joke with friends, and people with RBD often lash out when dreaming about fighting a foe. To develop better therapies for these disorders, it is essential to understand how the brain circuitry that underlies emotions regulates muscle tone. Cataplexy is mainly triggered by strong positive emotions, usually when socially interacting with close friends and family. The amygdala mediates behavioral responses to emotions, and prior research plus our pilot data suggest that cataplexy is triggered by neurons in the central nucleus of the amygdala that express the oxytocin receptor (CeAOTR). Specifically, with positive emotions, CeAOTR neurons may promote cataplexy by activating brainstem pathways that regulate the paralysis of REM sleep. Our long-term objectives are to determine the role of the CeAOTR neurons in regulating cataplexy, to define the brainstem mechanisms through which they trigger paralysis, and to identify the upstream signals through which they are activated. First, we will determine whether the CeAOTR neurons promote cataplexy by activating and inhibiting these neurons using chemogenetics. We will then record the activity of these neurons across cataplexy and sleep states using calcium imaging in freely moving mice. Next, we will define the neural targets through which the CeAOTR neurons promote cataplexy by mapping their connections to brainstem circuits that regulate muscle tone. We will establish if these neural pathways activate or inhibit these brainstem regions using brain slice recordings, and we will test the necessity of these projections using optogenetic activation or inhibition. Last, we will define the neural inputs to the CeAOTR neurons that promote cataplexy using conditional and conventional pathway tracing, and we will test if rewarding social interaction triggers cataplexy and whether this is mediated by oxytocin. Collectively, these multidisciplinary experiments will define the neural mechanisms through which positive emotions including social signals activate amygdala neurons and brainstem paralysis mechanisms. An improved understanding of how emotions regulate muscle tone should shed light on the normal regulation of muscle paralysis during REM sleep, and ultimately lead to better treatments for narcolepsy, RBD, and other disorders of muscle tone.

肌肉麻痹是快速眼动睡眠的正常现象，但麻痹系统的功能障碍会导致猝倒症，发作性睡病患者突然出现瘫痪。快速眼动睡眠中的情况正好相反行为障碍（RBD），人们将自己的梦想付诸实践，通常会导致受伤。伴有猝倒和 RBD，这些事件经常是由强烈的情绪引起的：大笑时经常会引发猝倒。与朋友开玩笑，患有 RBD 的人在梦见与敌人战斗时常常会大发雷霆。为了更好的发展对于这些疾病的治疗，有必要了解情绪背后的大脑回路如何调节肌肉张力。猝倒主要是由强烈的积极情绪引发的，通常是在与亲密的人进行社交互动时朋友和家人。杏仁核调节对情绪的行为反应，之前的研究加上我们的试点数据表明猝倒是由杏仁核中央核中的神经元触发的，这些神经元表达催产素受体（CeAOTR）。具体来说，在积极情绪下，CeAOTR 神经元可能通过以下方式促进猝倒激活调节快速眼动睡眠麻痹的脑干通路。我们的长期目标是确定 CeAOTR 神经元在调节猝倒中的作用，以定义触发瘫痪的脑干机制，并识别上游信号通过它它们被激活。首先，我们将确定 CeAOTR 神经元是否通过以下方式促进猝倒：使用化学遗传学激活和抑制这些神经元。然后我们将记录这些神经元的活动使用钙成像对自由活动的小鼠进行跨越猝倒和睡眠状态的研究。接下来，我们将定义神经网络 CeAOTR 神经元通过映射其与脑干的连接来促进猝倒的目标调节肌肉张力的电路。我们将确定这些神经通路是否激活或抑制这些脑干使用脑切片记录来预测这些区域，我们将使用光遗传学来测试这些预测的必要性激活或抑制。最后，我们将定义促进猝倒的 CeAOTR 神经元的神经输入使用条件和传统路径追踪，我们将测试奖励性社交互动是否会触发猝倒以及这是否是由催产素介导的。总的来说，这些多学科实验将定义神经机制包括社交信号在内的积极情绪会激活杏仁核神经元和脑干麻痹机制。一个更好地了解情绪如何调节肌张力应该有助于理解情绪的正常调节快速眼动睡眠期间的肌肉麻痹，最终导致发作性睡病、RBD 和其他疾病的更好治疗肌张力障碍。