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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一个正常方面，但麻痹系统的功能障碍会引起发作性睡病患者会突然瘫痪而在快速眼动睡眠中则正好相反一种行为障碍（RBD），人们将自己的梦想付诸行动，通常会导致受伤。同时伴有痉挛和 RBD，这些事件经常是由强烈的情绪引起的：当嘲笑一个人时，与朋友开玩笑，RBD患者在梦见与敌人战斗时经常会大发雷霆。开发更好对于这些疾病的治疗，了解情绪背后的大脑回路是如何运作的至关重要。调节肌肉张力。紧张症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.杏仁核调节情绪的行为反应，先前的研究加上我们的飞行员数据表明，紧张症是由杏仁核中央核中的神经元触发的，催产素受体（CeAOTR）。具体地说，在积极情绪下，CeAOTR神经元可能通过以下方式促进catabolism：激活调节快速眼动睡眠瘫痪的脑干通路。我们的长期目标是确定CeAOTR神经元在调节紧张症中的作用，确定脑干机制，通过它们触发瘫痪，并确定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catabolism：用化学遗传学激活和抑制这些神经元我们将记录这些神经元的活动在自由活动的小鼠中进行钙成像，接下来，我们将定义神经 CeAOTR神经元通过将其连接映射到脑干来促进cataemia的靶点调节肌肉张力的回路我们将确定这些神经通路是否激活或抑制这些脑干区域，我们将使用光遗传学来测试这些投射的必要性。激活或抑制。最后，我们将定义对CeAOTR神经元的神经输入，使用有条件和传统的路径追踪，我们将测试是否奖励社会互动触发以及这是否由催产素介导。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。一个对情绪如何调节肌肉张力的更好理解应该有助于了解肌肉张力的正常调节。快速眼动睡眠期间的肌肉麻痹，并最终导致更好的治疗嗜睡症，RBD，和其他肌肉张力紊乱。