Mechanisms of Cataplexy

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导致 发作性睡病患者的猝倒性、突发性瘫痪。而在REM睡眠中，情况正好相反 行为障碍(RBD)，人们把自己的梦想表现出来，通常会导致伤害。既有扑朔迷离的，又有 RBD，这些事件通常是由强烈的情绪引起的：当笑一个人的时候，通常会引发猝倒 与朋友开玩笑，患有RBD的人在梦到与敌人作战时经常会大发雷霆。为了更好地发展 对于这些疾病的治疗，了解情绪背后的大脑回路是至关重要的 调节肌肉张力。 猝倒主要是由强烈的积极情绪引发的，通常是在与亲密者进行社交互动时 朋友和家人。杏仁核调节对情绪的行为反应，先前的研究加上我们的飞行员 数据表明，癫痫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)。具体地说，有了积极的情绪，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瘫痪的脑干通路。 我们的长期目标是确定CeAOTR神经元在调节猝倒中的作用，以 定义它们触发瘫痪的脑干机制，并识别上游信号 通过它来激活它们。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 在自由活动的小鼠中使用钙成像跨越猝倒和睡眠状态。接下来，我们将定义神经 CeAOTR神经元通过映射其与脑干的联系促进猝倒的靶点 调节肌肉张力的回路。我们将确定这些神经通路是激活还是抑制这些脑干 使用大脑切片记录的区域，我们将使用光遗传学来测试这些投影的必要性 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 使用有条件的和常规的路径跟踪，我们将测试奖励的社交互动是否会触发 猝倒以及这是否由催产素介导。 总而言之，这些多学科实验将定义神经机制，通过这些机制 积极的情绪，包括社会信号，会激活杏仁核神经元和脑干瘫痪机制。一个 对情绪如何调节肌肉张力的更好理解应该有助于理解 快速眼动睡眠中的肌肉麻痹，最终导致对发作性睡病、RBD和其他疾病的更好治疗 肌肉紧张性障碍。

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.