Neural mechanisms underlying cataplexy control by MCH neurons

项目总结 了解发作性睡病合并猝倒(NC)的神经机制至关重要，考虑到 这种睡眠障碍的衰弱和危及生命的性质及其高患病率。之前的研究已经 确定食欲素的丢失是人类和动物NC的根本原因。然而，这个角色 黑色素浓缩激素(MCH)神经元，它们与食欲素神经元和 在睡眠-觉醒调节中发挥互补作用，其在NC的病理生理学中的作用尚不清楚。这个 拟议的工作旨在解决这个问题并定义MCH神经元所通过的神经回路 可能会影响猝倒。为了了解MCH神经元在癫痫发作期间是否活跃，在Aim1中，我们将成像 NC小鼠模型自发性癫痫发作过程中MCH神经元活动的动态变化 存在积极的情绪刺激，以增强晕厥。为了证明MCH神经元的因果作用 在猝发中，在目标2中，我们将使用化学遗传学方法选择性地激活和沉默MCH神经元。 并研究自发性猝倒和积极情绪触发猝倒(PES-Cataplexy)的变化。 由于MCH神经元大量投射到中脑运动区(MLR；参与促进肌肉张力 和运动活动)，其损害在大鼠中产生猝倒，然后我们假设MCH神经元 可能会以MLR为靶点来调节猝倒。在目标3中，我们将通过研究以下变化来验证这一假设 A)在体光遗传刺激MLR中的MCH终末后并发的猝倒 MCH胞体的化学发生抑制和b)MLR中MCH终末的光发生抑制 伴随着MCH胞体的同步化学激活。最后，在目标4中，用神经化学方法识别 参与MCH控制猝倒的MLR神经元的不同亚群(S)，我们将通过化学遗传学激活或 抑制食欲素对小鼠延髓核内谷氨酸能和氨基丁酸能神经元的影响 晕厥行为。总的来说，这些实验将通过以下方式确定具体的机制和途径 哪些MCH神经元影响猝倒，从而提高我们对NC的神经基础的理解。

PROJECT SUMMARY Understanding the neural mechanisms underlying narcolepsy with cataplexy (NC) is crucial, considering the debilitating and life-threatening nature of this sleep disorder and its high prevalence. Previous studies have established that the loss of orexins is the fundamental cause of NC in humans and animals. However, the role of melanin-concentrating hormone (MCH) neurons, which are reciprocally connected with orexin neurons and play a complementary role in sleep-wake regulation, in the pathophysiology of NC remains unclear. The proposed work is aimed to address this question and to define the neural circuitry through which MCH neurons may influence cataplexy. To understand if MCH neurons are active during cataplexy, in Aim1, we will image activity dynamics of MCH neurons in a mouse model of NC during spontaneous cataplexy as well as in the presence of positive emotional stimuli that enhance cataplexy. To demonstrate a causal role of MCH neurons in cataplexy, in Aim 2, we will selectively activate and silence the MCH neurons using chemogenetic methods and study the changes in spontaneous cataplexy and positive-emotion-triggered cataplexy (PES-cataplexy). As MCH neurons heavily project to the midbrain locomotor region (MLR; involved in facilitating muscle tone and locomotor activity), whose lesions in rats produced cataplexy, we then hypothesized that the MCH neurons might target the MLR to modulate cataplexy. We will test this hypothesis, in Aim 3, by studying the changes in cataplexy a) following in vivo optogenetic stimulation of the MCH terminals in the MLR with concurrent chemogenetic inhibition of MCH soma and b) following optogenetic inhibition of the MCH terminals in the MLR with concurrent chemogenetic activation of MCH soma. Finally, in Aim 4, to identify the neurochemically distinct subset(s) of MLR neurons involved in MCH control of cataplexy, we will chemogenetically activate or inhibit the glutamatergic and GABAergic neurons in the MLR in mice with or without orexins and study cataplexy behavior. Collectively, these experiments will identify the specific mechanisms and pathways by which MCH neurons influence cataplexy and thereby will improve our understanding of the neural basis of NC.