Neural mechanisms underlying cataplexy control by MCH neurons

MCH 神经元控制猝倒的神经机制

基本信息

批准号：
10295605
负责人：
Vetrivelan Ramalingam
金额：
$ 43.75万
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：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10295605
关键词：
Address Affect Animal Model Animals Attenuated Behavior Cataplexy Cell Nucleus Chocolate Chronic Data Development Diagnostic Disease Drowsiness Emotional Enterobacteria phage P1 Cre recombinase Epilepsy Exhibits Fiber Functional disorder Glutamates High Prevalence Human Hypothalamic structure Image Knock-out Knockout Mice Knowledge Lateral Lead Lesion Life Light Maintenance Methods Midbrain structure Motor Activity Mus Muscle Tonus Narcolepsy Nature Neurologic Neurons Outcome Parkinson Disease Pathology Pathway interactions Patients Pattern Play Pontine structure Population Publishing REM Sleep Rattus Regulation Role Running Signal Transduction Sleep Sleep Disorders Tegmentum Mesencephali Testing Therapeutic Transgenic Mice Work base emotional stimulus experimental study hypocretin improved in vivo melanin-concentrating hormone melanin-concentrating hormone receptor mouse model neural circuit neurochemistry neuromechanism neuronal cell body novel therapeutics optogenetics photoactivation positive emotional state prevent prognostic relating to nervous system

项目摘要

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.

项目概要考虑到猝倒症 (NC)，了解发作性睡病 (NC) 的神经机制至关重要这种睡眠障碍具有使人衰弱和危及生命的性质，而且发病率很高。之前的研究有确定食欲素的丧失是人类和动物NC的根本原因。然而，角色黑色素浓缩激素（MCH）神经元，与食欲素神经元相互连接，在睡眠-觉醒调节中发挥补充作用，但在 NC 的病理生理学中仍不清楚。这拟议的工作旨在解决这个问题并定义 MCH 神经元通过的神经回路可能会影响猝倒。为了了解 MCH 神经元在猝倒期间是否活跃，在 Aim1 中，我们将成像自发性猝倒期间 NC 小鼠模型中 MCH 神经元的活动动态存在增强猝倒的积极情绪刺激。证明 MCH 神经元的因果作用在猝倒症中，在目标 2 中，我们将使用化学遗传学方法选择性激活和沉默 MCH 神经元并研究自发性猝倒和积极情绪触发性猝倒（PES-猝倒）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），其在大鼠中的损伤导致猝倒，然后我们假设 MCH 神经元可能会针对 MLR 来调节猝倒。在目标 3 中，我们将通过研究 a) 体内光遗传学刺激 MLR 中的 MCH 末端后并发猝倒症 MCH 体细胞的化学遗传学抑制和 b) MLR 中 MCH 末端的光遗传学抑制并同时发生 MCH 体细胞的化学遗传学激活。最后，在目标 4 中，从神经化学角度识别参与 MCH 控制猝倒的 MLR 神经元的不同子集，我们将通过化学遗传学方法激活或在有或没有食欲素的小鼠中抑制 MLR 中的谷氨酸能和 GABA 能神经元并进行研究猝倒行为。总的来说，这些实验将通过以下方式确定具体机制和途径： MCH 神经元影响猝倒，从而提高我们对 NC 神经基础的理解。