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：
10606505
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/10606505
关键词：
Address Affect Animal Model Animals Attenuated Behavior Cataplexy Cell Nucleus Chocolate Chronic Complex Data Development Diagnostic Disease Drowsiness Emotional Enterobacteria phage P1 Cre recombinase Epilepsy Exhibits Fiber Functional disorder Genetic Glutamates High Prevalence Human Hypothalamic structure Image Knockout Mice Knowledge Lateral Lesion Life Maintenance Methods Midbrain structure Motor Activity Mus Muscle Tonus Narcolepsy Nature Neurologic Neurons Outcome Parkinson Disease Pathology Pathway interactions Patients Pattern Persons Photometry Play Pontine structure Population Publishing REM Sleep Rattus Regulation Role Running Signal Transduction Sleep Sleep Disorders Tegmentum Mesencephali Testing Therapeutic Transgenic Mice Work antagonist emotional stimulus experimental study hypocretin improved in vivo melanin-concentrating hormone melanin-concentrating hormone receptor mouse model neural neural circuit neurochemistry neuromechanism neuronal cell body novel therapeutics optogenetics photoactivation positive emotional state prevent prognostic

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.

项目摘要考虑到这一点这种睡眠障碍的衰弱和威胁生命的性质及其高流行。先前的研究已有确定丧失Orexins是人类和动物NC的基本原因。但是，角色黑色素浓缩激素（MCH）神经元，与Orexin神经元相互连接，在睡眠效果调节中起互补的作用，在NC的病理生理学中尚不清楚。这拟议的工作旨在解决这个问题并定义MCH神经元的神经回路可能会影响瘫痪。要了解MCH神经元在弹出过程中是否活跃，在AIM1中，我们将图像在自发性瘫痪期间以及在NC的小鼠模型中以及在存在积极的情绪刺激，从而增强了瘫痪。展示MCH神经元的因果作用在AIM 2中，我们将使用化学发生方法选择性地激活MCH神经元并使MCH神经元沉默并研究了自发脱封和阳性触发的脱封（PES-cataplexy）的变化。由于MCH神经元大量投射到中脑运动区域（MLR；参与促进肌肉张力和运动活性），其在大鼠中的病变产生了脱失术，然后我们假设MCH神经元可能靶向MLR以调节脱路。我们将在AIM 3中检验这一假设，通过研究的变化来检验脱氧a）遵循MLR中MCH终端的体内光遗传学刺激 MCH SOMA的化学发生抑制和B）在MLR中MCH末端的光遗传学抑制后与MCH SOMA的同时化学遗传激活。最后，在AIM 4中以识别神经化学参与MCH控制的MCH控制的MLR神经元的不同子集，我们将化学激活或抑制有或没有Orexins的小鼠中MLR中的谷氨酸能和GABA能神经元并进行研究瘫痪行为。总的来说，这些实验将通过 MCH神经元会影响瘫痪，从而将我们对NC神经基础的理解提高。