Neural mechanisms underlying cataplexy control by MCH neurons

MCH 神经元控制猝倒的神经机制

• 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
• 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

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 了解发作性睡病伴cataepsy（NC）的神经机制至关重要， 这种睡眠障碍的衰弱和危及生命的性质及其高患病率。先前的研究 确定食欲素的损失是人类和动物NC的根本原因。然而，作用 黑色素浓集激素（MCH）神经元，与食欲素神经元相连， 在睡眠-觉醒调节中发挥补充作用，在NC的病理生理学中仍不清楚。的 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 可能会影响癫痫发作。为了了解MCH神经元在cataemia期间是否活跃，在Aim 1中，我们将成像 在自发性紧张症期间以及在正常对照小鼠模型中，MCH神经元的活动动力学 积极的情绪刺激的存在，增强cataemotional。证明MCH神经元的因果作用 在目的2中，我们将使用化学发生学方法选择性地激活和沉默MCH神经元 研究自发性紧张症和正性情绪触发性紧张症（positive-emotional-triggered catabolism，PES-catabolism）的变化。 由于MCH神经元大量投射到中脑运动区（MLR;参与促进肌张力 和自发活动），其在大鼠中的损伤产生cataillance，然后我们假设MCH神经元 可能通过MLR来调节紧张症。在目标3中，我们将通过研究 在MLR中的MCH末端的体内光遗传学刺激后， MCH索马体的化学遗传学抑制和B）MLR中MCH末端的光遗传学抑制 伴随MCH索马体的化学发生活化。最后，在目标4中，为了从神经化学上识别 MLR神经元的一个或多个不同的子集参与MCH对cataemia的控制，我们将化学发生激活或 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， 灾难性的行为总的来说，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catabolism，从而将提高我们对NC的神经基础的理解。