Circuit Mapping for emotion-induced cataplexy of Narcolepsy

情绪诱发的发作性睡病猝倒的回路映射

• 批准号: 9299015
• 负责人: Meng Liu
• 金额: $ 18.14万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299015
• 关键词: Amygdaloid structure; Anger; Anxiety; Automobile Driving; Axon; Behavior; Brain; Canis familiaris; Cataplexy; Coyotes; Data; Development; Disease; Emotional; Emotions; Fright; Funding; Future; Gene Transfer; Genes; Genetic Engineering; Goals; Humor; Injectable; Knockout Mice; Laughter; Light; Link; Measures; Methodology; Modeling; Mus; Muscle; Muscle Tonus; Muscular Atrophy; Narcolepsy; Nerve Degeneration; Neuraxis; Neurons; Neuropeptides; Neurosciences; Operative Surgical Procedures; Opsin; Optics; Pattern; Pharmacology; Phenotype; Pontine structure; Population; Publications; Publishing; Research Personnel; Side; Site; Sleep; Sleep Disorders; Symptoms; Testing; Tracer; Transgenic Mice; Urine; Virus; gamma-Aminobutyric Acid; hypocretin; inhibitory neuron; mouse model; neural circuit; neuron loss; novel; optogenetics; photoactivation; repaired; sex; sleep abnormalities; success; tool; vector

Abstract I am a new young investigator with a proven publication record who is using new tools to correct specific circuits in the sleep disorder, narcolepsy. This disorder is linked to a specific loss of neurons containing the neuropeptide orexin, also known as hypocretin. My study was the first one to demonstrate that orexin gene transfer into the brains of narcoleptic mice blocks cataplexy. Indeed, orexin gene transfer into some neuron populations in the central nervous system has proven to be ineffective indicating that only specific surrogate neurons can repair narcoleptic behavior. This project will continue to focus on cataplexy, an important distinguishing symptom of narcolepsy. Cataplexy is a sudden loss of muscle tone during waking and it is often triggered by strong emotions including both positive (e.g. laughter, humor) and negative (e.g. anger, fear or sudden surprise) emotions. It is not known how emotions trigger cataplexy. I seek to identify this circuit by using novel brain circuit mapping tools that restrict expression of specific genes to phenotype and projection-specific neurons. The overall hypothesis driving the aims is that during strong emotions GABA input from the amygdala (CeA and BLA) to the dorsolateral pons (vlPAG/LC/LPT) triggers cataplexy by inhibiting the pontine circuit responsible for maintaining muscle tone. My published preliminary data supports this hypothesis because insertion of the orexin gene into amygdala neurons blocks both spontaneous and emotion-induced cataplexy. The primary goal of this project is to restrict expression of light sensitive opsins to amygdala-GABA neurons projecting to the dorsolateral pons (vlPAG/LC/LPT). We have strong preliminary data showing support for the hypothesis and feasibility of the approach. At the end of the funding period the project will have identified a meaningful neural circuit. This will have a significant impact in the development of potential therapies, including pharmacological agents that can be selectively directed to this circuit. The exploratory R21 project is a perfect vehicle to create new tools to correct circuits.

摘要 我是一个新的年轻的调查员与证明出版记录谁是使用新的工具来纠正 睡眠障碍发作性睡病的特殊回路这种疾病与特定的神经元损失有关 含有神经肽食欲素，也称为下丘脑分泌素。我的研究是第一个证明 将食欲素基因转移到发作性睡眠小鼠的大脑中可阻断cataemia。事实上，食欲素基因转移到 中枢神经系统中的一些神经元群体已被证明是无效的 特定的替代神经元可以修复发作性睡眠行为。该项目将继续关注cataerobic， 嗜睡症的一个重要的区别症状。cataetarian是一种突然失去肌肉张力在清醒期间 并且它通常由包括积极的（例如，笑声、幽默）和消极的（例如， 愤怒、恐惧或突然的惊讶）情绪。目前尚不清楚情绪是如何引发cataabolism的。我想找出 通过使用新的脑回路映射工具，将特定基因的表达限制在表型中， 和投射特异性神经元。驱动这些目标的总体假设是，在强烈情绪期间，GABA 从杏仁核（CeA和BLA）到背外侧脑桥（vlPAG/LC/LPT）的输入通过以下方式触发cataillance： 抑制负责维持肌肉张力的脑桥回路。我公布的初步数据支持 这一假设是因为将食欲素基因插入杏仁核神经元， 情绪诱发的神经衰弱本项目的主要目标是限制光敏感视蛋白的表达 杏仁核-GABA神经元投射到脑桥背外侧（vlPAG/LC/LPT）。我们有初步证据 表明支持假设和方法可行性的数据。在融资期结束时， 项目将确定一个有意义的神经回路。这将在发展中产生重大影响 潜在的治疗方法，包括可以选择性地引导到这个回路的药理学试剂。的 探索性的R21项目是一个完美的工具，创造新的工具来纠正电路。