Circuit Mapping for emotion-induced cataplexy of Narcolepsy

摘要 我是一名新的年轻调查员，有可靠的发表记录，正在使用新工具更正 睡眠障碍，发作性睡病的特定回路。这种疾病与一种特定的神经元丢失有关。 含有神经肽增食欲素，也被称为下丘脑素。我的研究是第一个证明 将食欲素基因转移到发作性睡病小鼠的大脑中可以阻止猝倒。的确，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，这表明只有 特定的代理神经元可以修复发作性睡病的行为。这个项目将继续专注于瀑布， 发作性睡病的一个重要的区别症状。猝倒是指醒着时突然失去肌肉张力。 它通常是由强烈的情绪触发的，包括积极的(例如，笑、幽默)和消极的(例如：笑、幽默)。 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猝倒的。我试图找出 通过使用新的大脑回路映射工具，将特定基因的表达限制在表型上 以及投射特定神经元。推动目标的总体假设是，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猝倒 抑制负责维持肌肉紧张度的脑桥环路。我公布的初步数据支持 这一假说是因为将增食欲素基因插入杏仁核神经元阻止了自发的和 情绪诱发的猝倒症。这个项目的主要目标是限制光敏感视蛋白的表达。 杏仁核-GABA神经元投射至脑桥背外侧(vlPAG/Lc/Lpt)。我们有很强的初步证据 数据表明支持这一假设和该方法的可行性。在资助期结束时， 该项目将识别出一个有意义的神经回路。这将对中国的发展产生重大影响。 可能的治疗方法，包括可以选择性地定向到这一回路的药理药物。这个 探索性R21项目是一个完美的工具，可以创建新的工具来纠正电路。

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.