Gene Transfer for 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，这表明只有特定的替代物 神经元可以修复发作性睡病的行为。该项目将继续专注于Catapplex，这是一个重要的 发作性睡病的明显症状。猝倒症是指在清醒时突然失去肌肉张力，它是 通常由强烈的情绪触发，包括积极的(例如，笑，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猝倒的。我试图找出这一点 通过结合食欲素基因转移、光遗传学和限制 特定基因在表型和投射特异性神经元中的表达。推动经济增长的总体假说 目的是在强烈情绪时，GABA从杏仁中央核(CEA)传入大脑 背外侧脑桥(vlPAG/LC/LPT)通过抑制桥脑环路而触发猝倒。 保持肌肉紧张度。初步数据支持这一假说，因为光遗传抑制或 将增食欲素插入投射到vlPAG/LC/LPT的杏仁核CEA神经元可降低情绪。 诱发性猝倒。本文提出了五个目标来检验总体假设。提出的目标是相互的。 支持，假设驱动，有明确的目标和明确的终点。广泛的初步数据显示 支持该方法的假设和可行性。在资助期结束时，该项目将 发现了一个有意义的神经回路。这将对发展潜力产生重大影响。 疗法，包括药剂，可以选择性地引导到这个回路。

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. Mine was the first study to demonstrate that orexin gene transfer into the brains of narcoleptic mice blocks cataplexy. Indeed, orexin gene transfer into some neuron populations in the CNS 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 combining orexin gene transfer, optogenetics and 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 central nucleus of the amygdala (CeA) to the dorsolateral pons (vlPAG/LC/LPT) triggers cataplexy by inhibiting the pontine circuit responsible for maintaining muscle tone. Preliminary data supports this hypothesis because optogenetic inhibition or insertion of orexin into the CeA amygdala neurons projecting to the vlPAG/LC/LPT decreases emotion- induced cataplexy. Five aims are proposed to test the overall hypothesis. The proposed aims are mutually supporting, hypothesis driven, with clear objectives and definite endpoints. Extensive preliminary data show 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.