Gene Transfer for Cataplexy of Narcolepsy

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 CNS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眠行为。该项目将继续侧重于cataerobic，一个重要的 嗜睡症的典型症状cataelation是一种突然失去肌肉张力在清醒期间，它是 通常由强烈的情绪触发，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。我试图找出 通过结合食欲素基因转移，光遗传学和新的大脑回路映射工具，限制 表型和投射特异性神经元的特异性基因表达。推动这一趋势的总体假设是， 目的是，在强烈的情绪GABA输入从中央核杏仁核（CeA）到 背外侧脑桥（vlPAG/LC/LPT）通过抑制负责以下的脑桥回路而触发cataillation： 保持肌肉张力初步数据支持这一假设，因为光遗传学抑制或 将食欲素插入到投射到vlPAG/LC/LPT的CeA杏仁核神经元中， 诱发性肌松症提出了五个目标来检验整体假设。提出的目标是相互的 支持性、假设驱动、目标明确、终点明确。大量的初步数据显示 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开发潜力产生重大影响 治疗，包括药物，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.