Orexin and the Control of Cataplexy

描述(申请人提供)：发作性睡病与猝倒影响1：2,000美国人，但对控制猝倒的神经通路知之甚少--通常由积极情绪引发的肌肉麻痹发作。神经肽增食欲素显然在这个系统中起着中心作用，因为食欲素信号缺乏的人、狗和小鼠都有发作性睡病和猝倒。我们和其他人在确定调节食欲素神经元活动的因素方面取得了良好的进展，现在我们计划研究食欲素神经元如何抑制猝发。利用发作性睡病的小鼠模型，我们将应用强大的遗传学、解剖学和生理学技术来定义猝倒背后的复杂神经回路。为了确定老鼠的猝倒是否类似于发作性睡病患者，我们将测试老鼠的猝倒是否由积极的情绪和已知影响人类猝倒的药物触发。接下来，我们将通过研究食欲素受体敲入小鼠来定义食欲素抑制猝倒的神经化学系统，这些小鼠只在产生儿茶酚胺、5-羟色胺或多巴胺D2受体的神经元中产生食欲素受体。为了确定增食欲素抑制猝倒的脑区，我们将一个含有Cre重组酶的腺相关病毒载体显微注射到这些增食欲素受体敲入小鼠的特定脑干区域，从而诱导增食欲素受体的局部表达，拯救猝倒表型。最后，我们将使用顺行和逆行追踪技术来描绘增食欲素抑制猝倒的神经通路。通过从生理学和解剖学上定义食欲素抑制猝倒的途径，我们将对紧张症的神经生物学有新的见解，这应该会导致更有效和合理的治疗猝倒、发作性睡病和其他运动控制障碍。

DESCRIPTION (provided by applicant): Narcolepsy with cataplexy affects 1:2,000 Americans, yet little is known about the neural pathways that control cataplexy - episodes of muscle paralysis that are often triggered by positive emotions. The neuropeptide orexin (hypocretin) clearly plays a central role in this system because people, dogs, and mice with deficient orexin signaling have narcolepsy with cataplexy. We and others have made good progress identifying the factors that regulate the activity of the orexin neurons, and we now plan to investigate how the orexin neurons suppress cataplexy. Using mouse models of narcolepsy, we will apply powerful genetic, anatomic, and physiologic techniques to define the complex neural circuits that underlie cataplexy. To determine whether mouse cataplexy is similar to that seen in people with narcolepsy, we will test whether mouse cataplexy is triggered by positive emotions and drugs known to affect human cataplexy. Next, we will define the neurochemical systems through which orexin suppresses cataplexy by studying orexin receptor knock-in mice that produce orexin receptors only in neurons producing catecholamines, serotonin, or dopamine D2 receptors. To define the brain regions through which orexin suppresses cataplexy, we will microinject an adeno-associated viral vector containing Cre recombinase into specific brainstem regions of these orexin receptor knock-in mice, thus inducing focal expression of orexin receptors and rescuing the cataplexy phenotype. Last, we will use anterograde and retrograde tracing techniques to map the neural pathways through which orexin suppresses cataplexy. By physiologically and anatomically defining the pathways through which orexin suppresses cataplexy, we will gain novel insights into the neurobiology of atonia that should lead to more effective and rational therapies for cataplexy, narcolepsy, and other disorders of motor control.