Orexin and the Control of Cataplexy

描述（由申请人提供）：发作性睡伴猝倒的美国人患病率为1:20 00，但人们对控制猝倒的神经通路知之甚少，即由积极情绪引发的肌肉麻痹发作。神经肽食欲素（下丘脑分泌素）显然在这个系统中起着核心作用，因为缺乏食欲素信号的人、狗和老鼠都有发作性睡病伴猝倒。我们和其他人已经在确定调节食欲素神经元活动的因素方面取得了很好的进展，我们现在计划研究食欲素神经元是如何抑制猝倒的。使用小鼠发作性睡病模型，我们将应用强大的遗传、解剖学和生理学技术来定义导致发作的复杂神经回路。为了确定小鼠的猝倒是否与人的发作性睡症相似，我们将测试小鼠的猝倒是否由积极情绪和已知影响人类猝倒的药物引发。接下来，我们将通过研究仅在产生儿茶酚胺、血清素或多巴胺D2受体的神经元中产生食欲素受体的食欲素受体敲入小鼠来确定食欲素抑制猝倒的神经化学系统。为了确定食欲素抑制猝倒的脑区，我们将含有Cre重组酶的腺相关病毒载体微注射到这些食欲素受体敲入小鼠的特定脑干区域，从而诱导食欲素受体的局灶表达，挽救猝倒表型。最后，我们将使用顺行和逆行追踪技术来绘制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，我们将对张力失调的神经生物学有新的认识，这将导致对猝倒、发作性睡病和其他运动控制疾病更有效和合理的治疗。

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.