Regulation of Sleep and Circadian Behaviors by TGF-alpha Signaling

描述(申请人提供)：3000多万美国人患有慢性睡眠障碍，如发作性睡病和失眠。然而，尽管睡眠障碍对医学有影响，但人们对睡眠和清醒背后的遗传和神经回路知之甚少。睡眠是整个动物界的一种保守行为，由对睡眠需求的内在提示做出反应的动态平衡过程以及对环境提示做出反应的昼夜节律过程来调节。然而，对大多数脊椎动物睡眠研究的一个警告是，它们依赖于夜间哺乳动物，如老鼠和大鼠来模拟睡眠行为。这些动物是动态平衡睡眠调节的良好模型，但尚不清楚昼夜节律方面的睡眠调节是否与人类等昼夜哺乳动物保守。我将利用斑马鱼相对简单但保守的神经回路，来测试关于转化生长因子α(转化生长因子α)在调节睡眠和昼夜行为中的作用的几个假说。首先，我将通过使用高通量运动活动和觉醒阈值分析进行功能获得和功能丧失的遗传学实验，来验证转化生长因子-α作为昼夜节律信号抑制运动活动的假设。其次，我将利用斑马鱼幼体对高通量药物给药和行为分析的适应性来确定斑马鱼中介导转化生长因子-α依赖行为的分子机制。第三，我将描述产生和响应转化生长因子-α信号的细胞的特征，并测试转化生长因子-α信号激活促进睡眠的神经细胞群体和沉默促进觉醒的神经细胞群体的假设。这些实验将有助于阐明转化生长因子-α调节昼夜动物清醒/睡眠状态的昼夜节律线索的遗传和神经机制。这些研究将提高我们对睡眠是如何调节的理解，并可能导致睡眠和昼夜节律紊乱的新疗法。

DESCRIPTION (provided by applicant): More than 30 million Americans suffer from chronic sleep disorders such as narcolepsy and insomnia. Yet, despite the medical impact of sleep disorders, relatively little is known of the genetic and neural circuits that underlie sleep and wakefulness. Sleep is a conserved behavior across the animal kingdom, and is regulated by homeostatic processes that respond to internal cues of sleep need, as well as a circadian process that responds to environmental cues. A caveat to most vertebrate sleep studies, however, is that they rely on nocturnal mammals such as mice and rats to model sleep behavior. These animals are good models for homeostatic sleep regulation, but it is unclear whether circadian aspects of sleep regulation are conserved with diurnal mammals such as humans. I will exploit the relatively simple yet conserved neural circuits of the zebrafish, a diurnal vertebrate, to test several hypotheses regarding the role of transforming growth factor alpha (TGF-alpha) in regulating sleep and circadian behaviors. First, I will test the hypothesis that TGF-alpha acts as a circadian signal to inhibit locomotor activity by performing gain and loss of function genetic experiments using high throughput locomotor activity and arousal threshold assays. Second, I will exploit the amenability of zebrafish larvae to high-throughput pharmacological administration and behavioral assays to determine the molecular mechanisms that mediate TGF-alpha-dependent behaviors in zebrafish. Third, I will characterize the cells that produce and respond to TGF-alpha signaling, and test the hypothesis that TGF-alpha signaling activates sleep-promoting neural populations and silences wake- promoting neural populations. These experiments will help to illuminate the genetic and neural mechanisms through which TGF-alpha mediates circadian cues that regulate wake/sleep states in diurnal animals. These studies will improve our understanding of how sleep is regulated and may lead to novel treatments for sleep and circadian rhythm disorders.