Regulation of Sleep and Circadian Behaviors by TGF-alpha Signaling

描述（申请人提供）：超过3000万美国人患有慢性睡眠障碍，如嗜睡症和失眠症。然而，尽管睡眠障碍对医学有影响，但对睡眠和觉醒的遗传和神经回路知之甚少。睡眠是动物王国中保守的行为，并且受到响应睡眠需求的内部线索的稳态过程以及响应环境线索的昼夜节律过程的调节。然而，大多数脊椎动物睡眠研究的一个警告是，他们依赖于夜间哺乳动物，如小鼠和大鼠来模拟睡眠行为。这些动物是稳态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昼夜哺乳动物（如人类）保持一致。我将利用相对简单但保守的神经回路的斑马鱼，昼夜脊椎动物，测试几个假设的作用，转化生长因子α（TGF-α）在调节睡眠和昼夜行为。首先，我将测试的假设，TGF-α作为一个昼夜信号，以抑制运动活动，通过使用高通量运动活动和唤醒阈值测定进行增益和功能遗传实验的损失。其次，我将利用斑马鱼幼虫的顺从性高通量药理学管理和行为测定，以确定介导的TGF-α依赖的行为在斑马鱼的分子机制。第三，我将描述产生和响应TGF-α信号的细胞，并测试TGF-α信号激活促进睡眠的神经群体和沉默促进觉醒的神经群体的假设。这些实验将有助于阐明TGF-α介导昼夜节律信号调节昼夜动物清醒/睡眠状态的遗传和神经机制。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.