Genetic Analysis of Sleep Regulation

许多生理过程和行为都受到生物钟的控制，包括睡眠。然而， 生物钟调节这些行为的分子和电路机制仍然很差。 明白了。我们最近在果蝇中发现了一种新的分子，名为广醒(WAKE)，它发挥着一种 在调节睡眠开始的昼夜节律中起关键作用。在我们最初研究这种分子的拨款中，我们 确定觉醒在促进觉醒的时钟神经元中有节奏地表达，并作用于上调 GABAA受体，从而周期性地抑制这些细胞促进睡眠的活动。有趣的是，不断增长 来自我们小组和其他人的证据表明，与觉醒相关的分子在空间上广泛发挥作用 以与时间相关的方式组织信号复合体。此外，有一个WAKE的同源 哺乳动物，包括人类，它富含在昼夜节律起搏器视交叉上核中。因此， 从研究苍蝇觉醒中获得的见解可能有助于解开昼夜节律系统是如何调节睡眠的 哺乳动物也是如此。在延续上一次拨款时，我们建议加深我们对 通过研究额外的电路和分子，睡眠昼夜节律调节的潜在机制 尾流调节这一过程的机制。具体来说，我们计划实现以下目标：1) 研究WAKE在调节额外表达WAKE的昼夜节律时钟神经元中的作用，以及这是如何实现的 调节影响下游唤醒回路；2)识别和表征其他相互作用的蛋白质 通过觉醒来调节睡眠；以及3)研究神经胶质细胞如何与这些表达觉醒的昼夜节律相互作用 调节睡眠的时钟电路。我们将使用多学科方法，包括细胞生物学、遗传学、 行为和电生理测试，以执行这些研究。睡眠的昼夜节律失调 估计影响了美国数百万人，并被牵连到对健康和 生产力。更好地了解生物钟是如何调节睡眠的，可能会为 以确定治疗这些疾病的新疗法。

Many physiological processes and behaviors are under circadian clock control, including sleep. However, the molecular and circuit mechanisms underlying how the circadian clock regulates these behaviors remain poorly understood. We recently identified a novel molecule in Drosophila named WIDE AWAKE (WAKE) that plays a key role in mediating the circadian timing of sleep onset. In our original grant studying this molecule, we determined that WAKE is rhythmically expressed in arousal-promoting clock neurons and acts to upregulate GABAA receptors, thus cyclically suppressing the activity of these cells to promote sleep. Interestingly, growing evidence from our group and others suggests that WAKE-related molecules broadly function to spatially organize signaling complexes in a time-dependent manner. Moreover, there is a single homolog of WAKE in mammals, including humans, which is enriched in the circadian pacemaker suprachiasmatic nucleus. Thus, insights gained from studying WAKE in flies may help unravel how the circadian system regulates sleep in mammals as well. In this renewal of our previous grant, we propose to further our understanding of the mechanisms underlying the circadian modulation of sleep, by studying additional circuit and molecular mechanisms by which WAKE modulates this process. Specifically, we plan to carry out the following aims: 1) study the role of WAKE in regulating additional WAKE-expressing circadian clock neurons, and how this regulation impacts downstream arousal circuits; 2) identify and characterize additional proteins that interact with WAKE to modulate sleep; and 3) examine how glia may interact with these WAKE-expressing circadian clock circuits to regulate sleep. We will use a multidisciplinary approach, including cell biological, genetic, behavioral, and electrophysiological assays, to perform these studies. Circadian dysregulation of sleep is estimated to impact millions of people in the U.S. and has been implicated in adverse effects on health and productivity. Developing a better understanding of how the circadian clock regulates sleep could pave the way for identifying novel therapies to treat these disorders.