Integration of sleep-regulating signals by the Drosophila Pars Intercerebralis

 描述(申请人提供)：虽然睡眠是生存和大脑正常运作的基本过程，但大脑如何决定何时入睡和醒来仍不清楚。越来越多的证据表明，由于睡眠在新陈代谢、免疫功能、记忆巩固等许多生理过程中的作用，睡眠剥夺和昼夜节律紊乱会导致慢性健康问题，从而进一步强调了睡眠的重要性。睡眠是来自两个系统的信息总和：生物钟和睡眠平衡系统。昼夜节律系统包含一个核心分子时钟，它通过视觉输入与一天中的时间同步，并在许多生理过程和行为中驱动24小时的节奏，包括睡眠。睡眠稳态系统发出信号，表明在长时间清醒后需要睡眠。动态平衡和昼夜节律信息是如何以及在哪里整合来驱动睡眠的，目前尚不清楚。这个建议的中心假设是，大脑间部(PI)是哺乳动物下丘脑的类似物，接收和整合昼夜节律和内环境平衡信息。PI参与控制睡眠时间和昼夜睡眠时间。睡眠时间是衡量体内平衡系统的一个指标。PI是控制休息-活动节律的昼夜节律输出通路的一部分，可能接受来自多个区域的输入，包括核心昼夜节律时钟和参与睡眠内稳的区域。PI的输出主要以不同的PI细胞群释放的多肽的形式存在。这些多肽信号可能在神经系统内外有不同的靶点。该项目的目的是1)确定PI细胞的放电是否反映了昼夜节律控制；2)确定PI细胞的放电行为是否也受睡眠稳态的影响；3)绘制昼夜节律和稳态控制的PI细胞之间可能的相互作用图。为了实现这些目标，将结合果蝇的遗传学和行为、电生理学和钙成像。了解睡眠-觉醒决策中涉及的神经回路将为如何影响这些决策以帮助健康睡眠和疾病预防打开新的假设之门。

 DESCRIPTION (provided by applicant): Although sleep is a fundamental process involved in survival and proper brain performance, how the brain determines when to fall asleep and wake up is still not understood. The importance of sleep is further underscored by accumulating evidence that sleep deprivation and circadian rhythm disruption contributes to chronic health issues, due to the role of sleep in many physiological processes including metabolism, immune function, memory consolidation and more. Sleep results from the sum of information from two systems: the circadian clock and the sleep homeostatic system. The circadian system contains a core molecular clock that is synchronized to the time of day by visual inputs and drives a 24h rhythm in many physiological processes and behaviors, including sleep. The sleep homeostasis system signals the need to sleep after prolonged wakefulness. How and where homeostatic and circadian information are integrated to drive sleep is not known. The central hypothesis of this proposal is that the Pars Intercerebralis (PI), an analog of the mammalian hypothalamus, receives and integrates both circadian and homeostatic information. The PI is involved in controlling both amount of sleep, which is a measure of the homeostatic system, as well as circadian timing of sleep. The PI is part of a circadian output pathway controlling rest-activity rhythms and likely receives input from multiple areas, including the core circadian clock and regions involved in sleep homeostasis. PI output is largely in the form of peptides released from distinct PI cell populations. These peptide signals may have diverse targets inside and outside the nervous system. The aims of this project are 1) To determine whether the firing of PI cells reflects circadian control; 2) To determine whether the firing behavior of PI cells is also affecte by the sleep homeostat and 3) To map the putative interactions of circadian and homeostatically controlled PI cells. To pursue these aims, a combination of Drosophila genetics and behavior, electrophysiology and calcium imaging will be used. Understanding the neural circuits involved in making sleep-wake decisions will open the door to novel hypotheses of how to influence these decisions to aid in healthy sleep and disease prevention.