Integration of sleep-regulating signals by the Drosophila Pars Intercerebralis

 描述（由申请人提供）：虽然睡眠是涉及生存和适当的大脑性能的基本过程，但大脑如何决定何时入睡和醒来仍然不清楚。越来越多的证据表明，睡眠剥夺和昼夜节律紊乱会导致慢性健康问题，这进一步强调了睡眠的重要性，这是由于睡眠在许多生理过程中的作用，包括新陈代谢，免疫功能，记忆巩固等。睡眠是由两个系统的信息总和产生的：生物钟和睡眠稳态系统。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小时节律，包括睡眠。睡眠稳态系统在长时间清醒后发出需要睡眠的信号。如何以及在何处整合稳态和昼夜节律信息来驱动睡眠尚不清楚。这个建议的中心假设是，Pars Intercerebralis（PI），哺乳动物下丘脑的类似物，接收和整合昼夜节律和稳态信息。PI参与控制睡眠量，这是一种自我平衡系统的测量，以及睡眠的昼夜节律。PI是控制休息-活动节律的昼夜输出通路的一部分，并且可能接收来自多个区域的输入，包括核心昼夜节律钟和涉及睡眠稳态的区域。PI输出主要以从不同PI细胞群释放的肽的形式。这些肽信号可能在神经系统内外具有不同的靶点。本项目的目的是：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到睡眠稳态的影响; 3）绘制昼夜节律和稳态控制的PI细胞之间的假定相互作用。为了实现这些目标，将使用果蝇遗传学和行为，电生理学和钙成像的组合。了解参与做出睡眠-觉醒决定的神经回路将为如何影响这些决定以帮助健康睡眠和疾病预防的新假设打开大门。

 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.