The Molecular and Cellular Basis of the Sleep Homeostat

项目摘要 了解我们为什么睡觉仍然是科学中最持久的谜团之一。几乎每一 被检查的生物，即使是缺乏中枢神经系统的水母， 睡眠状态。睡觉时，我们不能吃东西，交配，保护自己免受捕食者或照顾 我们的孩子睡眠不足会导致阿尔茨海默氏症和抑郁症等脑部疾病， 甚至是大脑以外的疾病，比如糖尿病和肥胖症。睡眠是自我平衡的 受监管，即，睡眠由先前清醒经历的持续时间和强度驱动。然而，在这方面， 睡眠稳态的机制基础仍然不清楚。觉醒是如何征税的 大脑？内稳态器如何感知这些效应？体内平衡器是如何触发睡眠的？ 睡眠如何恢复大脑？在大脑的功能中，睡眠几乎是独一无二的，它需要大脑的 广泛的大脑区域的协调活动。我们的目标是揭示分子和电路基础 睡眠自我调节器的研究。我们将采用创新 基因靶向转录组学和蛋白质组学方法，如单细胞RNA 在紧凑的果蝇大脑中进行测序和酶促邻近标记， 睡眠依赖的基因组和蛋白质组变化，在单个基因，单个蛋白质， 细胞分辨率然后，我们将利用果蝇遗传学的力量来评估功能性 睡眠/觉醒依赖神经元和基因的影响，通过检查对睡眠的影响，包括 睡眠依赖的功能，包括记忆巩固和寿命。根据我们的发现 控制睡眠的昼夜节律调节的神经机制是广泛保守的，我们 预测核心自我平衡机制将同样广泛保守。的整合 这些实验方法将产生将基因与神经元联系起来的机制见解， 行为，并应揭示变革性的见解的组成部分，逻辑和功能， 睡眠平衡器

Project Summary Understanding why we sleep remains one of the most enduring mysteries in science. Nearly every organism examined, even jellyfish that lack a centralized nervous system, exhibits a restorative sleep-like state. While asleep, we cannot eat, mate, defend ourselves from predators or care for our young. Inadequate sleep contributes to brain disease such as Alzheimer's and depression, and even diseases outside of the brain, such as diabetes and obesity. Sleep is homeostatically regulated, i.e., sleep is driven by the duration and intensity of prior waking experience. However, the mechanistic basis of the sleep homeostat remains unclear. How does wakefulness tax the brain? How does the homeostat sense those effects? How does the homeostat trigger sleep? How does sleep restore the brain? Almost uniquely among brain functions, sleep requires the coordinated activity of widespread brain regions. We aim to reveal the molecular and circuit basis of the sleep homeostat using a simple animal model Drosophila. We will apply innovative genetically targeted transcriptomic and proteomic approaches such as single-cell RNA sequencing and enzymatic proximity labeling in the compact Drosophila brain to provide insights into sleep-dependent genomic and proteomic changes at single gene, single protein, and single cell resolution. We will then exploit the power of Drosophila genetics to assess the functional impact of sleep/wake dependent neurons and genes by examining effects on sleep including sleep-dependent functions including memory consolidation and lifespan. Based on our discovery that neural mechanisms controlling the circadian regulation of sleep are widely conserved, we predict that core homeostatic mechanisms will similarly be widely conserved. The integration of these experimental approaches will produce mechanistic insights that link gene to neuron to behavior and should reveal transformative insights into the components, logic, and function of the sleep homeostat.