The Molecular and Cellular Basis of the Sleep Homeostat

睡眠稳态的分子和细胞基础

• 批准号: 10896547
• 负责人: Ravi Allada
• 金额: $ 55.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10896547
• 关键词: Address; Alzheimer' s Disease; Animal Model; Behavior; Brain; Brain Diseases; Brain region; Caring; Cells; Central Nervous System; Diabetes Mellitus; Disease; Drosophila genus; Eating; Exhibits; Genes; Genetic; Genomics; Jellyfish; Label; Link; Logic; Longevity; Mental Depression; Molecular; Neurons; Obesity; Organism; Partner in relationship; Proteins; Proteomics; Resolution; Role; Science; Sleep; Sleep Deprivation; Taxes; Wakefulness; circadian regulation; experience; innovation; insight; memory consolidation; nervous system disorder; neuromechanism; single-cell RNA sequencing; sleep regulation; tool; transcriptomics

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.

项目摘要 了解我们为什么睡觉仍然是科学界最经久不衰的谜团之一。几乎每一次 被检查的生物体，即使是缺乏集中神经系统的水母，也显示出一种恢复能力 类似睡眠的状态。当我们睡着的时候，我们不能吃，不能交配，不能保护自己不受捕食者的伤害，也不能关心 我们的年轻人。睡眠不足会导致阿尔茨海默氏症和抑郁症等脑部疾病， 甚至大脑以外的疾病，如糖尿病和肥胖症。睡眠是自平衡的 调节，即睡眠是由先前清醒经验的持续时间和强度驱动的。然而， 睡眠稳态的机制基础仍不清楚。觉醒是如何对 大脑？稳态是如何感觉到这些影响的？稳态是如何触发睡眠的？ 睡眠是如何恢复大脑的？在大脑功能中几乎是独一无二的，睡眠需要 广泛分布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。 用一个简单的果蝇动物模型来研究睡眠恒定器。我们将应用创新 以基因为靶点的转录和蛋白质组学方法，如单细胞RNA 紧凑果蝇脑中的测序和酶邻近标记提供洞察力 单基因、单蛋白和单基因的睡眠依赖基因组和蛋白质组的变化 单元格分辨率。然后我们将利用果蝇遗传学的力量来评估功能 睡眠/清醒依赖的神经元和基因通过检查对睡眠的影响，包括 睡眠依赖功能，包括记忆巩固和寿命。根据我们的发现 控制睡眠昼夜节律的神经机制被广泛保守，我们 预测核心的动态平衡机制将同样被广泛保守。整合了 这些实验方法将产生将基因与神经元联系起来的机械性见解 行为，应该揭示对组件、逻辑和功能的变革性见解 睡眠稳态。