Genetic, molecular, and neural mechanisms of alcohol-induced effects on sleep

- 项目概要/摘要- 酒精的使用和滥用影响到数百万人，对个人和公共健康造成巨大损失， 经济其中一个最报告的后果，积极使用酒精和恢复酒精使用障碍 失眠，包括入睡困难（睡眠潜伏期增加），保持睡眠，或实现高， 优质睡眠酒精引起的失眠高度预测复发，使其成为持续性失眠的重要驱动力。 酗酒为了改善酒精使用障碍的治疗和预防复发，我们需要了解 酒精相关的睡眠问题的机制，这是目前未知的。果蝇提供了一种宝贵的 由于这些机制与睡眠和酒精反应的翻译相关性， 以及它们的高规模经济。我的初步数据显示，单次高剂量酒精暴露 增加睡眠潜伏期，即入睡所需的时间，至少持续六个晚上。根据这些发现，在目标1中， 我建议确定酒精引起的睡眠延迟的遗传贡献。我将通过检查人类 全基因组关联研究确定的与酒精和睡眠表型相关的基因。我会 在果蝇神经系统中测试这些候选基因，检查它们对酒精诱导的神经系统的必要性。 睡眠效果在目标2中，我将确定神经元和保守的神经递质系统在酒精中的作用， 导致睡眠中断。我将利用我们实验室发现的几百个未鉴定的神经元的子集 影响睡眠潜伏期和酒精反应。我将研究这些在酒精诱导的睡眠中的作用 延迟和确定调节睡眠，酒精反应及其相互作用所需的神经递质 在这些神经元中。总之，这些实验将确定潜在的遗传和分子靶点， 酒精使用障碍及其相关的睡眠障碍。虽然我有很强的学术背景， 实验室经验集中在啮齿动物成瘾，我需要额外的培训，以发展为一个独立的 研究员作为一名研究生，我的目标是在神经遗传学，果蝇模型系统， 酒精滥用的神经生物学机制，行为分析，以及研究这些主题的工具。这 基金会将准备我追求我的长期职业目标，获得终身教职。我预计 我的初步数据加上这里描述的目标将产生至少一个科学手稿， 并为今后的资助申请提供初步数据。在此奖学金提供的培训下，我将 完善技术技能，加深我在酒精研究方面的专业知识，并在实验选择方面变得独立， 设计、分析和沟通。这些技能将推动我走向职业生涯的轨道， 独立研究者和教育者。在促进这些目标的同时，拟议的项目还将 酒精引起的睡眠丧失现象的必要的第一个机械光，这是一个关键的贡献者 人类持续饮酒的证据

–––– Project Summary/Abstract ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Alcohol use and abuse affect millions of people, exacting immense tolls on personal and public health and the economy. One of the most reported consequences of active alcohol use and recovery from alcohol use disorder is insomnia, which includes difficulties falling asleep (increased sleep latency), staying asleep, or achieving high- quality sleep. Alcohol-induced insomnia is highly predictive of relapse, making it an important driver of persistent alcohol abuse. For improved treatment of alcohol use disorder and prevention of relapse, we need to understand the mechanisms of alcohol-associated sleep problems, which are currently unknown. Drosophila offer a valuable approach to unraveling these mechanisms thanks to their translational relevance for sleep and alcohol responses and their high economy of scale. My preliminary data show that a single, high-dose alcohol exposure robustly increases sleep latency, the time it takes to fall asleep, for at least six nights. Based on these findings, in Aim 1, I propose determining the genetic contributions to alcohol-induced sleep delays. I will do so by examining human genes, identified with Genome-Wide Association Studies, that are linked to alcohol and sleep phenotypes. I will test these candidate genes in the Drosophila nervous system, examining their necessity for alcohol-induced sleep effects. In Aim 2, I will determine the roles of neurons and conserved neurotransmitter systems in alcohol- induced sleep disruptions. I will utilize a subset of a few hundred uncharacterized neurons that our lab has found to affect both sleep latency and alcohol responses. I will examine the role of these in alcohol-induced sleep delays and determine the neurotransmitters required for regulating sleep, alcohol responses, and their interaction in these neurons. Together, these experiments will identify potential genetic and molecular targets for treating alcohol use disorders and their associated sleep disturbances. While I have a strong academic background and laboratory experience focused on rodent addiction, I require additional training to develop as an independent researcher. My goals as a graduate student are to build strength in neurogenetics, Drosophila model systems, the neurobiological mechanisms of alcohol abuse, behavioral analysis, and tools for studying these topics. This foundation will prepare me to pursue my long-term career goal of obtaining a tenured faculty position. I anticipate that my preliminary data plus the aims described here will produce at least one scientific manuscript each while also supplying preliminary data for future grant applications. Under the training provided by this fellowship, I will refine technical skills, deepen my expertise in alcohol research, and become independent in experimental choice, design, analysis, and communication. These skills will propel me on my trajectory towards a career as an independent researcher and educator. While facilitating these goals, the proposed project will also shed necessary first mechanistic light on the phenomenon of alcohol-induced sleep loss, which is a critical contributor to persistent human alcohol use.