Sleep and Circadian Rhythm Disorders After Traumatic Brain Injury

项目总结/摘要 在美国，每年有近200万人遭受创伤性脑损伤（TBI）。 TBI是三分之一与伤害有关的死亡的一个促成因素， 幸存者遭受长期损害，包括睡眠和昼夜节律紊乱 （SCRDs）。这些疾病可能是代谢性疾病终生风险升高的基础或加剧 在TBI患者中发现的精神障碍、情绪障碍和神经退行性疾病。而 长期以来，在TBI患者中普遍存在SCRDs， 模型，这些疾病在分子和电路水平上的机制是 未知这项建议利用果蝇的遗传模型来识别 基因，有助于TBI诱导的SCRDs，并确定睡眠的作用， 介导TBI的分子和生理结果。根据出版的和 根据初步数据，我们假设TBI诱导的炎症反应破坏了昼夜节律， 和睡眠调节系统，形成一个积极的反馈回路， 炎症我们已经建立了一个可调的，头部特异性果蝇TBI范式， 导致慢性睡眠减少和运动行为的昼夜节律性降低， 损伤在该模型中，轻度损伤诱导SCRD而不影响死亡率。我们寻求答案 两个关键问题：（目标1）睡眠和昼夜节律重塑的遗传驱动因素是什么？ TBI后的不同阶段？(Aim 2）针对睡眠和昼夜节律紊乱的干预措施 是否能改善TBI的预后？在目标1中，我们将进行候选人击倒/击倒 筛选促炎基因，以确定有助于睡眠和 损伤后的昼夜节律紊乱。在目标2中，我们将进行第一次全面分析， TBI后雌雄果蝇睡眠结构的变化。我们将使用这些数据来设计一个 TBI后不同阶段的睡眠操作模式，以检查TBI后睡眠的变化 TBI影响寿命、运动功能以及神经元和神经胶质的健康。为了实现这些目标，我 将结合联合收割机基因工具，用于生理特征和睡眠控制， 在果蝇模型中可用的行为分析。使用新的果蝇TBI模型将允许 无与伦比的时间和空间控制的基因操作，以确定不仅是 基因在SCRDs中很重要，但它们在什么组织中起作用。拟议的研究将 它将定义将基本大脑过程与TBI联系起来的遗传途径， 为今后的翻译研究提供基础。

PROJECT SUMMARY/ABSTRACT Almost two million people sustain a traumatic brain injury (TBI) in the United States every year. TBI is a contributing factor to one-third of all injury-related deaths, and more than 40% of survivors suffer long-term impairments, including sleep and circadian rhythm disorders (SCRDs). These disorders may underlie or exacerbate the lifetime elevated risks of metabolic disorders, mood disorders, and neurodegenerative disease found in TBI patients. While the prevalence of SCRDs has long been recognized in TBI patients and recapitulated in animal models, the mechanisms underlying these disorders at the molecular and circuit levels are unknown. This proposal exploits the Drosophila melanogaster genetic model to identify genes that contribute to TBI-induced SCRDs and to determine the role of sleep in mediating molecular and physiological outcomes of TBI. Based on published and preliminary data, we hypothesize that TBI-induced inflammatory responses disrupt the circadian and sleep regulatory systems in the brain, forming a positive feedback loop that prolongs inflammation. We have established a tunable, head-specific Drosophila TBI paradigm that results in chronic sleep reduction and reduced circadian rhythmicity of locomotor behavior after injury. In this model, mild injury induces SCRD without affecting mortality. We seek to answer two key questions: (Aim 1) What are the genetic drivers of sleep and circadian remodeling at various phases after TBI? (Aim 2) Can interventions that target sleep and circadian disruption after injury improve TBI outcomes? In Aim 1 we will conduct a candidate knockdown/knockout screen of proinflammatory genes to identify genes that contribute to aspects of sleep and circadian disruption after injury. In Aim 2 we will conduct the first comprehensive analysis of sleep architecture changes after TBI in both sexes of flies. We will use this data to design a paradigm of sleep manipulation at various phases after TBI to examine how sleep changes after TBI affect longevity, locomotor function, and neuronal and glial health. To pursue these aims, I will combine genetic tools for physiological characterization and for sleep manipulation as well a behavioral assays available in the fly model. Use of a novel Drosophila TBI model will allow unparalleled temporally and spatially controlled genetic manipulations to identify not only which genes are important in SCRDs, but in what tissue(s) they act. The proposed study will be impactful as it will define genetic pathways that link fundamental brain processes to TBI and provide the foundation for future investigation with translational implications.