Sleep and Circadian Rhythm Disorders After Traumatic Brain Injury

项目摘要/摘要 在美国，每年有近200万人遭受创伤性脑损伤(TBI)。 在所有与伤害相关的死亡中，脑外伤是一个促成因素，超过40%的 幸存者遭受长期的损害，包括睡眠和昼夜节律紊乱 (SCRD)。这些疾病可能是导致或加剧终生代谢风险升高的基础 在脑外伤患者中发现精神障碍、情绪障碍和神经退行性疾病。而当 SCRD的患病率早已在脑外伤患者中得到认可，并在动物身上进行了总结 模型中，在分子和电路水平上导致这些紊乱的机制是 未知。这项建议利用果蝇的黑腹果蝇遗传模型来识别 与脑损伤诱发的SCRDS相关的基因和确定睡眠在脑损伤中的作用 介导脑外伤的分子和生理结果。基于已发布的和 初步数据，我们假设脑外伤引起的炎症反应扰乱了昼夜节律 和大脑中的睡眠调节系统，形成一个正反馈环路，延长 发炎。我们已经建立了一个可调的、头部特定的果蝇TBI范例 导致慢性睡眠减少和运动行为昼夜节律性降低 受伤。在这个模型中，轻微的损伤会导致SCRD，但不会影响死亡率。我们试图回答 两个关键问题：(目标1)睡眠和昼夜节律重塑的基因驱动因素是什么 创伤性脑损伤后的各个阶段？(目标2)针对睡眠和昼夜节律紊乱的干预措施 受伤后能改善脑损伤的预后吗？在目标1中，我们将进行候选击倒/击倒 筛选促炎基因以确定与睡眠和睡眠有关的基因 受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 颅脑损伤后雌雄果蝇的睡眠结构都发生了变化。我们将使用这些数据来设计一个 颅脑损伤后不同阶段的睡眠操作范式研究 脑外伤影响寿命、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 将结合用于生理特征和睡眠操作的遗传工具，以及 苍蝇模型中提供的行为分析。使用一种新的果蝇脑损伤模型将允许 无与伦比的时间和空间控制的基因操作，不仅识别哪些 基因在SCRD中很重要，但它们在什么组织中起作用(S)。拟议的研究将是 因为它将定义将基本大脑过程与脑损伤联系起来的遗传路径 为未来的调查奠定基础，具有翻译意义。

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.