Mechanistic Studies on the Impact of Sleep Deprivation on Gene Regulation

项目摘要 睡眠剥夺对个人健康和公共安全以及经济发展构成越来越大的威胁。 由于生产力损失、交通事故、职业事故和医疗费用飞涨而造成的负担。 受睡眠剥夺影响的人数出现了惊人的增长， 大约35%的美国成年人和70%的青少年报告睡眠不足。睡眠 剥夺会导致记忆力和表现的严重损害， 神经系统疾病和增加疾病的风险，特别是神经退行性疾病，如阿尔茨海默氏症 疾病考虑到大量的人受到睡眠剥夺的影响， 就疾病和痴呆症而言，睡眠不足的后果，识别细胞 睡眠剥夺的后果，并确定具体的分子目标和过程的影响。 最近的研究表明，急性睡眠剥夺对记忆的影响发生在细胞和神经系统。 突触水平，虽然睡眠剥夺发挥这些作用的具体机制仍然存在 不太了解。海马体是大脑中记忆的关键区域， 急性睡眠剥夺的影响。以前，我们发现睡眠剥夺会减少蛋白质的合成， 导致突触可塑性的损伤和缺陷。我们假设睡眠 剥夺针对影响基因表达调节的多个过程，包括 转录、RNA加工和定位以及蛋白质合成的变化。这一目标 他们的建议是确定睡眠剥夺影响基因的分子和细胞机制， 调节和定义海马内受影响的亚区和细胞类型。在具体目标1中， 关注睡眠剥夺影响蛋白质合成的信号通路， 长期记忆和突触可塑性，重点是识别对睡眠不足的恢复机制。在 具体目标2，我们研究睡眠剥夺对RNA命运在亚细胞水平的影响， 明确地详细描述了睡眠剥夺对可用于翻译的mRNA库的影响。具体目标 3，我们采用最先进的技术来确定睡眠剥夺对整个亚区域的影响， 海马和单个细胞类型内的图像，提供了海马的详细空间图和细胞特征。 睡眠剥夺的影响。从我们的综合提案整合体内行为的结果， 操作，以减轻睡眠剥夺对记忆的影响，亚细胞分析的影响， 睡眠剥夺对RNA命运和蛋白质合成的影响，以及睡眠的细胞特异性特征的鉴定 剥夺，将提供重要的见解睡眠剥夺对记忆的负面影响， 这可能导致治疗方法的发展，以抵消睡眠不足的后果， 认知和神经退行性疾病。

Project Summary Sleep deprivation presents an increasing threat to individual health and public safety as well as an economic burden due to lost productivity, traffic accidents, occupational accidents, and skyrocketing healthcare costs. There has been an astonishing rise in the number of individuals affected by sleep deprivation with approximately 35% of U.S. adults and a staggering 70% of teenagers reporting insufficient sleep. Sleep deprivation induces significant impairments in memory and performance, aggravates psychiatric and neurological disorders and increases disease risk, especially neurodegenerative disorders such as Alzheimer’s disease. Given the significant number of people affected by sleep deprivation, and the potentially devastating consequences of sleep loss in terms of disease and dementia, it is essential to identify the cellular consequences of sleep deprivation and to define the specific molecular targets and processes impacted. Recent research suggests that the influence of acute sleep deprivation on memory occurs at the cellular and synaptic level, although the specific mechanisms through which sleep deprivation exerts these effects remain poorly understood. The hippocampus, a critical brain region for memory, is particularly susceptible to the effects of acute sleep deprivation. Previously, we found that sleep deprivation decreases protein synthesis in the hippocampus leading to impairments and deficits in synaptic plasticity. We hypothesize that sleep deprivation targets multiple processes that affect the regulation of gene expression, which is comprised of changes in transcription, RNA processing and localization, and protein synthesis. The objectives of this proposal are to define the molecular and cellular mechanisms through which sleep deprivation impacts gene regulation and to define the affected subregions and cell types within the hippocampus. In Specific Aim 1, we focus on the signaling pathways through which sleep deprivation affects protein synthesis to adversely impact long-term memory and synaptic plasticity with a focus on identifying mechanisms of resilience to sleep loss. In Specific Aim 2, we investigate the effects of sleep deprivation on RNA fate at the subcellular level and explicitly detail the effects of sleep deprivation on the pool of mRNA available for translation. In Specific Aim 3, we employ state of the art techniques to define the impact of sleep deprivation across subregions within the hippocampus and within individual cell types providing a detailed spatial map and cellular signature of the effects of sleep deprivation. The results from our comprehensive proposal integrating in vivo behavioral manipulations to mitigate the effects of sleep deprivation on memory, the subcellular analysis of the effects of sleep deprivation on RNA fate and protein synthesis, and the identification of cell specific signatures of sleep deprivation, will provide significant insights into the negative impacts of sleep deprivation on memory, potentially leading to the development of therapeutics to counteract the consequences of sleep loss on cognition and neurodegenerative disorders.