Forgetting to sleep: metabolic consequences of sleep loss and associated neurocognitive deficits

项目摘要/摘要： 睡眠不足日益被认为是老年性痴呆的一个重要因素，影响广泛 关于健康和认知。几十年来，睡眠缺失的程度一直在不断增加，现代的 由于工作时间、社交时差、父母等因素导致睡眠缩短的社会 责任和技术。睡眠不足与衰老表型有明显的相互作用，包括在 阿尔茨海默氏症和帕金森氏症，但也被怀疑是年轻皈依的危险因素 人口到晚年的痴呆症。例如，睡眠不足会让年轻的人看起来很老。 而年轻人群的高质量睡眠可能会在晚年起到神经保护作用。然而，几乎没有什么是 已知睡眠与机体新陈代谢相互作用的不同机制以及如何 这种干扰与衰老表型重叠。此外，量化的认知评估具有 研究表明，个体不同程度地易受睡眠不足的影响，而这些睡眠缺失具有抵抗力或 “易受影响”的特征是相似的，因为它们超越了时间实验的界限， 可遗传的。在这里，我们建议描述血液中代谢物的变化作为神经行为反应的函数 通过利用之前在受控全面睡眠剥夺(TSD)研究中收集的数据来减少睡眠。我们 假设TSD的代谢物标志物将与我们先前研究中发现的类似 睡眠限制以及已发表的衰老研究，以及代谢物浓度和 节律对个体的神经行为反应很敏感。我们将在以下位置测试我们的总体假设 三个独立但重叠的目标旨在探索神经认知反应之间的关系 对于TSD，昼夜代谢节律的变化，以及睡眠缺失的新生物标记物。 目标1.将已知的睡眠缺失血液代谢标记物的变化定义为 使用靶向代谢组学方法研究完全睡眠剥夺对神经行为的易感性。 假设：我们希望观察到那些表明睡眠欠债的代谢物的迟钝反应 根据PVT反应定义的对失眠有抵抗力的个体群体。 目标2.使用全面和非靶向的代谢组学方法来阐明新的指标 睡眠脆弱和完全睡眠不足的问题。假设：代谢物的数量增加 响应于TSD的SR将被检测到与之前的标记相比较，并且这些标记将重叠 与帕金森氏症和阿尔茨海默病等神经认知缺陷的现有标记物。 目标3.建立完全睡眠剥夺对代谢物昼夜节律的影响 波动，以及与神经行为易感性有关的不同代谢物模式。 假设：在那些敏感度增加的人中，昼夜节律的幅度会增强，而且 与观察到的基因表达变化类似，对TSD耐药的个体的反应将会降低。

Project Summary / Abstract: Sleep loss is increasingly recognized as a significant factor in aging-related dementias with widespread impact on health and cognition. The extent of sleep loss has increased consistently for several decades, with modern society suffering from shortened sleep due to factors such as work hours, `social jetlag', parental responsibilities and technology. Sleep loss has a demonstrated interaction with aging phenotypes, including in Alzheimer's and Parkinson's diseases, but is also suspected to be a risk factor for conversion of younger populations to dementias later in life. For example, sleep loss makes the `young seem old' with respect to cognition, while quality sleep in younger populations may be neuroprotective later in life. However, little is known about the distinct mechanisms by which sleep interacts with organismal metabolism and how this disruption overlaps with aging phenotypes. Furthermore, quantitative cognitive assessments have shown that individuals are differentially susceptible to sleep loss, and these sleep loss `resistant' or `susceptible' characteristics are trait-like in that they transcend temporal experimental boundaries and are heritable. Here we propose to profile metabolite changes in blood as a function of neurobehavioral response to sleep loss by leveraging data previously collected in a controlled total sleep deprivation (TSD) study. We hypothesize that the metabolite markers of TSD will be similar to those found previously in our studies of sleep restriction as well as published aging studies, and that the metabolite concentrations and rhythms will be sensitive to individual neurobehavioral response. We will test our overall hypothesis in three independent but overlapping aims designed to probe the relationship between neurocognitive response to TSD, changes in diurnal metabolite rhythms, and novel biomarkers of sleep loss.  Aim 1. To define the variation in known blood metabolic markers of sleep loss as function of neurobehavioral susceptibility to total sleep deprivation using a targeted metabolomics approach. Hypothesis: We expect to observe a blunted response in those metabolites indicative of sleep debt in a population of individuals who are resistant to sleep loss as defined by PVT response.  Aim 2. To use a comprehensive and untargeted metabolomics approach to elucidate novel indicators of sleep vulnerability and total sleep deprivation. Hypothesis: An increased number of metabolites responsive to TSD compared to previous markers of SR will be detected, and that these markers will overlap with existing markers in neurocognitive deficits such as Parkinson's and Alzheimer's disease.  Aim 3. To establish the impact of total sleep deprivation on diurnal rhythms of metabolite fluctuations, and the differential metabolite patterns with respect to neurobehavioral susceptibility. Hypothesis: Diurnal rhythms will be enhanced in amplitude in those with increased susceptibility, and that similar to observed changes in gene expression, the response will be reduced in individuals resistant to TSD.