Molecular rhythms and substance abuse vulnerability in adolescents

项目摘要 物质使用障碍（SUD）在美国仍然是一个大问题。CARRS的主要目标 中心是了解如何睡眠和昼夜节律的特点和环境干扰在青春期 导致更容易滥用药物。我们预测，生物学和 环境因素导致这种风险增加。中心项目3的目标是提供 在人类受试者和啮齿动物模型中进行的转化研究， 昼夜节律和睡眠中断会改变奖赏回路。我们还将测试潜在的治疗方法， 青少年的社会时差可能会降低SUD的风险。在这里，我们将使用一种非侵入性的方法来评估 使用从毛囊收集的皮肤细胞的人类分子钟，已经完全优化， 分子节奏的量度。然而，迄今为止还没有研究从青少年培养细胞的分子， 节律测量，与其他睡眠、奖赏和昼夜节律测量相关的分子节律，或 研究了潜在的治疗化合物对这些节律的影响。在项目3中，我们将利用 从人类受试者的P1/2中收集毛囊样品并将该数据与彻底的节律联合收割机结合， 睡眠、认知和奖励数据。我们还将确定分子测量 与P4/5中收集的行为和电生理数据相关。此外，我们正在测试 对分子节律的潜在药理学干预将为未来的临床试验提供信息。我们也 使用啮齿类动物提供响应于特定的免疫应答的感兴趣的脑区域中的详细基因和蛋白质表达， 对睡眠和昼夜节律的控制。我们想回答的问题是：（1）睡眠和 昼夜节律表型和成瘾易感性与分子节律有关？这将在两个测试 人类和大鼠通过细胞培养研究。(2)昼夜节律的分子机制是什么 和睡眠中断的组合或独立导致药物滥用的脆弱性增加， 青少年？这将在核心B中产生的啮齿动物中进行测试，这些啮齿动物经历了特定的睡眠， 在PFC和NAc中进行昼夜节律操作，然后进行RNA测序和蛋白质组学。(3)有 药理学干预将改变和/或放大人类受试者的分子节律， 对有生理时钟型延迟和昼夜节律失调的青少年有用吗？这将直接在细胞中进行测试 文化总之，这些研究可以为青少年提供新的治疗方法， 物质使用障碍

PROJECT SUMMARY Substance use disorder (SUD) remains a large problem in the United States. The primary goal of the CARRS Center is to understand how sleep and circadian rhythm traits and environmental disruptions during adolescence lead to increased vulnerability for substance abuse. We predict that a combination of biological and environmental factors contribute to this increased risk. The goal of Project 3 in the Center is to provide translational studies in both human subjects and rodent models that determine mechanistic details of how circadian rhythm and sleep disruption alter reward circuitry. We will also test potential therapeutic treatments for social jet lag in adolescents that might mitigate risk for SUD. Here we will use a noninvasive method of assessing the human molecular clock using skin cells collected from hair follicles, which has been fully optimized for the measure of molecular rhythms. However, no study to date has cultured cells from adolescents for molecular rhythm measurement, associated molecular rhythms with other sleep, reward and circadian measures, or investigated the effects of potentially therapeutic compounds on these rhythms. In Project 3 we will be utilizing hair follicle samples collected in P1/2 from human subjects and combine this data with the thorough rhythm, sleep, cognition, and reward data collected in those projects. We will also determine how molecular measures in rodents correlate with behavioral and electrophysiological data collected in P4/5. Moreover, we are testing potential pharmacological interventions on molecular rhythms which will inform future clinical trials. We are also using rodents to provide detailed gene and protein expression in brain regions of interest in response to specific manipulations of sleep and circadian rhythms. The questions we want to answer are: (1) How are sleep and circadian rhythm phenotypes and addiction vulnerability related to molecular rhythms? This will be tested in both humans and rats through cell culture studies. (2) What are the molecular mechanisms by which circadian rhythm and sleep disruptions in combination or independently lead to increased vulnerability for substance abuse in adolescents? This will be tested in rodents generated in Core B that have experienced specific sleep and circadian manipulations followed by RNA sequencing and proteomics in PFC and NAc. (3) Are there pharmacological interventions that will shift and/or amplify molecular rhythms in human subjects that could be useful for adolescents with delayed chronotypes and circadian misalignment? This will be directly tested in cell culture. Taken together, these studies could point towards novel treatments for adolescents that are at risk for substance use disorders.