Molecular rhythms and substance abuse vulnerability in adolescents

项目总结 物质使用障碍(SUD)在美国仍然是一个大问题。CARRS的主要目标是 中心是为了了解青春期的睡眠和昼夜节律特征以及环境破坏 导致药物滥用的脆弱性增加。我们预测，生物和生物的结合 环境因素导致了这种风险的增加。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翻译研究，确定了机制细节如何 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 青少年的社交时差可能会降低罹患SUD的风险。在这里，我们将使用一种非侵入性方法来评估 使用从毛囊中收集的皮肤细胞的人类分子钟，它已经为 分子节律的量度。然而，迄今为止还没有研究将青少年的细胞培养成分子细胞。 节律测量，将分子节律与其他睡眠、奖励和昼夜节律测量相关联，或 研究了潜在的治疗性化合物对这些节律的影响。在项目3中，我们将利用 从受试者的P1/2中采集毛囊样本，并将该数据与彻底的节律相结合， 在这些项目中收集的睡眠、认知和奖励数据。我们还将确定分子测量如何 与在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物干预将为未来的临床试验提供信息。我们也是 利用啮齿动物在大脑感兴趣区域提供详细的基因和蛋白质表达，以响应特定的 对睡眠和昼夜节律的控制。我们想要回答的问题是：(1)睡眠和 与分子节律有关的昼夜节律表型和成瘾易感性？这将在两个方面进行测试 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？ 睡眠中断联合或单独导致药物滥用的易感性增加 青少年？这将在核心B产生的啮齿动物身上进行测试，这些啮齿动物经历了特定的睡眠和 在PFC和NAC中，昼夜节律操作之后是RNA测序和蛋白质组学。(3)有没有 药物干预将改变和/或放大人类受试者的分子节律 对时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。综上所述，这些研究可能指向针对有患心脏病风险的青少年的新治疗方法。 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.