Proximal prospective associations between circadian alignment, reward function and alcohol use in adolescents

项目摘要 各种证据表明，睡眠和昼夜节律影响酒精使用的发展 青少年期疾病（AUDs）。然而，这些关系背后的确切机制 睡眠/昼夜节律功能和Au仍然是未知的，因此是本申请的焦点。我们特别 假设青少年睡眠和昼夜节律紊乱导致奖励功能失调（即， 减少的冲动控制和增加的奖赏敏感性），这又导致增加的Au。我们 拟议的研究将检查睡眠/昼夜因素，奖励功能， 和Au，从而为AUD的新预防和干预方法的开发提供信息。在 特别是，我们提出了一个前瞻性的，混合方法的方法在150个12年级（17-19岁/o）的样本 学生每周报告Au。新的设计结合了最先进的体内方法（以增强 生态有效性和精确性，同时限制回忆偏差）和实验室方法（以提高科学严谨性）。 具体而言，我们将收集（1）8天的生态瞬时评估（自我报告的渴望和Au），（2） 睡眠和内源性昼夜节律定时的客观测量（体动记录、唾液褪黑激素、时钟基因 表达），和（3）奖励功能的客观测量（行为和fMRI）。我们还将评估自我- 在3个月和6个月的随访中报告了睡眠/昼夜节律因素、奖励功能和Au，使我们能够检查 我们感兴趣的关键结构之间的近端和纵向关联。我们的设计充分利用了 “自然实验”的工作日-周末的睡眠变化，昼夜节律，和Au。评估 周末前后的睡眠/昼夜节律因素将使我们能够检查昼夜节律调整是否 和/或睡眠持续时间前瞻性地预测周末Au，反之亦然。包括周末前的行为 功能磁共振成像任务将使我们能够评估奖励功能的客观测量作为干预变量 睡眠/昼夜节律因素和Au之间的关系。具体目标1是确定近端前瞻性 睡眠/昼夜因素、奖赏功能和Au之间的关联。具体目标2是建立 睡眠/昼夜因素、奖赏功能和Au之间的远端关联程度。 这个创新的建议将严格测试我们的新概念模型，提出一个昼夜节律奖励路径， 青少年AUD和检查近端和更远端的时间范围。它将产生重大影响， 公共卫生意义，有可能阐明Au问题的新机制， 发育阶段证明睡眠/昼夜节律对Au的影响将提供科学依据 用于测试辅助睡眠/昼夜节律干预以预防AUD。

PROJECT SUMMARY A variety of evidence suggests that sleep and circadian rhythms influence the development of alcohol use disorders (AUDs) during adolescence. However, the precise mechanisms underlying the relationships between sleep/circadian function and AU remain unknown, and thus are the focus of this application. Specifically, we hypothesize that adolescent sleep and circadian disturbances result in dysregulated reward function (i.e., diminished impulse control and increased reward sensitivity), which in turn leads to increased AU. Our proposed study will examine the short-term causal dynamics between sleep/circadian factors, reward function, and AU, thereby informing the development of novel prevention and intervention approaches for AUDs. In particular, we propose a prospective, mixed-methods approach in a sample of 150 12th grade (17-19 y/o) students reporting weekly AU. The novel design combines state-of-the-art in vivo methods (to enhance ecological validity and precision, while limiting recall bias) and laboratory methods (to enhance scientific rigor). Specifically, we will collect (1) 8 days of ecological momentary assessment (self-reported craving and AU), (2) objective measurements of sleep and endogenous circadian timing (actigraphy, salivary melatonin, clock gene expression), and (3) objective measures (behavioral and fMRI) of reward function. We will also assess self- reported sleep/circadian factors, reward function, and AU at 3- and 6-month follow-ups, allowing us to examine both proximal and longitudinal associations between our key constructs of interest. Our design capitalizes on the “natural experiment” of weekday-weekend changes in sleep, circadian rhythms, and AU. Assessing sleep/circadian factors both pre- and post-weekend will enable us to examine whether circadian alignment and/or sleep duration prospectively predict weekend AU, and vice versa. Including pre-weekend behavioral and fMRI tasks will allow us to evaluate objective measures of reward function as intervening variables between sleep/circadian factors and AU. Specific Aim 1 is to establish the extent of proximal prospective associations between sleep/circadian factors, reward function, and AU. Specific Aim 2 is to establish the extent of distal associations between sleep/circadian factors, reward function, and AU. This innovative proposal will rigorously test our novel conceptual model proposing a circadian-reward path to adolescent AUD and examining both proximal and more distal timeframes. It will have substantial impact and public health significance, with the potential to elucidate novel mechanisms of AU problems at a key developmental stage. Demonstration of a sleep/circadian influence on AU would provide scientific justification for testing empirically-supported sleep/circadian interventions to AUD prevention.