Determining the role of adolescent sleep and circadian factors on risk for substance use in a rat model

确定青少年睡眠和昼夜节律因素对大鼠模型物质使用风险的作用

• 批准号: 10442466
• 负责人: Mary M Torregrossa
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442466
• 关键词: Acute; Adolescence; Adolescent; Affect; Attention; Behavior; Behavioral; Brain; Calcium; Chronic; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Clinical; Cognition; Complement; Conflict (Psychology); Data; Development; Dopamine; Drug abuse; Drug usage; Electrophysiology (science); Environmental Risk Factor; Ethics; Exhibits; Female; Fiber; Functional disorder; Genetic; Human; Impulsivity; Individual; Individual Differences; Intervention; Lead; Marijuana; Measures; Modeling; Molecular; Neurons; Nicotine; Nucleus Accumbens; Outcome; Parents; Pattern; Persons; Pharmaceutical Preparations; Phase; Phenotype; Photometry; Prefrontal Cortex; Prevention strategy; Rattus; Reaction Time; Rewards; Risk; Risk-Taking; Role; Schools; Self Administration; Sleep; Sleep Deprivation; Sleep disturbances; Substance Use Disorder; Testing; Tetrahydrocannabinol; Time; Variant; abuse liability; addiction; behavioral study; biobank; circadian; cognitive control; cognitive function; cognitive testing; drug action; early adolescence; emerging adult; executive function; experience; in vivo; indexing; male; neural circuit; neurodevelopment; neuroimaging; peer; preference; relating to nervous system; risk minimization; sedative; sensor; substance use; trait

PROJECT SUMMARY Adolescence is a period of enhanced vulnerability to develop substance use disorders in part do to the ongoing development of neural circuits associated with reward and executive function (i.e., impulsivity, attention, reward sensitivity). In addition, adolescents experience a developmentally regulated shift in circadian rhythms to a more evening chronotype and have less perceived sleep drive. Thus, adolescents are biologically driven to stay up later at night and wake later in the morning. However, this natural shift in circadian rhythms is in conflict with societal norms, particularly early school start times, which can lead to a chronic state of circadian misalignment and insufficient sleep. The degree to which chronic circadian and sleep disturbances in adolescence impacts brain development and risk for drug abuse is not well understood. Moreover, there is a wide variation in the degree of circadian shift amongst adolescents, leading to the possibility that certain individuals are more at risk than others for circadian and sleep-associated dysfunction. Therefore, an increased understanding of the behavioral and neural consequences of sleep and circadian disturbances, and their interaction with individual differences in sleep and circadian preferences, is needed to inform new interventions and preventative strategies. Project 4 of the Center for Adolescent Reward, Rhythms, and Sleep (CARRS) aims to determine the effects individual differences in chronotype (Aim 1), circadian misalignment in the absence of sleep loss (Aim 2), and acute and chronic sleep disruption (Aim 3) on behavioral indices of addiction risk and corticolimbic neural activity in adolescent rats. Identification of individual differences in sleep and circadian preferences will be facilitated by using the heterogeneous stock (HS) outbred rats that produce more variability than standard outbred strains, and allow for precise genetic identification of trait differences. Rats will be phenotyped for circadian and sleep preferences in early adolescence by our Phenotyping and Bio-banking Core B. We will then examine how these phenotypes related to impulsivity and execute function on the 5-choice serial reaction time task (5-CSRTT) and if rats with extreme chronotypes (early vs. late) exhibit differences in nicotine or THC self-administration. Aims 2 and 3 will focus on how manipulations of circadian rhythms and sleep alter behavior on the 5-CSRTT and drug self-administration. In addition, we will test how corticolimbic activity is altered by circadian and sleep manipulations during behavior using in vivo fiber photometry. Results of these studies will be integrated with human neuroimaging data obtained in Projects 1 and 2, and with the molecular and ex vivo electrophysiological results obtained in Projects 3 and 5.

项目概要 青春期是一个更容易发生药物滥用障碍的时期，部分原因是持续的药物使用障碍 与奖励和执行功能（即冲动、注意力、奖励 灵敏度）。此外，青少年经历了昼夜节律的发育调节转变，变得更加规律。 晚上的睡眠时间型，感知的睡眠动力较少。因此，青少年在生理上被迫熬夜 晚上晚些时候，早上醒来。然而，昼夜节律的这种自然变化与 社会规范，尤其是过早的上学时间，可能会导致昼夜节律失调的慢性状态 和睡眠不足。青春期慢性昼夜节律和睡眠障碍的影响程度 大脑发育和药物滥用风险尚不清楚。此外，存在很大的差异 青少年昼夜节律变化的程度，导致某些人面临更高风险的可能性 与其他人相比，昼夜节律和睡眠相关的功能障碍。因此，加深了对 睡眠和昼夜节律紊乱的行为和神经后果，以及它们与个体的相互作用 睡眠和昼夜节律偏好的差异需要为新的干预措施和预防措施提供信息 策略。青少年奖赏、节奏和睡眠中心 (CARRS) 的项目 4 旨在确定 睡眠类型的个体差异（目标 1）、在没有睡眠不足的情况下昼夜节律失调（目标 2）以及急性和慢性睡眠中断（目标 3）对成瘾风险和皮质边缘神经行为指标的影响 青春期大鼠的活动。识别睡眠和昼夜节律偏好的个体差异将 通过使用异质种群（HS）远交大鼠来促进，其产生比标准更多的变异性 远交品种，并允许对性状差异进行精确的遗传鉴定。将对大鼠进行表型分析 通过我们的表型分析和生物库核心 B 确定青春期早期的昼夜节律和睡眠偏好。我们将 然后检查这些表型如何与冲动性相关并在 5 个选择系列反应中执行功能 时间任务 (5-CSRTT) 以及具有极端时间型（早期与晚期）的大鼠是否表现出尼古丁或 THC 差异 自我管理。目标 2 和 3 将重点关注昼夜节律和睡眠的操纵如何改变行为 5-CSRTT 和药物自我给药。此外，我们将测试皮质边缘活动如何被改变 使用体内纤维光度测定法对行为过程中的昼夜节律和睡眠进行控制。这些研究的结果将 与项目 1 和 2 中获得的人类神经影像数据以及分子和体外 项目 3 和 5 中获得的电生理结果。