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.

项目摘要 青春期是一种增强的脆弱性，以此对正在进行的疾病发展 发展与奖励和执行功能相关的神经回路（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展转变 傍晚时期，睡眠驱动器的感知较少。因此，青少年在生物学上驱动着熬夜 晚上晚些时候，早上晚些时候醒来。但是，这种昼夜节律的自然转变与 社会规范，尤其是早期学校的开始时间，这可能导致慢性昼夜节律未对准状态 和睡眠不足。慢性昼夜节律和青春期睡眠障碍的程度影响 尚不清楚大脑发育和吸毒的风险。而且， 昼夜节律在青少年之间的转变程度，导致某些人面临更大的风险 比其他人的昼夜节律和与睡眠相关的功能障碍。因此，对 睡眠和昼夜节律的行为和神经后果，以及它们与个人的互动 需要睡眠和昼夜节律偏好的差异，以告知新的干预措施和预防措施 策略。青少年奖励，节奏和睡眠（CARRS）的项目4旨在确定 在没有睡眠损失的情况下，表型的个体差异（AIM 1），昼夜节律的未对准（AIM） 2），以及成瘾风险和皮质唇神经的行为指数的急性和慢性睡眠破坏（目标3） 青少年大鼠的活动。识别睡眠和昼夜节律偏好的个体差异将是 通过使用异质库存（HS）近代大鼠可促进可变性的可变性 杂种菌株，并允许精确的性状差异遗传鉴定。大鼠将被表型 通过我们的表型和生物银行核心B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和执行功能相关的5个选择序列反应 时间任务（5-CSRTT）和如果具有极端变色型的大鼠（早期与晚期）在尼古丁或THC上表现出差异 自我管理。目标2和3将重点介绍昼夜节律和睡眠的操纵如何改变行为 在5-CSRTT和药物自我管理上。此外，我们将测试如何改变皮质的活性 昼夜节律和睡眠操作在行为期间使用体内纤维光度法。这些研究的结果将 与在项目1和2中获得的人类神经影像学数据集成，并与分子和离体相结合 在项目3和5中获得的电生理结果。