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

项目摘要 青春期是一个更容易发展为物质使用障碍的时期，部分原因是由于正在进行的 与奖励和执行功能相关的神经回路的发展（即，冲动，注意力，奖励 灵敏度）。此外，青少年经历了发育调节的昼夜节律转变， 晚上的生理时钟类型和较少感知的睡眠驱动力。因此，青少年在生理上被驱使熬夜 晚上睡得更晚早上醒得更晚然而，这种昼夜节律的自然变化与 社会规范，特别是早期的学校开始时间，这可能导致慢性的昼夜失调状态 睡眠不足。青春期慢性昼夜节律和睡眠障碍对青少年的影响程度 大脑发育和药物滥用的风险还没有得到很好的理解。此外，在这方面存在着广泛的差异。 青少年之间的昼夜节律变化程度，导致某些人更有可能处于危险之中 与昼夜节律和睡眠相关的功能障碍。因此，增加对 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。 战略布局青少年奖励，节奏和睡眠中心（CARRS）的项目4旨在确定 影响个体差异的生理时钟型（目标1），昼夜失调的情况下，睡眠损失（目标 2），以及急性和慢性睡眠中断（目的3）对成瘾风险和皮质边缘神经行为指标的影响 青春期老鼠的活动。识别睡眠和昼夜节律偏好的个体差异将是 通过使用产生比标准更大变异性的异源原种（HS）远系繁殖大鼠来促进 远交品系，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， 我们的表型分析和生物银行核心B在青春期早期的昼夜节律和睡眠偏好。我们将 然后研究这些表型与冲动性的关系，并在5-选择系列反应中起作用 时间任务（5-CSRTT），如果具有极端时间型（早与晚）的大鼠在尼古丁或THC方面表现出差异， 自我管理。目标2和3将集中在如何操纵昼夜节律和睡眠改变行为 5-CSRTT和药物自我给药。此外，我们将测试皮质边缘活动是如何改变的， 使用体内纤维光度测定法在行为过程中进行昼夜节律和睡眠操纵。这些研究的结果将 与项目1和2中获得的人类神经成像数据相结合，并与分子和离体 在项目3和5中获得的电生理结果。

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.