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

项目总结 青春期是一个易患物质使用障碍的时期，部分原因是正在进行的 与奖赏和执行功能(即冲动、注意力、奖赏)相关的神经回路的发展 敏感度)。此外，青少年经历了一种发育调节的昼夜节律转变为更 晚间时型和睡眠驱动力较少。因此，青少年在生理上被驱使熬夜。 晚上晚些时候，早上晚些时候醒来。然而，昼夜节律的这种自然变化与 社会规范，特别是早期开学时间，这可能导致长期的昼夜节律失调 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的风险还没有被很好地理解。此外，在不同的国家， 青少年昼夜节律变化的程度，导致某些人更有可能面临更大的风险 比其他人在昼夜节律和睡眠相关的功能障碍方面要好。因此，增加对 睡眠和昼夜节律紊乱的行为和神经后果及其与个体的相互作用 睡眠和昼夜节律偏好的差异，需要为新的干预和预防提供信息 战略。青少年奖励、节律和睡眠中心(CARRS)的项目4旨在确定 在没有睡眠缺失的情况下，个体在时型差异(目标1)、昼夜节律失调(目标1)方面的影响 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。确定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多变异性的异种种群(HS)繁殖的大鼠来促进 远缘繁殖的品系，并允许精确的性状差异的遗传识别。将对老鼠进行表型鉴定 我们的表型和生物银行核心B在青春期早期的昼夜节律和睡眠偏好。我们将 然后研究这些表型如何与冲动有关，并在5个选择的系列反应上执行函数 时间任务(5-CSRTT)和极端时型(早与晚)的大鼠在尼古丁或THC方面表现出差异 自治。目标2和3将集中于昼夜节律和睡眠的操纵如何改变行为 关于5-CSRTT和药物自我给药。此外，我们还将测试如何改变皮质边缘活动。 使用体内纤维光度法对行为过程中的昼夜节律和睡眠进行处理。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以及与分子和体外实验数据相结合 项目3和项目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.