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

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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.