Regulation of Prefrontal Cortex - Nucleus Accumbens Circuit by Sleep and Circadian Rhythm

PROJECT SUMMARY PROJECT 5 Adolescence is a vulnerable period for initiating substance use and abuse, during which time sleep and circadian rhythm disruptions are pervasive. It is increasingly recognized that sleep and circadian rhythm causally, and powerfully regulate reward processing, but the underlying mechanisms remain poorly understood. Whether and how do sleep and circadian disruptions lead to increased vulnerability for substance use in adolescents? Could sleep and circadian rhythm traits be related to substance abuse risks? The central hypothesis of CARRS is that adolescent development-associated changes in sleep and circadian rhythms impact cortico-limbic functions critical to substance use risks (e.g., reward and cognitive control). It is further hypothesized that: 1) These relationships are influenced by sex and other biological, social, and environmental factors; and 2) Screening algorithms and biological markers reflective of sleep-circadian function will identify early adolescents at risks for substance use and substance use disorder. During CARRS-1, rodent studies in Projects 3-5 have identified a large number of gene expression changes following sleep or circadian disturbances in the medial prefrontal cortex (mPFC)-nucleus accumbens (NAc) circuit, as well as changes in reward-seeking behaviors, and Project 5 has identified changes in cellular physiology in NAc and the behavioral impacts. During CARRS-2, Project 5 will focus on mPFC, which provides critical inputs to the NAc, shows more extensive transcriptomic changes than NAc and functional disintegration following sleep disturbances, and determine the cellular and synaptic mechanisms. Specifically, Project 5 will test whether and how sleep and circadian rhythm disturbances alter neuronal activities and synaptic plasticity in mPFC and mPFC-NAc projection. Project 5 will further test how sleep and circadian rhythm disturbances alter sleep EEG phenotypes indicative of drug-taking risks in the rats, and to identify corresponding sleep EEG features in human adolescents. The expected outcome of Project 5 will integrate and extend findings from molecular genetic (Project 3) and behavioral (Project 4) studies, which together will provide mechanistic insights to inform and further develop human studies (Projects 1&2).