Molecular changes associated with sleep and circadian disruption in adolescence: relevance to substance use

PROJECT SUMMARY PROJECT 3 Circadian rhythm and sleep disruptions are common during adolescence, a critical neurodevelopmental window. The primary goal of the CARRS Center is to understand how sleep and circadian rhythm traits and environmental disruptions during adolescence lead to increased vulnerability for substance abuse. We predict that a combination of biological and environmental factors contribute to this increased risk. The goal of Project 3 of CARRS is to provide translational studies in both human subjects and rodent models that determine mechanistic details of how circadian rhythm and sleep disruption alter reward circuitry. Data from our first funding cycle (CARRS-1) found that sleep and circadian disruptions led to substantial changes in gene expression and cellular function within cortico-accumbens circuitry. These changes, in turn, likely contribute to increased risk for substance use (SU). In the CARRS renewal (CARRS-2), we plan to continue these studies, extending into an older, higher risk population and delving more deeply into the cellular and molecular mechanisms that underlie these associations. Project 3 will first identify sleep and circadian markers in peripheral biological human samples collected by Project 1. In Aim 1, we will assess genetically-determined circadian traits using fibroblasts collected from hair follicles as well as state-dependent circadian measures using buccal cells. In Aim 2, we will perform proteomics on brain-derived and cell type-specific extracellular vesicles isolated from plasma collected in Project 1. For Aim 1 and Aim 2, we will be employing machine learning algorithms (described in Core C) to integrate the molecular clock measures with measures of reward value, reward circuit function, cognition, and impulsivity so that we can gain a full picture of exactly how these measures line up in individuals, and what factors put someone at greatest risk for SU. In Aim 3 of CARRS-2, we will use rats and state-of-the-art single nucleus RNA-sequencing to delve more deeply into cell type-specific molecular alterations in cortico-accumbens circuitry that are impacted by chronic sleep fragmentation as well as a circadian misalignment. Together, this translational project will help identify both biomarkers and molecular mechanisms of risk for SU.