Circadian rhythms and homeostatic sleep regulation during adolescence: Implications for reward, cognitive control, and substance use risk

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

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Abstract

PROJECT SUMMARY PROJECT 1 Substance use disorders (SUD) are widely prevalent and pose devastating health, financial, and societal costs. The incidence of SU increases across adolescence, making this sensitive developmental period one of both heightened risk and heightened opportunity for prevention and intervention. However, to develop effective interventions, we need to identify novel and modifiable risk factors and mechanisms for SUD. Circadian rhythm and sleep disturbances have strong ties to SU risk, and their effects on intermediary markers of SU risk in adolescence—reward and cognitive control systems—provides a plausible mechanistic substrate. The conceptual model of the Center for Adolescent Reward, Rhythms, and Sleep (CARRS) posits that adolescent development is associated with enhanced reward function relative to cognitive control, phase delay in endogenous circadian rhythms, and lower homeostatic sleep drive. Environmental and social factors interact with these developmental processes, often resulting in late sleep timing, short sleep duration, and circadian misalignment—each of which is associated with increased SU in teens and young adults. To date, P1 has studied 61 teens (ages 13.0-15.9) with a range of habitual sleep timing and limited SU history. Participants completed a “120-minute day” ultradian protocol (repeated 80-min wake and 40-min sleep opportunities) over 36 hours to measure circadian rhythms, homeostatic sleep drive, and their combined effects on reward/cognitive control. We identified novel associations between circadian and homeostatic sleep markers and self-report, behavioral, and neural measures of reward and cognitive control relevant to SUD risk. Building on findings from P1 and other CARRS-1 projects, we will expand P1 in three critical ways during CARRS-2: 1) recruit a sizeable subsample at high risk of SUD; 2) examine sex effects on circadian-reward interactions identified in the CARRS-1 rodent studies; and 3) institute translational EEG measures related to reward positivity and REM sleep. In addition, we will collect biological samples to be analyzed in P3 to examine their association with addiction and/or sleep/circadian phenotypes, including hair follicle fibroblasts and buccal cells to examine circadian gene expression (circadian phase and amplitude in genes NR1D1, PER1 and PER2), and blood samples to extract neuronal- or astrocyte-specific extracellular vesicles. P1 will study 120 adolescents ages 13–18, stratified 2:1 by high or low risk for SUD, as defined by cannabis use prior to age 15, greater than monthly cannabis use, and/or parent/sibling with past-year cannabis use. As in CARRS-1, we will conduct a home study to monitor participants’ sleep patterns for 2 weeks (actigraphy; sleep diary); fMRI scan (to measure reward and cognitive control); overnight polysomnography; and a 28-hour ultradian protocol. Longitudinal online surveys will collect data on sleep, reward, cognitive control, and SU every 6 months through study conclusion. P1 draws directly on resources provided by the Center Cores. CARRS and P1 will innovatively advance understanding of distinct circadian and sleep homeostatic effects on reward-cognitive control function and the development of SU.