Adolescent circadian rhythm disruption increases reward and risk-taking

Circadian rhythm disturbances have long been associated with the development of psychiatric disorders, including mood and substance use disorders. Adolescence is a particularly vulnerable time for the onset of psychiatric disorders and for circadian rhythm and sleep disruptions. Preclinical studies have found that circadian rhythm disruption (CRD) impacts the brain and behavior, but this research is largely focused on adult disruptions. Here, we sought to determine the long-term behavioral and neurobiological effects of CRD during early adolescence by exposing mice to 12 h shifts in the light/dark cycle. We hypothesized that adolescent CRD would have a greater effect on psychiatric-related behaviors, relative to adult disruption. To identify possible mechanisms, we also measured gene expression in brain regions relevant to circadian rhythms, mood and reward. We found that disruption during early adolescence, but not adulthood, persistently increased exploratory drive (risk-taking behavior) and cocaine preference when tested later in life. Interestingly, we found sex differences when intravenous cocaine self-administration was tested. While female mice with a history of adolescent CRD had a greater propensity to self-administer cocaine, as well as increased motivation and cue-induced reinstatement, male adolescent CRD mice had reduced motivation and extinction responding. Overall, adolescent CRD in mice caused persistent increases in risky behavior, cocaine reward and cocaine self-administration, which suggests that CRD during adolescence may predispose individuals towards substance use disorders. Importantly, we found that many transcripts were affected by adolescent CRD and these were largely distinct across sex and brain region. Future research is required to elucidate how adolescent CRD affects behaviors relevant to mood- and substance use-related disorders across the 24-hour day, as well as to identify intervention strategies to alleviate disruption during adolescence and novel therapeutic approaches once symptoms have begun. Overall design: The prefrontal cortex (PFC), nucleus accumbens (NAc), and suprachiasmatic nucleus (SCN) were punched and isolated from frozen brain tissue using a cryostat. Individual animals were each used as a sample (n=4-8 per condition). Tissue was homogenized and total RNA was isolated using the RNeasy Plus Micro Kit (Qiagen). RNA quantity and quality were assessed using fluorometry (Qubit RNA High Sensitivity Assay Kit and 322 Fluorometer; Invitrogen) and chromatography (Bioanalyzer and RNA 6000 Pico Kit; Agilent) respectively. Libraries were prepared with 10 ng of RNA from each sample using the Smartseq HT ultra-low input sample preparation kits (Illumina). Paired-end dual-indexed sequencing (75 bp) was performed using the NextSeq 500 platform (Illumina). A total of 30 million reads per sample was targeted. Sequencing was performed at the University of Pittsburgh Health Sciences Sequencing Core at UPMC Children's Hospital of Pittsburgh.