Investigating the long-term effects of prenatal circadian rhythm disruption on substance use-related disorders - Project Summary/Abstract Circadian rhythms are a vulnerability factor associated with substance use. Drugs of abuse entrain and disrupt circadian rhythms and those with disrupted rhythms are vulnerable to developing substance use disorders, creating a vicious cycle. At least 20% of Americans are at risk for environmental circadian rhythm disruptions (CRD) due to working nonstandard shifts, including evening, night or rotating shift work. Shift workers are at risk for substantial negative health outcomes, but females are particularly affected due to greater vulnerability for substance use and additional negative outcomes associated with pregnancy. Not only do female shift workers experience adverse outcomes during pregnancy, but offspring are also affected, both at birth and later in life. Specifically, depression, risky behavior and substance use are all increased in the offspring of shift workers. Importantly, prenatal CRD (pCRD) in mice recapitulates these risks, increasing adverse pregnancy outcomes and anxiety-like behavior in adult offspring. These consistent results across species suggest environmental CRD via light/dark cycle shifting in rodents is a good translational model for studying the outcomes of prenatal disruptions in humans. Although substance use is associated with shift work, in parents and offspring, it is unclear how pCRD induces long-term risk for substance use. In my preliminary experiments, I measured a variety of substance use-related outcomes in adult mice with pCRD. I found consistent sex differences where male offspring of dams with CRD showed a profound substance use-like phenotype, with increased drug preference, food self-administration, reinforcing and motivational properties of cocaine. On the other hand, female offspring showed an opposite, anhedonic-like phenotype with decreased food self-administration, cocaine self- administration and the reinforcing properties of cocaine, as well as maladaptive premature habit formation. Since drugs of abuse entrain circadian rhythms, increasing craving and seeking when drugs are anticipated, increased reward sensitivity in males after pCRD could be due to underlying changes in circadian rhythms. In addition, evidence from our lab suggests that altered circadian rhythms in reward-related brain regions, through genetic manipulations, directly effect behavioral responses to cocaine. These data suggest that pCRD disrupts circadian rhythms in locomotor activity and reward in adulthood, perhaps by altering the expression and rhythmicity of circadian and circadian-regulated genes. Developmental hormones are also a potential factor that could impact sex-specific effects of pCRD since exposure to gonadal hormones during sensitive periods induces long-term changes to the brain and behavior (organizational). Therefore, the hypothesis of this proposal is that pCRD interacts with developmental, organizational hormones to alter rhythms in reward, locomotor activity rhythms and gene expression in reward- and/or circadian-related brain regions, leading to a substance use-like phenotype in males and anhedonic-like in females.
