GSE160495
Early life adversity promotes sex-specific resilience to opioid addiction-related phenotypes
Early life stress that is not overwhelming can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal day 2–9 and their dams were exposed to a low resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions.  High levels of impulsivity are associated with substance abuse, but LBN reduced impulsive choice compared to controls in males. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. LBN had no effect on addiction-related behavior in females. The nucleus accumbens (NAc) mediates these behaviors, so we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced sEPSC frequency in males, but not females. Only in males, LBN prevented a morphine-induced increased in the AMPA/NMDA ratio. RNA sequencing and genome-wide assessments of histone modifications were performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Remodeling of unique histone marks may have contributed to these distinct transcriptional profiles. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients. Overall design: 20 total samples were analyzed including 4 male control, 5 male LBN, 5 female control, and 6 female LBN samples.