Dynamic resilience: stress phenotypes impact opioid-taking behavior, brain activity, and gene expression

Stress is a common experience with individual differences in vulnerability. While some individuals succumb to lasting maladaptive behaviors, such as substance use disorders, others demonstrate resilience—a dynamic ability to return to baseline functioning over time. Assessing stress-related behaviors at a single time point may overlook key aspects of resilience. Chronic social defeat stress (CSDS) was used to investigate phenotypic stability in male mice. At 24 h post-final defeat, the anticipated distribution of susceptible and resilient phenotypes was observed; upon retesting three weeks later, most animals maintained their original stress phenotype. To evaluate potential differences in initial addiction liability we examined intravenous self-administration (IVSA) of remifentanil in susceptible and resilient mice. One-week post-CSDS, all stressed mice increased opioid intake, regardless of phenotype. At three weeks, susceptible mice maintained high opioid intake while resilient mice returned to baseline levels. This behavioral recovery was mirrored by neuronal activity. Susceptible mice exhibited persistently high neural activity (cFOS) in the basolateral amygdala (BLA), a key stress and fear center, and in the nucleus accumbens (NAc), a hub for motivation. In contrast, resilient mice showed normalized activity in the NAc at three weeks, which was accompanied by a systematic reprogramming of the NAc transcriptome. Our findings show that resilience is an active neuroadaptive process characterized by the recovery of specific brain circuits, not merely the absence of pathology. By moving beyond a single timepoint, we identify the BLA and NAc as critical nodes governing the transition, offering new targets for intervention in substance use disorders.