Dynamic Resilience: Stress Phenotypes and Their Impact on Opioid-Taking Behavior, Brain Activity, and Gene Expression

Stress is a common experience that reveals 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. We used chronic social defeat stress (CSDS) to examine phenotypic stability and found mice distributed into the expected susceptible/resilient ratio at both 24 hours and three weeks, with most maintaining their phenotype over the three-week period. We then evaluated intravenous self-administration (IVSA) of remifentanil. One-week post-CSDS, all stressed mice showed increased opioid intake, regardless of phenotype. However, by three weeks, intake in resilient mice returned to baseline levels, while intake in susceptible mice remained elevated. To examine neural correlates of these behavioral shifts, we measured cFOS activity in the basolateral amygdala (BLA) and nucleus accumbens (NAc). In susceptible mice, BLA cFOS remained elevated at both time points. NAc activity was elevated in both groups at one week but normalized in resilient mice by three weeks. This pattern paralleled opioid intake behavior. Additionally, we found distinct gene expression changes that may underlie the adaptive shifts seen in resilient mice. These findings underscore that resilience is a dynamic process characterized by evolving behavioral and neural responses. By evaluating multiple time points, our research provides new insights into how different stress phenotypes influence opioid use trajectories and highlights critical brain regions involved in these processes.