Neurobiological correlates of behavioral resilience to chronic alcohol and acute stress in male and female rats

Chronic alcohol use and stress are major risk factors for psychiatric disorders, frequently disrupting emotion regulation and behavioral inhibition. Yet, many individuals exposed to alcohol or stress do not develop pathology, highlighting the need to identify mechanisms that confer vulnerability or resilience. Using a conditioned inhibition paradigm, we examined how prior alcohol intake and acute stress shape fear- and reward-related behavioral control. Male and female Long Evans rats underwent either intermittent two-bottle alcohol access or water-only control conditions, followed by exposure to an acute stressor or non-stress context. Animals then completed cue discrimination and conditioned inhibition training, after which corticolimbic tissue was processed for parvalbumin, somatostatin, and protein kinase C-δ (PKCδ) immunohistochemistry. Stress exposure delayed discrimination learning across groups, but all subjects ultimately distinguished reward, fear, and inhibitory cues. However, when an inhibitor cue was presented concurrently with a fear cue, females with combined alcohol and stress histories failed to suppress fear responses, unlike all other groups. Across conditions, subsets of animals displayed either resilient or non-resilient behavioral profiles, which were linked to distinctive interregional correlations of parvalbumin- and PKCδ-expressing interneurons within the corticolimbic network. These findings reveal how alcohol and stress interact to disrupt inhibitory control over fear, particularly in females, and show that resilience is associated with coordinated shifts in interneuron network organization. Our conditioned inhibition approach provides a sensitive framework for parsing the neural substrates of vulnerability and resilience across fear and reward systems.