Neurobiological Correlates of Behavioral Resilience to Chronic Alcohol and Acute Stress in Male and Female Rats

Background: Chronic alcohol use and stress exposure are risk factors for psychiatric disorders, often leading to emotion dysregulation and impaired behavioral inhibition. While stress-related disorders are often comorbid with alcohol use disorder, not all individuals exposed to stress or alcohol develop either condition. One approach to assessing impaired behavioral inhibition of fear and reward behaviors is through conditioned inhibition paradigms. Methods: Sixty-three male and seventy-five female Long Evans rats were assigned to either an intermittent two-bottle choice paradigm (alcohol versus water) or a water-only control condition, followed by exposure to an acute stressor or a non-stress control context. Subsequently, all subjects underwent a cue discrimination and conditioned inhibition learning protocol, after which brain tissue was collected for immunohistochemical analyses. Results: Stress-exposed groups exhibited delayed acquisition of discrimination learning but ultimately achieved accurate differentiation among reward, fear, and inhibitor cues. When the inhibitor cue was presented concurrently with the fear cue, females subjected to both alcohol and stress failed to suppress fear responses, unlike all other groups. Notably, subsets of animals exposed to stress and/or alcohol demonstrated resilient behavioral phenotypes, which were associated with significant interregional correlations of parvalbumin and PKCδ within the corticolimbic network. Conclusions: Our conditioned inhibition task for fear and reward uncovered nuanced patterns of behavioral regulation in response to fear, reward, and inhibitory cues, particularly when these cues were presented concurrently. These patterns enabled the classification of resilient versus non-resilient phenotypes, which were linked to distinct shifts in correlation profiles among interneuron subtypes.