8/8: INIA Stress and Chronic Alcohol Interactions: Cross-species plasticity signatures of alcohol and stress

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Project Summary Preexisting cognitive deficits or exposure to stressors both increase the probability of alcohol use disorder (AUD). These relationships are bidirectional, and excessive alcohol consumption can also directly impact cognition and dysregulate stress systems. Individual differences in cognition and stress reactivity are thought to define phenotypes within the AUD spectrum which may differ in disease prognosis and responsivity across treatment strategies. As such, precisely defining the behavioral and neurobiological substrates mediating covariance across cognitive, stress, and drinking domains is critical for our understanding of AUD. However, until recently we have lacked technical approaches which would allow for determination of whether individual differences in these behaviors arise from the same neurons or from distinct populations within brain regions. To parse how these phenotypes manifest we must 1) quantify the complex individual differences that emerge at the intersection of stress, alcohol drinking, and cognitive function and 2) determine the precise neurons in the brain that control these interactions. To this end, we will first use deep phenotyping of both behavioral and neuronal features to computationally define individual differences across domains in mice. Previous studies have demonstrated that prefrontal cortex is a critical mediator of cognitive function, responses to stressors, and drinking, but the precise degree of shared circuitry between these behaviors is unclear. Thus, we will use a longitudinal design to define the neuronal plasticity signatures in prefrontal cortex that govern expression and interactions between these behaviors within the same subjects. Mouse models offer unique advantages for defining the precise cell-types within the prefrontal cortex that give rise to these behaviors, but it will also be essential to determine if these neurobehavioral relationships are conserved in higher-order species. Using a cross-species approach, conservation of relationships between plasticity in specific cortical cell-types and individual differences in cognitive, stress, and alcohol interactions observed in mice will then be directly tested in ex vivo brain slices from non-human primates. Successful completion of this proposal will provide novel insight into the circuit basis of alcohol and stress interactions and advance these hypotheses across species towards translational endpoints.