PROJECT SUMMARY Social stress is a prevailing factor in the lives of all social species and can motivate the misuse of reinforcing drugs such as alcohol. Individuals that use alcohol to alleviate the negative emotions created by social stress are more likely to develop pathological drinking patterns, which can lead to an alcohol use disorder (AUD). Indeed, an individual’s standing in a social hierarchy (i.e. social rank) is inversely related to alcohol consumption in rodents and non-human primates as well as problematic drinking in humans, highlighting the conserved impact of subordination stress on motivation for alcohol. Social rank also influences how individuals respond to challenges, and social isolation is a particularly profound stressor with increasing human relevance. Our preliminary data identify a previously unknown relationship between mouse social rank and isolation- associated escalated alcohol drinking, where subordinates display a greater magnitude increase in drinking following social isolation compared to dominants. These data suggest that low social rank may be a potent risk factor for developing pathological alcohol drinking patterns. Understanding the neurobiological mechanisms by which social stress experiences engender aberrant alcohol drinking could have important translational implications for AUD. It is becoming increasingly evident that social stress induces microglia-mediated neuroimmune responses in select stress-responsive brain regions, including the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), which contribute to stress-induced behavioral adaptations. Notably, social isolation-induced escalation of alcohol strongly parallels increases in microglia previously seen following social stress, supporting a potential role for microglia in isolation-induced adaptations in alcohol drinking. Despite the substantial evidence linking social stress and alcohol drinking as well as the impact of social stress on neuroimmune signaling, virtually nothing is known regarding the neuroimmune regulation of circuits underlying social stress-induced behavioral adaptions in alcohol drinking. To fill this gap, this proposal will test the central hypothesis that social stress activates microglia-mediated neuroimmune signaling, which re-shapes amygdalar-cortical circuits underlying escalated alcohol drinking. Preliminary data show that social isolation increases BLA excitability, and the BLA-mPFC circuit regulates alcohol drinking. Dr. Patel will use her new training in advanced circuit imaging and dissection technologies and previous training in cell type specific transcriptomic analysis and ex vivo electrophysiology to 1) dissect the BLA-mPFC contribution to social rank- and isolation-induced alcohol drinking, 2) delineate the impact of BLA substrates on mPFC encoding of alcohol consumption, and 3) identify social stress-induced neuroimmune determinants driving circuit adaptations underlying aberrant alcohol drinking. In...