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 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. In addition, our data show a critical role of the amygdala- cortical circuit in social isolation-induced escalated alcohol drinking. Notably, 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. Indeed, 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. This supplement will fill this gap by (1) determining if BLA and mPFC glial activation is predictive of social rank and isolation-associated alcohol drinking and (2) determining if individual differences in social anxiety underlie social rank and isolation-associated alcohol drinking. The findings will provide insight into the role of immune signaling and motivational differences underlying social rank and isolation-associated alcohol drinking to further support the overarching goal of the parent grant. In addition, this award provides an opportunity for the candidate, who belongs to multiple underrepresented groups in biomedical science, to gain new training in fundamental neuroscience techniques, foundational knowledge on addiction neuroscience, and professional development skills in a vibrant scientific environment under the mentorship of a NIAAA-funded PI. Ultimately, the...