Project Summary/Abstract Neuroimmune signaling is strongly implicated in the development and progression of alcohol use disorder (AUD). Innate immune molecules are upregulated in human postmortem brains from alcoholics and are correlated with lifetime alcohol use. Human genome-wide association studies (GWAS) also link immune/inflammatory genes to alcohol dependence. We hypothesize that alcohol consumption initiates a positive feedback loop involving neuroimmune activation and proinflammatory responses that promote excessive alcohol consumption. Neuroimmune signaling also regulates voluntary alcohol consumption in rodent models and activation of specific pathways results in escalation of drinking. Our recent work shows that immune signaling in glial cells have emerged as key regulators of alcohol drinking. Using single cell and spatial transcriptome technologies, we are now able to precisely define the role of individual types of brain cells in the context of excessive alcohol consumption. Our overarching hypothesis is phenotypic changes characteristic of escalated alcohol consumption and preference are due, in part, to spatially distinct and cell-specific molecular mechanisms that significantly reshape the neuroimmune transcriptome. Multi-omic genetic changes at the cellular level from human and animal models will reveal new gene candidates and therapeutic targets.