PROJECT SUMMARY This is a competing renewal application for the Integrative Neuroscience Initiative on Alcoholism (INIA)- Neuroimmune consortium (Notice# RFA-AA-20-011, RFA-AA-20-013) to integrate multidisciplinary research projects based on the genomic, cellular, and behavioral neuroadaptations related to excessive alcohol consumption. This consortium has identified gene networks and pathways associated with excessive alcohol drinking in humans and animals and focuses on potential drug targets within neuroimmune and neuroinflammatory signaling pathways. In the next phase of this initiative, our collective proposals will address several documented NIAAA goals which include: 1) understanding the genomics, electrophysiology, and pharmacology of brain immune signaling systems in neurons and glial cells and their role in causes and treatments of alcohol dependence; 2) using new technologies such as single cell and spatial transcriptomics, proteomics, and multimodal functional and structural imaging to study these systems; 3) promoting reproducibility and translation of data through testing in multiple laboratories and in multiple assays; 4) guiding investigators in determining the translatability of their findings for preclinical and clinical studies by NIAAA- supported units outside the consortium. The overall hypothesis for INIA-N is that systematic analysis of neuroimmune mechanisms will inform strategies for treatment of excessive drinking associated with Alcohol Use Disorder. Ten Research Components and an Administrative Core comprise the consortium. INIA-N will be directed by the Administrative Core in cooperation with the Executive and Steering Committees and guided by a distinguished Scientific Advisory Board. The Administrative Core will provide leadership, oversight of scientific projects, and integration and translation of project data. INIA-N has six goals: 1) expand gene expression datasets with results from single nuclei sequencing and spatial transcriptomics to generate cell-type specific and anatomical transcriptome maps and integrate human cellular transcriptome data with human genome wide association studies; 2) define the contribution of specific non-neuronal cell types (astrocytes and microglia) to the molecular and behavioral effects of excessive alcohol consumption through a collaborative investigation of immune related cells of the brain; 3) examine alcohol-induced changes in perineuronal nets and in the abundance and post-translational modifications of extracellular matrix proteins as mechanisms for glial-neuronal cross talk that impact brain circuits regulating alcohol consumption; 4) pursue biochemical and electrophysiological studies of cytokine signaling to understand innate immune mechanisms by which excessive alcohol consumption changes brain function; 5) apply systems-level, connectomics approaches to identify mechanisms by which excessive alcohol consumption changes whole brain function, with emphasis on the role of ou...