Project Summary This renewal application of the Portland Alcohol Research Center (PARC) proposes funding for Years 26 to 30. Over the years of its existence, the number of Portland investigators engaged in alcohol research has increased and their associated research efforts and other mutually supportive interactions have matured. Historically, the PARC is recognized for its combined expertise directed toward the goals of developing and applying genetic animal models to interrogate mechanisms associated with acute and chronic effects of alcohol. The PARC has focused on connecting neurocircuitry and genetics as a unique goal, and the opportunity now exists to comprehensively test focused hypotheses. The PARC renewal is comprised of 4 Research Projects and 4 Cores. Two Projects (P001, P004) are continuing and 2 are new; 1 Core (C001) is new. We continue to emphasize phenotypes with translational relevance through cutting-edge genetics and genomics, and add astrocyte transcriptomics and DNA methylomics. The Overall Center Theme unites the PARC components: The Role of the Tetrapartite Synapse in Risk for and Response to Alcohol Drinking. Our coordinated research examines the roles of the extracellular matrix (ECM), perineuronal nets, and brain circuits/synaptic function, applying transcriptomics and methylomics in our animal models. We consider sex differences, cognitive flexibility, and individual differences in populations at high genetic risk for alcohol consumption that may inform protective mechanisms. P001 characterizes the transcriptomic profiles of mice bred for high vs. low alcohol preference, and for residual individual variation in alcohol preference that persists after strong directional selection for high intake. Cognitive flexibility, a putative predictor of future alcohol intake, is examined, and there is a unique focus on the primary cilium. P002 considers the role of astrocyte- expressed ECM proteins and proteases in alcohol drinking, and of ECM glycosaminoglycans (GAGs) relevant to neuronal plasticity, including hyaluronic acid (HA). P003 integrates mouse and monkey findings via analysis of the brain methylome of low and heavy alcohol drinking animals of both species. Compelling novel gene targets and regulatory regions with a role in synaptic plasticity will be investigated by gene editing, circuit modifications and functional analysis of excitatory/inhibitory neurotransmission. Finally, P004 also integrates research in monkeys and mice to characterize corticostriatal functional connectivity and synaptic plasticity associated with deficits in cognitive flexibility and alcohol intake, and to examine the role of HA. The Administrative Core (AC001) will provide organizational and oversight services for all components of the Center. The Animal & Resource Core (C001) will generate mice, conduct behavioral phenotyping, and generate sequencing data for mouse and monkey samples. The Bioinformatics Core (C002) will provide analytic and data ...