Project Summary/Abstract Activation of the innate immune system results in the release of pro-inflammatory cytokines, which may lead to changes in neuroimmune signaling and behavioral abnormalities, such as high alcohol (ethanol) consumption, which may ultimately lead to the development of alcohol use disorder (AUD). We lack understanding of how changes in neuroimmune signaling are integrated into neuronal networks that mediate the transition from normal (social) drinking to excessive alcohol consumption. Here, we propose the neuroimmune model of excessive alcohol consumption, where repeated injections of the immune activator Poly(I:C) produce progressive escalation of alcohol intake over several weeks of drinking. We hypothesize that immune activation induces cell type-specific changes in gene expression, which are integrated to affect neuronal functions and drive excessive drinking. We will use a combination of molecular, cellular, behavioral and computational approaches to test this hypothesis. Gene expression will be measured in neurons, astrocytes and microglia to investigate cell type-specific molecular mechanisms of immune activation. We will then use molecular signatures from different cell types and computationally-driven drug-repurposing approaches to identify and test pharmacological compounds with the potential to reduce high alcohol drinking. We will investigate roles of specific neural networks in immune-induced escalation of drinking by measuring neuronal functions and manipulating excitability of critical projection neurons. Temporal profiling across three critical time points will identify dynamic changes in cell type-specific transcriptomes and neuronal functions. Results of the proposed experiments will advance our understanding of the role of neuroimmune signaling in the transition to AUD and will be widely applicable to brain disorders with pro- inflammatory phenotypes.