PROJECT SUMMARY Acute alcohol triggers an immune response in the brain. A hallmark of this response is the activation of the brain's primary immune cells, microglia. Microglia readily adapt to repeated stimuli, which can enhance or attenuate microglia responses over time. However, preclinical findings characterizing these effects are highly mixed depending on species, dose, alcohol chronicity, and timing. It is important to characterize adaptive microglia processes during repeated alcohol exposures because innate neuroimmune factors are linked with escalating alcohol drinking. Yet, these mechanisms cannot be evaluated yet in primates due to limited noninvasive tools that measure microglia responses to acute immune challenges. This 2-phase proposal will first develop a novel positron emission tomography (PET) radiotracer specific for the colony stimulating factor 1 receptor (CSF1R) that will characterize microglia dynamics from repeated alcohol exposures. CSF1R is advantageous over current PET targets because it is expressed exclusively on microglia. This CSF1R PET radiotracer will be evaluated for suitable imaging properties and sensitivity to an acute alcohol challenge. Confirmation of these properties will provide a key tool for the second phase. Phase 2 will use this imaging tool to measure the acute immune response to alcohol in nonhuman primates at three time points: alcohol naïve, a week after initial alcohol challenge, and after 4 months alcohol self-administration. The data collected will characterize adaptive microglia processes occur during alcohol initiation and escalating drinking, and determine the relationship of these process with drinking behaviors. The findings will advance the field by providing a new imaging tool ripe for translation to human studies while testing important hypotheses regarding dynamic microglia processes from alcohol exposure and their effects on drinking behaviors. The results will have clear translational implications for future human studies evaluating adaptive microglia processes in people with alcohol use disorder and populations with high risk for future alcohol use disorder.