It is increasingly clear that women are more vulnerable than men to some of the negative effects of chronic alcohol consumption, including immune system dysfunction and neurodegeneration. This is important since the rates of problem drinking in women are rapidly increasing, and the currently available treatments are only moderately effective. There is mounting evidence that men and women drink for different reasons. Women tend to drink to regulate stress and negative affect, whereas men report drinking for alcohol-related positive reinforcement. This provides an important opportunity to explore sex-appropriate treatments. In particular, we need to understand the neurochemical mechanisms that underlie and contribute to these behavioral sex differences in order to provide new treatment targets for medication development. In this proposed Yale- SCORE, Project 2 will focus on identifying sex differences in biomarkers of alcohol-induced neurodegeneration that lead to neural adaptations that drive the addiction cycle. Using state-of-the-art positron emission tomography (PET) technology, we will examine sex differences in levels of microglia and synaptic density in living individuals with alcohol use disorder (AUD). Microglia, the brains’ resident immune cells, are involved in a variety of physiologic and pathologic processes, most notably surveying the brains’ environment for danger and carrying out necessary repair functions. Alcohol initially activates microglia but chronic consumption has been shown to suppress both peripheral and neuroimmune systems. We have preliminary data suggesting more severe neuroimmune suppression in women vs. men with AUD, which may underlie the findings that women with AUD exhibit worse mood and neurocognitive dysfunction than men. Microglia are also critical for supporting synaptic structure and function and conversely, microglial dysfunction leads to deficits in synapse number and contributes to mood and cognitive impairment. However, the relationships between microglia, synaptic density, stress, mood, and neurocognitive function in living humans with AUD are not known. In the current study, we will examine whether chronic alcohol consumption is associated with reductions in microglia (Aim 1) and synaptic density (Aim 2) and if the impairment varies by sex. We hypothesize that women with AUD evidence greater deficits in microglia and synaptic density, which underlie sex differences in stress reactivity, negative affect, and neurocognitive dysfunction in AUD (Aim 3). Thus, the proposed project has the potential to measure, for the first time, sex differences in neurochemical markers of neurodegeneration in the living brain of patients with AUD and their relationship to critical clinical outcomes. These findings will advance the alcohol field by uncovering novel, sex-appropriate treatment targets.