The NADIA consortium is dedicated to identifying the mechanisms underlying the long-term effects of adolescent intermittent ethanol exposure (AIE) on brain and behavior and exploring approaches to prevent or reverse them. Component 1 has focused on the enduring effects of AIE on hippocampal structure and function and their behavioral sequelae. Based on our findings, our overarching hypothesis AIE causes an enduring but reversible compromise of hippocampal synaptic function driven by interacting epigenetic, neuroinflammatory, and glial mechanisms. During the last NADIA funding cycle we found that AIE produces a pro-inflammatory milieu in the hippocampal formation, alterations of dendritic spine density and morphology, altered histone acetylation and methylation, diminished astrocyte-synaptic proximity, decreases in neurogenesis, and increases in the mobilization cell death molecular machinery. Through NADIA collaborations, we further identified epigenetic changes that suggest specific molecular mechanisms underlying those effects. Importantly, we have also shown that many of those effects are reversible in adulthood with pharmacological agents in current clinical use. Our recent findings indicate that AIE results in a propensity toward anxiety-like behavior after environmental challenge, thus suggesting the need to expand our assessments to the ventral hippocampus. This has obvious translational implications because anxiety and stress reactivity are strong predictors of AUD development and relapse, and suggests that some of the AIE-induced changes we have observed in the dorsal hippocampus may be similar in the ventral region. Against this backdrop we propose three Specific Aims that will more fully characterize the AIE-induced phenotypes we have identified, identify mechanisms underlying them, and explore treatments to reverse them. Aim 1 will address the role of histone H3K27 acetylation, and other possible molecular mechanisms, in AIE- induced dendritic spine changes, and further characterize our previously-reported reversal of AIE-induced spine changes by donepezil. Aim 2 will follow-up our recent findings to identify mechanisms underlying AIE- induced induction of hippocampal inflammatory markers and corresponding reductions of neurogenesis and increased cell death cascade markers. Aim 3 is founded on preliminary data indicating that AIE causes a decrease in astrocyte-synaptic proximity that could be of functional synaptic significance. We will confirm and expand that finding, and assess its pharmacological reversibility in adulthood. Our goal is to explore possible interlacing mechanisms underlying AIE effects on synaptic, inflammatory, and glial function. These proposed studies are all based on distinct sets of preliminary data, will address specific epigenetic and molecular mechanisms underlying AIE effects on hippocampal structure and function, and will expand our understanding of translationally-relevant AIE-induced phenotypes.