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Neurosci."],"accepted":{"date-parts":[[2026,2,28]]},"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:p>\n                    The serotonergic system regulates diverse social and emotional processes, including formation of social networks that continue to mature throughout adolescence. In adolescent intermittent ethanol (AIE)-exposed male and female rats and postmortem human dorsal raphe nucleus (DRN) tissue from adolescent-onset alcohol use disorder (AUD) cases, we observed persistent reductions of serotonergic markers (TPH2+, 5HT+) within the DRN and its projections, accompanied by robust neuroimmune activation (HMGB1, TLR4, pNF\u03baBp65). Reduced DRN prodynorphin and selective reductions of medial DRN serotonergic neurons (TPH2+, 5HT+) suggest that specific serotonergic subpopulations are suppressed by AIE. We further found increased repressive histone markers (H3K9me2) and decreased activating markers (H3K4me3Q5ser) at the\n                    <jats:italic>Tph2<\/jats:italic>\n                    gene promoter in the DRN, consistent with epigenetic repression of the serotonergic neuron phenotype. Post-AIE treatment with glycyrrhizic acid\u2014an HMGB1 antagonist\u2014or post-AIE exercise restored serotonergic neuron populations and their projections, reversed induction of neuroimmune signaling molecules, and normalized\n                    <jats:italic>Tph2<\/jats:italic>\n                    promoter chromatin states, indicating reversible neuroimmune-mediated suppression of serotonergic phenotype rather than neuronal loss. Parallel changes in human AUD DRN tissue support a conserved mechanism. Behaviorally, AIE induced social deficits in rats that mirrors social withdrawal in AUD, an effect that was rescued by post-AIE glycyrrhizic acid treatment. In humans, early-onset problematic alcohol use is associated with social dysfunction, which is mitigated in individuals with high physical activity or anti-inflammatory interventions. Together, these findings implicate epigenetic regulation of serotonergic neuron phenotype as a key mechanism linking adolescent alcohol exposure to social pathology and identify potential targets for therapeutic interventions in individuals with adolescent-onset AUD.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.2004-25.2026","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T17:50:14Z","timestamp":1773683414000},"page":"e2004252026","update-policy":"https:\/\/doi.org\/10.1523\/jneurosci.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Repression of the Serotonergic Neuron Phenotype Following Adolescent Binge Drinking Is Restored through Inhibition of Proinflammatory Signaling by Exercise and Glycyrrhizic Acid"],"prefix":"10.1523","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3580-6819","authenticated-orcid":false,"given":"Sagan T.","family":"de 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