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White matter expansion in frontal regions during adolescence is essential for mature decision-making and stress regulation, yet the cellular mechanisms by which alcohol disrupts this process remain poorly understood. We used multi-label immunofluorescence and confocal microscopy to visualize proteins in oligodendrocyte lineage cells and myelin ensheathment of axons in the anterior cingulate cortex (Cg1) and corpus callosum (CC) following four weeks of episodic voluntary binge drinking using the Drinking-in-the-Dark model in adolescent male and female C57BL\/6NJ mice beginning on postnatal day 28. Contrary to our initial hypothesis that alcohol targets early-stage oligodendrocyte precursor cells (OPCs), binge drinking selectively depleted mature oligodendrocytes expressing aspartoacylase (ASPA) in the Cg1 and CC of male mice, but not females. This enzyme is essential for lipid biosynthesis and myelin production, and this cell-specific loss was accompanied by significant hypomyelination of axons only in males. These findings identify a later maturational stage of oligodendroglial development as a sex-dependent target of alcohol, advancing our mechanistic understanding of prefrontal myelin deficits in adolescent drinking. Furthermore, ASPA emerges as a potential therapeutic target for alcohol use disorder and demyelinating diseases, with differential vulnerability across sex carrying important implications for adult neurodevelopmental outcomes.<\/jats:p>","DOI":"10.64898\/2026.04.01.715654","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T05:10:18Z","timestamp":1775452218000},"source":"Crossref","is-referenced-by-count":0,"title":["Adolescent drinking causes a loss of aspartoacylase-expressing oligodendrocytes and hypomyelination of anterior cingulate and corpus callosum axons in male mice, but not females"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8118-6892","authenticated-orcid":false,"given":"Said","family":"Akli","sequence":"first","affiliation":[{"name":"Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5804-4872","authenticated-orcid":false,"given":"Annabelle","family":"Flores-Bonilla","sequence":"additional","affiliation":[{"name":"Neuroscience and Behavior Graduate Program, University of Massachusetts, Amherst, MA 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirisha","family":"Nouduri","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Scott","sequence":"additional","affiliation":[{"name":"Neuroscience and Behavior Graduate Program, University of Massachusetts, Amherst, MA 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7659-1212","authenticated-orcid":false,"given":"Heather N.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA 01003"},{"name":"Neuroscience and Behavior Graduate Program, University of Massachusetts, Amherst, MA 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026040803250860000_2026.04.01.715654v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20806"},{"key":"2026040803250860000_2026.04.01.715654v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23276-8"},{"key":"2026040803250860000_2026.04.01.715654v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22327"},{"key":"2026040803250860000_2026.04.01.715654v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010100"},{"key":"2026040803250860000_2026.04.01.715654v1.5","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed. 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