Adolescent drinking causes a loss of aspartoacylase-expressing oligodendrocytes and hypomyelination of anterior cingulate and corpus callosum axons in male mice, but not females.
Adolescent binge drinking is a strong predictor of alcohol use disorder and related mental health outcomes in adulthood, which may be due to disruptions in myelination during this dynamic period of brain development. White matter expansion in frontal regions during adolescence is essential for mature decision-making and stress regulation, yet the cellular mechanisms by which alcohol impairs myelination remain poorly understood. Multi-label immunofluorescence and confocal microscopy were used to visualize proteins in oligodendrocyte lineage cells and myelin ensheathment of axons in the anterior cingulate cortex (Cg1) and corpus callosum (CC) of male and female C57BL/6NJ mice following four weeks of episodic voluntary binge drinking during adolescent development using the Drinking-in-the-Dark model. Contrary to our hypothesis, alcohol targeted mature oligodendrocytes rather than early-stage oligodendrocyte precursor cells (OPCs). Binge drinking reduced oligodendrocytes expressing aspartoacylase (ASPA) in the Cg1 and CC. This enzyme is essential for lipid biosynthesis and myelin production, and cellular loss was accompanied by hypomyelination of axons. Notably, males appear especially sensitive to adolescent alcohol, as ASPA+ oligodendrocytes and myelin were not reduced in binge-drinking females. Differential vulnerability could carry important implications for adult neurodevelopmental outcomes. Altogether the findings advance our mechanistic understanding of myelin deficits after alcohol, identifying late-stage oligodendroglial development and ASPA as possible targets for therapeutic intervention in the treatment of alcohol use disorder and demyelinating diseases.