Beyond neurons: Oligodendrocyte dysfunction and myelin pathophysiology in alcohol use disorder.

Alcohol Use Disorder (AUD) is a leading risk factor for negative health consequences associated with disruptions in neural functions. While ethanol-induced neuronal adaptations have remained in the spotlight for researchers investigating AUD, growing evidence highlights glial cell populations and their contributions to AUD pathology. This review explores the role of oligodendrocytes (OLs) and their progenitors (OPCs) in ethanol-induced alterations of white matter (WM), myelin structure, composition, and integrity. Human neuroimaging studies reveal reductions in WM volume and microstructural integrity, accompanied by molecular evidence of impaired myelin architecture and lipid composition in postmortem brains. Preclinical models provide causal evidence linking ethanol to dose-, length of exposure-, and brain-region-dependent dysregulation of OLs at transcriptional, structural, and metabolic levels. Investigations of the underlying mechanisms implicate oxidative stress, neuroinflammation, transcriptional changes, epigenetic modifications, and lipid dysregulation as key pathways through which ethanol disrupts OLs. Because OLs are essential for proper myelination, neural function, and brain connectivity, ethanol-induced changes in these processes likely contribute to the cognitive, learning, and emotional deficits associated with AUD. Investigations into prenatal and adolescent ethanol exposure reveal impairments in OL maturation and myelination that produce long-lasting deficits which persist into adulthood. Together, these findings support ethanol-induced OL dysregulation and circuit disruption as drivers in AUD pathology. Understanding how ethanol impacts OLs and OPCs at both molecular and developmental levels is critical for identifying novel therapeutic targets aimed at ameliorating disruptions to WM integrity, diagnosing AUD, and improving outcomes for individuals impacted by AUD.