Long-term excessive alcohol consumption enhances myelination in the mouse nucleus accumbens

Chronic excessive alcohol (ethanol) consumption induces neuroadaptations in the brain's reward system, including biochemical and structural abnormalities in white matter that are implicated in addiction phenotypes. Here, we demonstrate that long-term (12-week) voluntary ethanol consumption enhances myelination in the nucleus accumbens (NAc) of female and male adult mice, as evidenced by molecular, ultrastructural, and cellular alterations. Specifically, transmission electron microscopy analysis showed increased myelin thickness in the NAc following long-term ethanol consumption, while axon diameter remained unaffected. These changes were paralleled by increased mRNA transcript levels of key transcription factors essential for oligodendrocyte differentiation, along with elevated expression of critical myelination-related genes. In addition, diffusion tensor imaging (DTI) revealed increased connectivity between the NAc and the prefrontal cortex (PFC), reflected by a higher number of tracts connecting these regions. We also observed ethanol-induced effects on oligodendrocyte (OL) lineage cells, with a reduction in the number of mature OLs (mOLs) after 3 weeks of ethanol consumption, followed by an increase after 6 weeks. These findings suggest that ethanol alters OL development prior to increasing myelination in the NAc. Finally, chronic administration of the pro-myelination drug clemastine to mice with a history of heavy ethanol consumption further elevated ethanol intake and preference, suggesting that increased myelination may contribute to escalated drinking behavior. Together, these findings suggest that heavy ethanol consumption disrupts OL development, induces enhanced myelination in the NAc, and may drive further ethanol intake, reinforcing addictive behaviors. Significance Statement The myelin sheath is crucial for the development, maintenance, and normal functioning of the brain. Here, we provide evidence for the involvement of myelin alterations in alcohol (ethanol)-drinking behaviors. We show that chronic ethanol intake leads to enhanced myelination in the nucleus accumbens of adult mice. Moreover, we demonstrate that increasing myelination in heavily drinking mice leads to an escalation in ethanol intake. Thus, our results suggest that ethanol affects myelination processes, which, in turn, may affect ethanol-drinking patterns. Understanding the impact of ethanol on myelination could enhance our comprehension of alcohol addiction and open new avenues for treatment.