In oligodendrocytes, we observed differences in expression and chromatin accessibility in thousands of genes, and enrichment in biological pathways relating to neurotransmitter uptake and depolarization. The gene encoding myelin basic protein had slightly, but significantly, lower expression in individuals with AUD. There is evidence that action potential propagation through axons can be regulated by oligodendrocyte depolarization.71 In pathological conditions such as excitotoxicity, excessive neurotransmitter release from neurons can lead to an excessive intracellular Ca2+ flux into oligodendrocytes, damaging myelinating processes.72 Lower MBP expression was limited to cells marked by higher expression of OLIG2 (Fig. 6G-H). OLIG2, a master regulator in mature and developing oligodendrocytes, has been shown to have higher activity after brain injury,73 and is linked to myelination: replacing Olig2 with its dominant-active form in rodents led to decreased expression of MBP,74 and deletion of the Olig2 gene accelerated remyelinating processes.75 This suggests that our observed increase in OLIG2 activity in individuals with AUD may in part lead to dysregulation of myelination in oligodendrocytes. Indeed, alcohol consumption and alcohol use disorder have been found to be associated with white
