We integrated the transcriptomic and epigenetic alterations in each cell type into predictions of upstream signaling events. We found increased signaling via TFGB1-ITGB8 from both microglia and astrocytes to oligodendrocytes. TGF-β1 signaling is known to increase after injury, and studies have shown that ethanol exposure induces TGF-β1 signaling in rats67,68. Signaling from microglial cells to astrocytes that involves pro-inflammatory molecules IL-1β, TNF, and oncostatin M is higher in individuals with AUD, concordant with the hypothesis that activated microglia induce neurotoxic reactive astrocytes47. These three molecules work synergistically in astrocytes and other cells to induce pro-inflammatory and neurotoxic molecules such as nitric oxide69 and prostaglandin E(2)49. Although reactive astrocytes can induce death of neurons and oligodendrocytes, we did not observe a significant difference between individuals with and without AUD in relative proportions of neuronal cell types or oligodendrocytes.
