In astrocytes from individuals with AUD there was significantly higher expression of astrocyte reactivity marker C3. This extends to the caudate evidence from studies that demonstrated that inflammation evoked by ethanol exposure is accompanied by reactive astrogliosis.8,69 The cells with increased C3 expression also had significantly higher predicted activity of bZIP transcription factors such as JUND, suggesting that changes in these transcription factors may be regulating astrocytes as they undergo reactive astrogliosis. Gene regulatory network analysis identified a group of genes with similar patterns of trans-regulation that had decreased expression in AUD. These genes were overrepresented within gene sets related to glutamatergic synapses, consistent with previous work linking the disruption of glutamate homeostasis in astrocytes to AUD.69 Other enriched pathways in these co-expressed and regulatory genes in astrocytes include nervous system development and negative regulation of Wnt signaling. A recent study implicated the disruption of Wnt signaling in the striatum of rats as an effect of high cocaine self-administration,70 but its potential link with alcohol is novel. Together this suggests that decreased regulation of Wnt signaling, especially in astrocytes, may play an important role in alcohol addiction.
