Pathways related to RNA processing (“RNA Metabolism,” “Processing of Capped Intron-Containing pre-mRNA”) and immune response (“Innate Immune System,” complement-related pathways) were enriched in D1- and D2-type MSNs (the projection neurons of the basal ganglia) in individuals with AUD. Gene regulatory network analysis allowed us to identify transcription factors that may regulate these differences. For example, FOXO1 was predicted to have significantly lower activity in D2 MSNs from individuals with AUD, based on the chromatin openness of its target genes. In mice, FoxO1 has been linked to the regulation of energy homeostasis in neurons41, and a lack of FoxO1 in the brain caused a depressive-like phenotype42,43. This might be relevant to the frequent co-occurrence of AUD and major depression54. The finding that different regulatory modules were enriched for genes associated with PAU vs. AUD further reinforces the genetic differences between those traits8,55.
