Using gene set enrichment analyses (GSEA)55, we identified pathways significantly enriched in aggregate cell types and across specific cell types. Across cell types, we found 286 pathways (34 ± 7 pathways per cell type; FDR < 0.05, Supplementary Data 1-S7) and 51 differentially regulated transcription factor regulatory modules (5.1 ± 0.7 per cell type, FDR < 0.05, Supplementary Data 1-S8). The cell type-specific transcriptional differences in individuals with OUD were represented largely by distinct biological processes between neurons and glia (Fig. S6). Among MSNs, DEGs tended to be shared between MSN subtypes, while DEGs tended to be more distinct between glial subtypes and between interneuron subtypes (Fig. S5). We identified a higher number of DEGs in interneuron subtypes and D1/D2-hybrid MSNs compared to canonical D1-MSNs or D2-MSNs. DEGs in D1/D2-hybrid MSNs were unique relative to canonical MSNs, suggesting subpopulations of striatal MSNs exhibit different molecular responses to chronic opioid use and other factors associated with OUD (Fig. S5).
