Compared to upregulated modules, we identified almost twice as many significantly downregulated transcription factor gene regulatory modules in individuals with OUD (Fig. 3d). We identified several downregulated pathways involved in neuroprotection (Fig. 3d). For example, the humanin-like 8 gene, MTRNR2L8, was significantly downregulated in OUD across every neuronal subtype (log2FC <−3.79, FDR < 0.0054). MTRHR2L8 and the mitochondrial paralog, MTRNR2, act as neuroprotective factors in response to neurodegeneration and the induction of DNA damage74,75. The top DEGs within clusters of pathways involved in UV irradiation, another potential link to DNA damage (FDR < 0.029, Fig. 3d), included FOXO1, TLE4, SHOC2, MEIS2, and THBS1 (log2FC <−0.64, FDR < 0.0422) in interneurons and CLASP1, PIK3C3, and MTUS1 (log2FC <−0.64, FDR < 0.042) in D1/D2-hybrid MSNs. Additionally, downregulation of MEF2B and BACH1 transcription factor gene regulatory modules were found in D1-matrix MSNs in OUD (Fig. 3e), accompanied by downregulation of MAF, EST1, ETV1, and PRRX1 modules in D1/D2 hybrid MSNs (FDR < 0.043), each of which are implicated in neuronal stress76,77. Notably, BACH1, BCL11A, and PRRX1 have downstream targets with concordant differential expression
