We conducted separate pathway analyses on upregulated and downregulated transcripts (Fig. 3a) between unaffected individuals and individuals with OUD. In neurons, most of the upregulated pathways in OUD were related to processes of cell stress response (Fig. 3c). For example, pathways of DNA replication and cell cycle re-entry were upregulated in MSNs (Fig. 3c; Supplementary Data 1-S9)56. Both MCM8 (log2FC > 1.06, FDR < 0.041) and myosin light-chain 6, MYL6, (log2FC > 1.13, FDR < 0.045), genes involved in DNA replication, were significantly upregulated in striatal MSNs (Fig. 3a). MCM8, forms a complex with MCM9 to facilitate repair of double-stranded DNA breaks57,58. MYL6 is a key factor in rho-GTPase signaling, known to facilitate glutamate receptor endocytosis59 and neuroplasticity60,61, and may be involved in DNA damage via the activation of RAC162. APOE63–65 (striosome MSNs and D2-matrix MSNs: log2FC > 2.50, FDR < 0.025; Fig. 3a) and GPX4 (D1-striosome MSNs: log2FC > 1.17, FDR < 0.044) were also upregulated in MSNs of individuals with OUD. Both APOE and GPX4 are involved in neuronal oxidative stress, where GPX4 buffers the accumulation of reactive
