< 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 oxygen species to prevent apoptosis63–65. Accumulation of reactive oxygen species and oxidative stress in neurons involves alterations in redox signaling and mitochondrial respiration66. Indeed, across multiple MSN subtypes, genes involved in mitochondrial respiration were significantly upregulated in OUD, including a complex III subunit of the mitochondrial respiratory chain, UQCR11 (log2FC > 1.36, FDR < 0.042), and a subunit of complex I, NDUFA4 (log2FC > 1.29, FDR < 0.030).
