In the brain, FKBP5101,102 is likely a key factor involved in stress and opioids in females. FKBP5 was significantly upregulated in astrocytes, oligodendrocytes, and oligodendrocyte precursor cells of females with OUD (Fig. 6c; log2FCF glia > 1.30, FDRF glia < 0.0165, log2FCM = −1.62, FDRM interneurons < 0.040). Preclinical studies have found marked sex differences of Fkbp5 expression in dorsal striatum in response to opioids103,104, and thus, investigated whether there were similarities in gene changes between rodents and humans in dorsal striatum. Indeed, gene sets from rodents exposed to opioids were significantly enriched for genes we found in both glia and oligodendrocytes of females with OUD (FDRF glia < 0.027; Supplementary Data 1-S16). Cross-species enriched DEGs were associated with reduced expression of genes involved in synaptic regulation, particularly in astrocytes (Fig. 6b; cluster 6), spanning both pre- and postsynaptic compartments (Fig. 6d; Supplementary Data 1–S14, S15). In contrast, male-biased molecular alterations in OUD were largely found in microglia, MSNs, and interneurons (Fig. 6e; clusters 12, 15, 16), enriched in mitochondrial pathways (Fig. 6f). Collectively, our evidence of sex differences in cell type-specific molecular signaling suggests an augmented, magnified glial cell response in females compared to males with OUD.
