We identified several transcription factor gene regulatory modules that were significantly upregulated in different neuronal subtypes, including cell senescence, DNA damage, and inflammation, and stress (Fig. 3b, e; FDR < 0.05). For example, the module linked to BCLAF1 was upregulated in OUD, a transcription factor involved in the transduction of NFkB-dependent signaling and the activation of DNA-damage-induced senescence39,67,68 (Fig. 3e). Another module was associated with the upregulation of the neuron-specific glucocorticoid receptor transcription factor, NR3C1, previously linked to the impact of psychosocial stress on the human brain69,70 (Fig. 3e). Other stress-related transcription factor gene regulatory modules were upregulated in OUD, including ATF271 and ZNF518A. Both transcription factor modules were upregulated primarily in D1-matrix and D2-matrix MSNs (FDR < 0.04). ATF2 is induced by stress in mouse dorsal striatum71 and phosphorylated downstream of delta opioid receptor activation72, suggesting delta opioid receptor activation of ATF2-dependent transcription in striatal matrix MSNs73 may be due to an interplay between stress and opioids in OUD.
