Phenotype-Specific Transcriptomic Responses to Glucocorticoid Signaling in the Prefrontal Cortex and Dorsal Raphe...

Chronic stress produces marked individual differences in behavioral adaptation and glucocorticoid sensitivity, but the molecular basis of this variability remains poorly understood. Here, we examined transcriptional responses to glucocorticoid receptor activation after chronic social defeat stress (CSDS) in male C57BL/6J mice. Based on behavioral responses during social interaction, stressed animals were classified into active coping strategy (AS) and passive coping strategy (PS) phenotypes. A total of 24 h after the final stress session, mice received 2 µg/g of dexamethasone (DEX) or a saline injection, and transcriptomic profiling of the prefrontal cortex (PFC) and dorsal raphe nucleus (DRN) was performed 6 h later using RNA sequencing. Chronic stress induced pronounced phenotype- and region-specific transcriptional alterations. The PFC showed extensive stress-associated gene expression changes, particularly in PS animals, whereas the DRN displayed comparatively fewer differentially expressed genes. Functional enrichment analysis nevertheless revealed substantial pathway-level remodeling in both regions. PS animals exhibited extensive pathway reorganization in the DRN, while AS animals showed broader suppression of enriched biological pathways in the PFC. Acute DEX administration further revealed marked phenotype-dependent differences in glucocorticoid-responsive transcriptional programs, with the strongest response observed in AS animals. Together, these findings demonstrate that chronic stress establishes distinct transcriptional states that shape subsequent DEX-induced transcriptional responses in a phenotype- and brain region-specific manner. Our results provide new insight into the molecular mechanisms underlying heterogeneity in stress adaptation.