Chronic Pre‐Trauma Corticosterone Attenuates Trauma Memory Formation and Alters Gene Expression in Glucocorticoid Signalling Pathways

Glucocorticoid signalling plays a central role in the processing of traumatic memories and contributes to adaptive and pathological responses to stress, with dysregulation frequently reported in trauma-related conditions such as post-traumatic stress disorder (PTSD). A key stage in trauma memory formation is the early consolidation window, during which aversive experiences are stabilised into long-term memory through protein synthesis and activity-dependent gene expression. To investigate how glucocorticoid levels during trauma exposure shape this process, we examined the behavioural and molecular consequences of acute and chronic corticosterone elevation, the rodent analogue of cortisol. Adult male mice received either repeated corticosterone injections for 5 days prior to fear conditioning (FC) or vehicle injections for 5 days followed by a single corticosterone injection immediately before FC. Two hours after FC, we quantified expression of genes encoding mineralocorticoid receptors (Nr3c2, MR), glucocorticoid receptors (Nr3c1, GR), and FK506-binding protein 5 (Fkbp5) in the amygdala, hippocampus, and anterior cingulate cortex (ACC). Trauma memory was assessed 24 h later by measuring freezing and exploratory behaviour to conditioned cues in separate experimental cohorts. Chronic corticosterone exposure was associated with attenuated conditioning-related behavioural responses, whereas acute corticosterone did not alter these responses. These effects were accompanied by region-specific alterations in glucocorticoid-signalling gene expression, most notably coordinated regulation of hippocampal and ACC Nr3c2 following FC. We propose that this regional Nr3c2 transcriptional signature represents an early molecular adaptation to prolonged glucocorticoid exposure that may alter hippocampal-prefrontal communication during trauma-memory formation.