Social hierarchy shapes behavioral and transcriptional responses to chronic stress and ketamine in male mice

Chronic stress is a major risk factor for psychiatric disorders, yet the mechanisms underlying individual variability in stress vulnerability and treatment response remain poorly understood. Here, we combined a novel behavioral phenotyping system with high-throughput gene expression profiling to examine how chronic stress and ketamine treatment interact over time. Bulk RNA sequencing was performed in the medial prefrontal cortex and ventral hippocampus, revealing a hierarchy-dependent transcriptional response with 141 differentially expressed genes in the medial prefrontal cortex of dominant, ketamine-treated mice, enriched in synaptic and postsynaptic compartments. These findings identify synaptic remodeling as a substrate for ketamine’s sustained antidepressant effects and underscore social rank as a critical factor when dissecting molecular responses to stress and treatment.