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 differences in vulnerability and treatment response remain poorly understood. Using the Social Box, a seminatural environment, we performed high-resolution, continuous tracking of group-housed male mice during 11 days, capturing behavior during both active and inactive phases. We found that social hierarchy within a group strongly shapes stress outcomes, with dominant individuals exhibiting amplified behavioral alterations following chronic stress, including rest fragmentation and disrupted social interactions. A single ketamine administration mitigated these effects, restoring baseline behavioral signatures in dominant individuals. Bulk mRNA sequencing was performed in the medial prefrontal cortex and ventral hippocampus. This revealed a hierarchy-dependent transcriptional response with 141 differentially expressed genes in the medial prefrontal cortex of dominant, ketamine-treated mice. Overall, this study provides a framework for examining stress and pharmacological interventions in group-housed mice, enabling high-resolution, longitudinal analyses under semi-naturalistic conditions.