Multidimensional Behavioral Analysis Reveals Sex-Specific Vulnerability to a mouse PTSD Model

Post-traumatic stress disorder (PTSD) shows individual variability and sex differences that may be obscured by group analyses. We characterized sex-specific responses to single prolonged stress (SPS) and tested whether multidimensional analyses could identify vulnerability/resilience profiles. Males and females underwent SPS or control treatment. Behavior was assessed using fear conditioning/extinction, recovery, reinstatement, Y-maze, light–dark box, open field, elevated plus-maze, and tail suspension. ANOVA was complemented by control-referenced z-scores integrating risk assessment, avoidance, cognition, and active/passive coping, followed by sex-specific clustering. SPS increased freezing during extinction session 2 in males only (p<0.05). Females showed no fear-conditioning changes but displayed perseveration and longer Y-maze alternation latencies (p<0.05). SPS increased passive coping in both sexes (p<0.05). Multidimensional analyses revealed sex-dependent patterns: SPS increased males in a high-freezing extinction cluster (χ² p=0.04), but not vulnerable/resilient clusters, whereas SPS females were more often classified in a vulnerable profile (χ² p=0.0039) characterized by avoidance, negative cognition, and passive coping. These findings show SPS produces heterogeneous, sex-specific phenotypes and support individual-level multidimensional analyses for detecting vulnerability. Such approaches may better capture human heterogeneity and strengthen translational relevance.