Behavioral phenotype analysis highlights sleep heterogeneity and brain cellular activations in a mouse model of PTSD

Exposure to intense and unavoidable stressor can lead to Post Traumatic Stress Disorder (PTSD) in some individuals. The heterogeneity of symptom expression, including sleep alterations, may explain the high rate of both non-responder and relapse of current treatments. Understanding individual-specific brain activity related to stress behavioral responses seems crucial for developing refined and personalized treatments strategies. For this purpose, we evaluated the behavior of outbred mice through multiple tests up to 28 days after two inescapable electrical foot-shocks (FS). A two-step behavioral phenotype analysis successfully identified three phenotypes among FS mice. First, the scoring of behavioral alterations severity, based on PTSD-like symptoms, differentiated susceptible and resilient animals. Second, the specific type of stress-induced defensive behaviors further categorized two susceptible phenotypes: freezers and escapers. Sleep patterns specific to phenotype emerged 14 days after the FS exposure. Notably, resilient mice exhibited more time spent in rapid eye movement sleep than susceptible animals, a variable that was negatively correlated to the behavioral alteration severity score. Finally, behavioral profiling highlighted different c-Fos protein expressions in amygdala (AMG) and in the periaqueductal gray matter (PAG) across phenotypes, suggesting region-specific neural responses. Specifically, the severity of PTSD-like behaviors was correlated to the right lateral and central-lateral AMG cellular activations. In conclusion, this study emphasizes the relevance of using composite score of multiple behavioral tests to better understand the complexity of stress responses and interindividual variability. Moreover, our findings suggest a role of REM sleep in promoting behavioral resilience to high-intensity stress.