Development of a novel analysis method for evaluating PTSD-like behavior in mice based on DSM-V criteria

Posttraumatic stress disorder (PTSD) occurs after exposure to a traumatic event, leading to debilitating symptoms, including avoidance, hypervigilance, and functional impairment. There is a paucity of effective therapies to treat PTSD, partially due to the difficulty in identifying consistent underlying mechanisms. Using a modified single prolonged stress (mSPS) paradigm combined with single housing to induce both acute fear conditioning and chronic stress in mice, we developed a novel analysis method to robustly define a PTSD-like phenotype based on the criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V). Following mSPS exposure, C57BL/6NHsd mice underwent behavioral testing to examine each of the criteria of PTSD according to the DSM-V. Specific parameters with the largest effect sizes between mSPS and non-mSPS mice were chosen. Absolute z-scores were generated for each behavioral parameter, and mSPS mice whose z-scores were outside the 85th confidence interval for at least one parameter for each of the eight criteria were defined as susceptible; the remainder of the exposed mice were considered resilient. Finally, resilient mice were evaluated for anhedonia and hyperlocomotive behaviors. The results demonstrated that a PTSD-like phenotype can be robustly defined in mice based on all 8 DSM-V criteria. Importantly, 29.76% of mSPS mice were classified as susceptible, which is similar to the incidence observed in humans exposed to trauma. This novel behavioral analysis method may assist in better defining a PTSD-like phenotype, identifying a more robust population, which may help facilitate the discovery of the underlying mechanism(s) of PTSD and its association with other comorbidities.