Translational animal models for studying
post-traumatic stress disorder (
PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of
PTSD-like phenotypes triggered after exposure to a single traumatic event,
trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-
trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-
trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent
PTSD-like phenotypes including exaggerated fear reactivity and avoidance of
trauma-related cue (up to 75 days post-
trauma), increased avoidance-like behavior and social/
cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by
PTSD-related genes as well as dysfunction of hypothalamic-pituitary-adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with
trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with
paroxetine ameliorated the
PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of
PTSD. It might shed light on the unclear
PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder.