Development of PTSD-like behavior in adult mice after observing an acute traumatic event

In human post-traumatic stress disorder (PTSD), a major psychiatry challenge is how diverse stress reactions emerge after a protracted symptom-free period. Here, we study the behavioral development in mice isolated after observing an aggressive encounter inflicted upon their pair-housed partners and compared the results with those in multiple control paradigms. Compared with mice plainly isolated, mice isolated following the acute witnessing social stress gradually developed a wide range of long-term differences of their physiological conditions, spontaneous behaviors, and social interactions, including paradoxical results if interpreted in traditional ways. To address this developmental diversity, we applied fine-scale behavioral analysis to standard behavioral tests and showed that the seemingly sudden emergent behavioral differences developed gradually. Mice showed different developmental patterns in different zones of a behavior testing apparatus. However, the results of the fine-scale analysis together with state-space behavioral characterization allow a consistent interpretation of the seemingly conflicting observations among multiple tests. Interestingly, these behavioral differences were not observed if the aggressive encounter happened to a stranger mouse. Additionally, traumatized mice showed rebound responses to their partners after the long separation. In contrast, mice pair-housed with their attacked partners after the aggressive encounters still showed a difference in social interactions, while a difference in spontaneous behaviors did not occur. Accordingly, we propose that social relationship is the single common factor underlying the otherwise independent development of behavioral differences in this mouse paradigm and that the gained insights could have parallels in human PTSD development.