Sex-divergent long-term effects of single prolonged stress in adult rats

Single prolonged stress (SPS) is an experimental model that recapitulates in rodents some of the core symptoms of post-traumatic stress disorder (PTSD). Although women have a two-fold greater risk to develop PTSD, most preclinical studies have been carried out in males. Furthermore, the long-term effects of behavioral alterations induced by SPS have been rarely investigated. Here, we evaluated the long-term effects of SPS on PTSD-relevant behavioral domains in rats and whether these effects were sex-dependent. To this aim, separate cohorts of male and female adult rats were subjected to SPS and, 30 days later, long-term effects were assessed. We found that SPS exposure reduced locomotor activity in both sexes in an open field task. Males only showed increased anxiety-like behavior in the elevated plus maze and marble burying tests, enhanced acoustic startle response and impaired spatial memory retention while females were unaffected. SPS exposure did not alter auditory fear memory dynamics in males, but it did alter extinction retrieval in females. We provide the first evidence that SPS reproduces long-term emotional alterations in male, but not in female, rats which were observed 30 days following trauma exposure, thus resembling some of the hallmark symptoms of PTSD. Furthermore, our results show for the first time a long-term SPS-induced alteration of cued fear extinction in females. Our findings are relevant to future research on trauma-related disorders and may help develop sex-specific interventions to treat PTSD.