Sex-specific vulnerability to single prolonged stress: behavioral alterations and redox imbalance in the developing brain

Single prolonged stress (SPS) is a validated rodent model for post-traumatic stress disorder (PTSD)-like symptoms. While its effects have been extensively characterized in adults, little is known about its impact during the juvenile phase, a critical period for brain maturation. In this study, male and female rats were subjected to SPS at postnatal day 23 and, 7 days later, behavioral outcomes were assessed. Given increasing evidence implicating redox dysregulation in stress-related disorders, we also investigated the redox-related markers in the prefrontal cortex (PFC) and hippocampus, two stress-sensitive brain areas. We found that SPS increased anxious-like behavior in males and decreased it in females, and it reduced social play behavior in both sexes with a more pronounced effect in males, while cognitive performance remained unaffected. Furthermore, SPS-exposed males exhibited a decrease in the antioxidant enzyme superoxide dismutase 1 (SOD-1) in both the PFC and the hippocampus. In contrast, SPS-exposed females showed an increase in the antioxidant catalase (CAT) within the PFC and nuclear factor erythroid 2-related factor 2 (NRF-2) in the hippocampus, along with a decrease in the CAT in the hippocampus. Additionally, a reduction in oxidative stress-related markers, such as 4-hydroxynonenal (4HNE) and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX-2), was observed in the hippocampus, suggesting region-specific differences in oxidative stress regulation. Taken together, our findings indicate that SPS induces sex-divergent effects in early-adolescent rats at both behavioral and redox levels. This study provides valuable insights for future research, highlighting potential pharmacological targets for the treatment of stressrelated disorders.