Sex differential effects of early maternal separation on PTSD susceptibility in adult rats accompanied by telomere shortening in the hippocampus

•Different degrees of MS have varying effects on the susceptibility of adult rats to PTSD.•Rats subjected to short-term MS demonstrate adaptability when confronted with 'secondary stress'.•This process involves telomere shortening in the hippocampus, with notable gender differences.•The relative gene and protein expressions levels of TRF1 and TRF2 were upregulated. Early life stress (ELS) is thought to be a leading cause of mental disorders in adulthood, including PTSD. Recent studies have found that such stress has a gender and resilient specific effect on adult PTSD. This study aimed to assess emotion, and cognitive behavior, and to examine the sex differences and resilience of ELS on adult PTSD. At the same time, the expression of hippocampal telomere length and telomere repeat binding factors (TRF1 and TRF2) were detected to explore the mechanism of telomere length change. Rat offspring were separated from their dams (3 h/day or 6 h/day from PND2 ∼ PND14). Then, pups were treated with a single prolonged stress (SPS) procedure when they reached adulthood (PND80). Rats exposed early to MS and SPS showed anxiety-like and depression-like behaviors as well as impaired learning and memory. The rats exposed to MS3h showed reduced anxiety-like and depression-like behavior upon re-experiencing “secondary stress” compared to the SPS and MS6h groups. Behavioral results showed no significant gender difference. However, gender and SPS factors significantly affected telomere length and TRF1 and TRF2 gene expression in hippocampus. The SPS effect and MS*SPS interaction significantly impacted TRF1 and TRF2 protein expression. In conclusion, this study shows that MS has different effects on anxiety, depression, and cognitive memory deficits in rats experiencing “secondary stress” in adulthood and is accompanied by telomere shortening in the hippocampus. This reveals the potential impact of early MS on PTSD and provides a new perspective for further research in the field of psychological stress.