Late treatment with RU486 normalizes the programming effects of brief and repeated periods of social isolation stress in adolescent rats

Social isolation stress (SIS) is one of the most commonly used stress paradigms to reproduce psychiatric-like disorders in rodents and it is generally conducted for several weeks from weaning to adulthood. However, the long-term effects of briefer periods of SIS only during early-adolescence, a critical phase for brain development, are less explored. Here, male Sprague-Dawley rats were subjected to 2 hours of SIS per day during early-adolescence (postnatal day, PND 28-34). Adult animals stressed in early-adolescence and their relative control groups were intraperitoneally treated with the glucocorticoid receptor antagonist RU486 (30 mg/kg) or vehicle at PND 83, 85 and 87. Then, the programming effects induced by SIS during early-adolescence on the emotional domain and the effectiveness of antiglucocorticoid treatment to normalize behavior were evaluated. To investigate the neurobiological underpinnings of such effects, transcriptome analysis was performed within ventral and dorsal hippocampus. Our results demonstrated that SIS during early-adolescence induced the development of anxious-like profile later in life. Strikingly, we found that treatment with RU486 at adulthood normalized such SIS-induced programming effects in rats tested 1 week after treatment. However, transcriptome analysis did not reveal significant alterations within ventral and dorsal hippocampus, indicating that gene expression in these two brain areas is not involved in the behavioral effects of SIS and treatment. Our data reveal that SIS during early-adolescence profoundly affect behavior at adulthood and that antiglucocorticoid treatment normalizes these behavioral alterations. Additional studies will be performed to better understand the neurobiological underpinnings involved in this process.