Late glucocorticoid receptor antagonism 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. The present study aims at investigating the programming effects induced by brief and repeated SIS at early-adolescence and the potential effectiveness of late glucocorticoid receptor (GR) antagonism in counteracting such SIS-induced alterations. Further, the neurobiological mechanisms underlying these effects were evaluated as well. Male Sprague-Dawley rats were subjected to two hours of SIS per day during early-adolescence from postnatal day (PND) 28 to PND 34. Adult animals stressed in early-adolescence and their relative control groups were intraperitoneally treated with the GR antagonist RU486 (30 mg/kg) or vehicle at PND 83, 85 and 87. Potential reversal of programming effects on behavioral reactivity was evaluated starting 1 week after treatment (PND 90). To investigate the neurobiological mechanisms underlying such effects, transcriptome analysis was performed within ventral and dorsal hippocampus. Our results demonstrated that brief and repeated periods of SIS during early-adolescence induced a reduction of time spent in the open arms, number of entries in the open arms and frequency of head-dippings in the elevated plus maze task, and an enhanced emotional reactivity in the acoustic startle response task, suggesting 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 glucocorticoid stress hormones due to SIS exposure during early-adolescence induced effects on emotional reactivity which persist later in life and which are counteracted by late GR antagonism. These findings have a groundbreaking potential of introducing a promising therapeutic approach to treat and counteract the development of stress-related disorders long-after trauma. However, additional studies are needed to understand the neurobiological underpinnings of this process.