Late glucocorticoid receptor antagonism counteracts the programming effects of brief and repeated social isolation stress in early-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. Manipulations during critical phases for brain development can have long-term effects on emotional reactivity. Such ‘programming’ of the brain in early-life can be reversible by treatment with glucocorticoid receptor antagonists during adult life, through unknown mechanisms. In this current study, 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 glucocorticoid receptor 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, given that these areas are involved in the regulation of emotionality and cognitive functions, and are still not completely developed during the early-adolescence. We found in two independent experiments that SIS during adolescence induced anxiety-like behavior in the elevated plus maze and acoustic startle response tasks in adulthood. Strikingly, we found that treatment with RU486 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, suggesting that gene expression in these two brain areas is not involved in the behavioral effects of treatment. Our data suggest that glucocorticoid stress hormones maintain the programming effects on emotional reactivity, but additional studies are needed to understand the neurobiological underpinnings of this process.