Early-life stress: from later psychopathologies to pharmacological interventions

Background Exposure to stress represents a major environmental risk factor for psychopathologies. However, not all individuals exposed to stressful events develop mental illness, suggesting that vulnerability or resilience arises from a complex interplay of factors, including previous life experiences. In particular, early-life adverse events have been shown to interfere with neurodevelopmental trajectories, potentially shaping susceptibility to stress-related disorders later in life. Methods Separate cohorts of adolescent Sprague-Dawley rats were exposed to different stressors during early-adolescence, including social defeat stress and social isolation stress. To assess the long-term programming effects, animals underwent a battery of behavioral tests targeting emotional and cognitive domains. According to the two-hit model, animals were later exposed to an additional stressor in adulthood to evaluate whether early-life stress (first hit) alters the response to a subsequent challenge (second hit), thereby modulating vulnerability or resilience for the development of stress-related alterations. In parallel cohorts, rats received systemic pharmacological treatment in adulthood with the glucocorticoid receptor (GR) antagonist RU486 to assess whether targeting stress-related pathways could reverse the behavioral programming effects induced by early-life stress. Results Our results demonstrated that early-life adverse events induced programming effects depending on the type of stressor. These effects were associated with alterations across multiple neurobiological pathways and brain regions. Importantly, early-life stress differentially modulated the response to a second stressor in adulthood, with outcomes varying according to the nature of the first stress exposure and the behavioral domain assessed, reflecting both vulnerability- and resilience- related profiles. Sex-dependent effects were also observed, consistent with the known modulatory role of sex hormones on stress-response systems. Notably, pharmacological blockade of glucocorticoid receptors (GR) in adulthood normalized stress-induced behavioral programming effects, supporting a key role of glucocorticoid signaling in mediating the long-term consequences of early-life stress. Conclusions These findings highlighted the critical role of early-life stress in shaping programming outcomes, as well as the importance of stressor type and sex as modulatory factors. Importantly, our results identified GR signaling as a novel pharmacological target, with potential implications for the prevention and/or treatment of stress-related psychopathologies in humans.