Early life stress-induced vulnerability to postpartum mental disturbance: prolonged dysregulation of the HPA axis and behavior

Early life stress (ELS) increases the risk for postpartum depression (PPD). Patients with depression who experienced ELS tend to be treatment refractory. Nevertheless, it remains elusive how ELS underlies the pathophysiology of PPD at the mechanistic level. Here we observed that adolescent social isolation in mice resulted in an aberrantly sustained elevation of glucocorticoids via hypothalamic-pituitary-adrenal (HPA) axis dysregulation and long-lasting behavioral deficits during the postpartum period. The postpartum behavioral changes elicited by ELS were not ameliorated by the medicines currently used for PPD in behavioral assays that are frequently used in drug discovery for human depression. However, post-delivery treatment with a glucocorticoid receptor antagonist effectively ameliorated the deficits. We also demonstrated a significant impact of ELS on the HPA axis dysregulation and PPD in humans. In summary, we show the validity and utility of a novel model and a novel option of treatment for a subset of treatment-refractory PPD.