Cumulative mild stress during early life alters prefrontal astrocytic proteins and elevates peripheral S100B in young adult mice.

The prevalence of major depressive disorder (MDD) in young adulthood has increased in recent decades and represents a leading cause of psychological burden, highlighting the importance of prevention and early intervention for depression in young adults. Early-life stress has been closely associated with the onset of depression in young adulthood, leading to adverse outcomes, including reduced quality of life, impaired social functioning, and socioeconomic burden. Among the various neuropathological features of depression, astrocytic abnormalities are increasingly recognized as key contributors. Therefore, we aimed to investigate the association between dysregulated astrocyte expression and depression in young adults. We utilized CPMS (cumulative mild prenatal stress, maternal separation and social defeat) mice as a young adult depression model, in which animals were exposed to a cumulative mild stress (CMS) paradigm during development, including prenatal stress, maternal separation, and social defeat. We further categorized CPMS mice into susceptible and resilient groups based on social interaction behavior. To explore the translational relevance of our findings, we subsequently analyzed blood samples from drug-naïve patients with MDD in young adulthood (mean age of 24 years). CPMS-susceptible mice of both sexes exhibited anxiety- and depression-like behaviors, accompanied by reduced expression of astrocytic markers in the prefrontal cortex. Furthermore, elevated S100B protein levels were observed in the blood of both CPMS mice and patients, showing a positive correlation with the severity of clinical symptoms. Together, these findings indicate that exposure to CMS during early life is associated with altered astrocytic protein expression and elevated circulating S100B, highlighting its potential relevance as a biomarker for depression in young adulthood.