Stress in the early stage of development, especially in early adolescence, has a long term impact on the brain and behaviors so that increases the risk of mood disorders significantly. Autophagy is one of the basic functions to maintain cell homeostasis, which plays an important role in brain development and stress responses.Recent clinical and experimental evidence has shown that patients who suffered from mood disorders and relevant model animals had abnormal autophagy responses, but its role in the pathogenesis of psychopathology and its correlation with specific symptomatic phenotypes are still unclear. Whether and how autophagy influences the susceptibility to early stress induced disease is not understood yet.
Adolescence is a high incidence and sensitive period for kinds of mood disorders. While social stress is an important predisposing factor for mood disorders. The established adolescent social stress paradigm and adult forced swimming stress were carried out in the investigation of 1) basal emotional behaviors and susceptibility to subsequent stress at adulthood; 2) brain basal autophagy activity and response to subsequent stress; 3) relationship between emotional behavior and autophagy responses inner brain. Sucrose preference test, three chambers social behavior test, and forced swimming test were conducted to evaluate depressive behavior. Open field tests and eleva ted plus maze tests were perform ed to assess anxiety behavior. The social avoidance test was used as an indicator of experience related fear behavior. Weste rn blot experiments were carri e d out to detect the expression levels of autophagy-related proteins in emotion-related brain regions, including the medial Prefrontal cortex (mPFC) and subcortical limbic regions (hippocampus, amygdala, nucleus accumbens, and hypothalamus). The upstream autophagy protein Beclin-1, LC3II protein which is located in the membranes of the autophagosome, and the autophagy substrate degradation marker p62 were chosen as the biomarkers of autophagy flow.
Results: 1) Adolescent social defeat stress stably induced fear behavior and decreased interest in social interaction in adult mice, but no significant changes in anxiety behaviors at baseline. Adult animals which experienced adolescent social defeat stress behaved more anxious in open field test after the second hit, suggesting susceptibility to secondary stress. 2) In the stress group, the expression of LC3II in the hippocampus decreased in the basal state of adult mice, indicating a lower autophagic level. While it expressed the opposite trend after the second hi t. The expression levels of LC3II and Beclin 1 in the medial prefrontal cortex were decreased after secondary stress, indicating decreased autophagy levels. However, there were no significant changes in the expression of autophagy related proteins in the a mygdala, nucleus accumbens and hypothalamus. 3) Correlation analysis suggested fear behavior was negatively correlated with autophagy activity in the medial prefrontal cortex and positively correlated with autophagy activity in the hippocampus after second ary stress. There was a significant positive correlation between social interest and medial prefrontal autophagy activity. There was a marginal correlation between animal anxiety behaviors in the open field and LC3II protein expression in mPFC after the se condary stress.
Conclusion: In this study, we found autophagy activity changes in the emotion regulating brain region may be involved in the long lasting effect of adolescent social stress on adulthood emotional behavior, which provides new evidence to fur ther study the role of autophagy in early stress induced susceptibility to mood disorders.