Exercise improves depressive-like behavior in adolescent mice by regulating sphingosine and ceramide metabolism through microglial CerS1

Given the unique onset period of adolescent depression, it is crucial to prioritize treatment modalities that are not only effective but also carry low side effects and promote overall health, with exercise emerging as a notable option. High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) stand out as two prominent forms of exercise, proven to be beneficial in addressing a multitude of disorders. Microglia mediated neuroinflammation is one of the main hypotheses leading to depression. Neuroinflammation leads to abnormal synaptic function, impaired neuroplasticity, and ultimately depressive symptoms. However, the exact mechanisms of exercise in microglia and adolescent depression remain unclear. In this study, we found that exercise can increase the expression of microglial ceramide synthase 1 (CerS1), promote the synthesis of C18 ceramide from sphingosine, and improve depressive-like behaviors in adolescent mice. Overexpression of CerS1 in the CA1 region using microglia specific adeno-associated virus (AAV) inhibits chronic unpredictable mild stress (CUMS) induced neuroinflammation. Meanwhile, overexpression of CerS1 in primary microglia inhibits lipopolysaccharide (LPS) induced neuroinflammation. These results provide new theoretical support for the treatment of adolescent depression with exercise from the perspective of animal models.