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

Summary

Regular exercise, especially high-intensity training, can help improve depression symptoms in young people by changing how immune cells in the brain function. The study shows that exercise increases production of a specific enzyme (CerS1) in microglia, which are the brain’s immune cells. This enzyme helps balance certain fatty molecules that reduce brain inflammation, ultimately improving mood and reducing depression-like behaviors. The findings suggest exercise works similarly to antidepressant medications for adolescent depression.

Background

Adolescent depression is increasingly prevalent and differs from adult depression in etiology and treatment response. Microglia-mediated neuroinflammation is a key hypothesis in depression pathogenesis. Exercise shows promise as a low-side-effect treatment, but mechanisms in adolescent depression remain unclear.

Objective

To investigate how high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) improve depressive-like behaviors in adolescent mice through microglial ceramide synthase 1 (CerS1) and sphingolipid metabolism.

Results

Both HIIT and MICT increased microglial CerS1 expression and improved depressive-like and anxiety-like behaviors in CUMS mice. CerS1 overexpression inhibited LPS-induced neuroinflammation in vitro and reduced CUMS-induced neuroinflammation in vivo. CerS1 promotes C18 ceramide synthesis from sphingosine while suppressing pro-inflammatory signaling via NF-κB/MAPK pathways.

Conclusion

Exercise alleviates adolescent depression by increasing microglial CerS1 expression, which regulates sphingolipid metabolism to suppress neuroinflammation. Microglial CerS1 represents a potential therapeutic target for adolescent depression treatment.
  • Published in:Communications Biology,
  • Study Type:Animal Model Study,
  • Source: 10.1038/s42003-025-08347-7, PMID: 40537488
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