Therapeutic effects of exercise on depression: The role of microglia

•Stress-induced microglial activation mediates thepathogenesis of depression through various mechanisms.•Exercise therapy can shift the balance of microglial M1/M2 polarization and regulate inflammatory responses.•Microglia are crucial targets for exercise-based therapeutic interventions for depression. Major depressive disorderadversely affects mental health. Traditional therapeutic approaches, including medication, psychological intervention, and physical therapy, exert beneficial effects on depression. However, these approaches are associated with some limitations, such as high cost, adverse reactions, recurrent episodes, and low patient adherence. Previous studies have demonstrated that exercise therapy can effectively mitigate depressive symptoms, although the underlying mechanism has not been elucidated. Recent studies have suggested that depression is a microglial disease. Microglia regulate the inflammatory response, synaptic plasticity, neurogenesis, kynurenine pathway and the activation of hypothalamic-pituitary-adrenal axis, all of which affect depression. Exercise therapy is reported to shift the balance of microglial M1/M2 polarization in the hippocampus, frontal lobe, and striatum, suppressing the release of pro-inflammatory factors and consequently alleviating behavioral deficits in animal models of depression. Further studies are needed to examine the specific effects of different exercise regimens on microglia to identify the exercise regimen with the best therapeutic effect.