Running exercise reverses depression-induced bone marrow myeloid skewing and neuroinflammation via the lactate-GPR81 axis.

Exercise has emerged as a powerful non-pharmacological intervention for mental health, yet its precise mechanisms in alleviating depression remain incompletely understood. Here, using a chronic unpredictable stress (CUS) mouse model, we demonstrate that prolonged stress induces hematopoietic stem cell (HSC) activation, leading to myeloid-biased hematopoiesis and an overproduction of Ly6Chigh monocytes, which contribute to systemic and hippocampal inflammation. Notably, treadmill running exercise effectively mitigated depressive and anxiety-like behaviors in CUS mice by suppressing stress-induced HSC activation, restoring hematopoietic balance, and reducing peripheral Ly6Chigh monocyte infiltration into the brain. Mechanistically, we identified systemic lactate elevation as a key mediator of exercise-induced benefits. Circulating lactate levels were markedly increased following exercise in stressed mice, coinciding with upregulation of its receptor GPR81 in bone marrow HSCs. Genetic ablation of GPR81 abrogated the protective effects of exercise, including normalization of HSC proliferation, myeloid skewing, and behavioral recovery, implicating lactate-GPR81 signaling as a critical axis. Furthermore, pharmacological activation of GPR81 in sedentary CUS mice recapitulated the antidepressant and hematopoietic effects of exercise, underscoring its therapeutic potential.