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Exercise can have antidepressant effects in humans and in animal models, but questions remain about the underlying mechanisms. A study by Moon et al. now shows that in rodents, the pleiotropic cytokine microphage migration inhibitory factor (MIF) mediates these effects by increasing hippocampal brain-derived neurotrophic factor (Bdnf) transcription and serotonin synthesis.

The authors subjected rats to 28 days of voluntary wheel running (VWR) and found that this treatment increased Mif mRNA and protein levels in the hippocampus.

Hippocampal neurogenesis has been implicated in the antidepressant effects of exercise. The authors showed that MIF treatment upregulated the expression of the neurogenesis-related gene Bdnf in vitro and that intracerebroventricular (ICV) MIF injections increased hippocampal Bdnf expression in rats. Furthermore, VWR increased hippocampal levels of Bdnf and doublecortin mRNA (a marker for new neurons) in wild-type mice but not in Mif-deficient (Mif−/−) mice.

Increases in serotonin levels have also been implicated in the effects of exercise. MIF administration increased the expression of the gene encoding tryptophan hydroxylase 2 (Tph2) — the rate-limiting enzyme in serotonin biosynthesis — in vitro and in vivo, and MIF treatment increased intracellular serotonin levels in vitro in a dose- and time-dependent manner. Importantly, VWR increased hippocampal Tph2 expression in rats and wild-type mice but not in Mif−/− mice.

The authors next showed that inhibition of the MIF-binding protein CD74 or its effector GTPase RHOA (which activates the extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathway) reduced the induction of Bdnf and Tph2 and the increase in serotonin levels by MIF treatment in a neuronal cell line.

ICV administration of MIF in rats reduced immobility in a forced swim test, providing direct evidence for an antidepressant role for the cytokine. Furthermore, in this test, Mif−/− mice were more immobile than wild-type mice and, unlike in wild-type mice, VWR did not increase mobility in Mif−/− mice.

Together, these findings suggest that VWR-induced MIF expression may — through ERK1/2 signalling — underlie both the increased hippocampal Bdnf expression and the activation of the serotonin system associated with VWR and its antidepressant effects.