Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.
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We would like to thank S. Salton (Mount Sinai School of Medicine) for providing us with male C57BL/6J mice; J.W. Koo for his assistance with the restraint studies; J.W. Koo and J. Quinn for their assistance with the statistical analysis; and K. Patterson and C. Montgomery for assistance in breeding and genotyping VGF-mutant mice. We would like to acknowledge the support of the National Research Service Award fellowship, US National Institute of Mental Health grants MH25642 and MH45481, US NIH grants DK57702 and NS45305, the US National Alliance for Research on Schizophrenia and Depression grants DK-071308 andU24 NS05186, and the Connecticut Mental Health Center.
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Hunsberger, J., Newton, S., Bennett, A. et al. Antidepressant actions of the exercise-regulated gene VGF. Nat Med 13, 1476–1482 (2007). https://doi.org/10.1038/nm1669
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