Antidepressant actions of the exercise-regulated gene VGF

Abstract

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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Figure 1: Profile and secondary validation of exercise regulated genes.
Figure 2: Analysis of VGF and BDNF immunoreactivity and colocalization with selective neuronal markers after 1 week of exercise.
Figure 3: VGF produces antidepressant-like effects in mouse and rat behavioral models.
Figure 4: Heterozygous VGF-deletion mice show deficits in animal models of antidepressant-like activity.
Figure 5: VGF hippocampal infusions induce local gene expression of exercise-regulated genes.

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Acknowledgements

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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Contributions

J.G.H. assisted with all aspects of the research, including optimization of the microarray and data analysis, conducted all other molecular and behavioral experiments, and prepared the original draft of manuscript. S.S.N. was responsible for the development, optimization and experimental use of custom array. A.H.B. assisted in the optimization, use and analysis of microarrays. C.H.D. assisted in development of the running procedure and behavioral analysis. D.S.R. assisted in analysis of the microarray data, PC12 culture work and discussion of results. S.R.S. assisted in conceptual aspects of the studies, the development of VGF-mutant mice and interpretation of the data. R.S.D. was involved in the development of the overall study design, data analysis, interpretation of results and the preparation of manuscript and figures. All authors discussed results and contributed intellectually to the manuscript.

Corresponding author

Correspondence to Ronald S Duman.

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Supplementary Tables 1–6, Supplementary Figs. 1 and 2, Supplementary References and Supplementary Methods (PDF 763 kb)

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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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