Antidepressant actions of the exercise-regulated gene VGF


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Kavanagh, T. Exercise and the heart. Ann. Acad. Med. Singapore 12, 331–337 (1983).

    CAS  PubMed  Google Scholar 

  2. 2

    Anderson, B.J. et al. Exercise influences spatial learning in the radial arm maze. Physiol. Behav. 70, 425–429 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Kramer, A.F. et al. Ageing, fitness and neurocognitive function. Nature 400, 418–419 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Carro, E., Trejo, J.L., Busiguina, S. & Torres-Aleman, I. Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J. Neurosci. 21, 5678–5684 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Larson, E.B. et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann. Intern. Med. 144, 73–81 (2006).

    Article  Google Scholar 

  6. 6

    Greenwood, B.N. et al. Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons. J. Neurosci. 23, 2889–2898 (2003).

    CAS  Article  Google Scholar 

  7. 7

    Dimeo, F., Bauer, M., Varahram, I., Proest, G. & Halter, U. Benefits from aerobic exercise in patients with major depression: a pilot study. Br. J. Sports Med. 35, 114–117 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Lai, S.M. et al. Therapeutic exercise and depressive symptoms after stroke. J. Am. Geriatr. Soc. 54, 240–247 (2006).

    Article  Google Scholar 

  9. 9

    Kessler, R.C. et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). J. Am. Med. Assoc. 289, 3095–3105 (2003).

    Article  Google Scholar 

  10. 10

    Greenberg, P.E. et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J. Clin. Psychiatry 64, 1465–1475 (2003).

    Article  Google Scholar 

  11. 11

    Fava, M. & Davidson, K.G. Definition and epidemiology of treatment-resistant depression. Psychiatr. Clin. North Am. 19, 179–200 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Nibuya, M., Morinobu, S. & Duman, R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 7539–7547 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Karssen, A.M. et al. Application of microarray technology in primate behavioral neuroscience research. Methods 38, 227–234 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Alfonso, J., Frasch, A.C. & Flugge, G. Chronic stress, depression and antidepressants: effects on gene transcription in the hippocampus. Rev. Neurosci. 16, 43–56 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Duman, R.S. Neurotrophic factors and regulation of mood: role of exercise, diet and metabolism. Neurobiol. Aging 26 (Suppl. 1), 88–93 (2005).

    Article  Google Scholar 

  16. 16

    Allen, D.L. et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J. Appl. Physiol. 90, 1900–1908 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Duman, R.S., Malberg, J. & Thome, J. Neural plasticity to stress and antidepressant treatment. Biol. Psychiatry 46, 1181–1191 (1999).

    CAS  Article  Google Scholar 

  18. 18

    Russo-Neustadt, A., Beard, R.C. & Cotman, C.W. Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology 21, 679–682 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Neeper, S.A., Gomez-Pinilla, F., Choi, J. & Cotman, C.W. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 726, 49–56 (1996).

    CAS  Article  Google Scholar 

  20. 20

    Salton, S.R. et al. VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. Front. Neuroendocrinol. 21, 199–219 (2000).

    CAS  Article  Google Scholar 

  21. 21

    Nedivi, E., Wu, G.Y. & Cline, H.T. Promotion of dendritic growth by CPG15, an activity-induced signaling molecule. Science 281, 1863–1866 (1998).

    CAS  Article  Google Scholar 

  22. 22

    Naeve, G.S. et al. Neuritin: a gene induced by neural activity and neurotrophins that promotes neuritogenesis. Proc. Natl. Acad. Sci. USA 94, 2648–2653 (1997).

    CAS  Article  Google Scholar 

  23. 23

    Tong, L., Shen, H., Perreau, V.M., Balazs, R. & Cotman, C.W. Effects of exercise on gene-expression profile in the rat hippocampus. Neurobiol. Dis. 8, 1046–1056 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Eagleson, K.L., Fairfull, L.D., Salton, S.R. & Levitt, P. Regional differences in neurotrophin availability regulate selective expression of VGF in the developing limbic cortex. J. Neurosci. 21, 9315–9324 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Levi, A., Eldridge, J.D. & Paterson, B.M. Molecular cloning of a gene sequence regulated by nerve growth factor. Science 229, 393–395 (1985).

    CAS  Article  Google Scholar 

  26. 26

    Newton, S.S. et al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J. Neurosci. 23, 10841–10851 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Hahm, S. et al. Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance. Neuron 23, 537–548 (1999).

    CAS  Article  Google Scholar 

  28. 28

    Alder, J. et al. Brain-derived neurotrophic factor–induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J. Neurosci. 23, 10800–10808 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Cryan, J.F., Markou, A. & Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol. Sci. 23, 238–245 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Dulawa, S.C. & Hen, R. Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci. Biobehav. Rev. 29, 771–783 (2005).

    CAS  Article  Google Scholar 

  31. 31

    Salton, S.R. Neurotrophins, growth-factor–regulated genes and the control of energy balance. Mt. Sinai J. Med. 70, 93–100 (2003).

    PubMed  Google Scholar 

  32. 32

    Vaynman, S., Ying, Z. & Gomez-Pinilla, F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur. J. Neurosci. 20, 2580–2590 (2004).

    Article  Google Scholar 

  33. 33

    Ying, Z., Roy, R.R., Edgerton, V.R. & Gomez-Pinilla, F. Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Exp. Neurol. 193, 411–419 (2005).

    CAS  Article  Google Scholar 

  34. 34

    McEwen, B.S. & Chattarji, S. Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine. Eur. Neuropsychopharmacol. 14 (Suppl. 5), S497–S502 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Lu, B., Greengard, P. & Poo, M.M. Exogenous synapsin I promotes functional maturation of developing neuromuscular synapses. Neuron 8, 521–529 (1992).

    CAS  Article  Google Scholar 

  36. 36

    Cui, X.S. & Kim, N.H. Polyamines inhibit apoptosis in porcine parthenotes developing in vitro. Mol. Reprod. Dev. 70, 471–477 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Newton, S.S., Collier, E.F., Bennett, A.H., Russell, D.S. & Duman, R.S. Regulation of growth factor receptor bound 2 by electroconvulsive seizure. Brain Res. Mol. Brain Res. 129, 185–188 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Kishi, T. & Elmquist, J.K. Body weight is regulated by the brain: A link between feeding and emotion. Mol. Psychiatry 10, 132–146 (2005).

    CAS  Article  Google Scholar 

  39. 39

    Vaynman, S.S., Ying, Z., Yin, D. & Gomez-Pinilla, F. Exercise differentially regulates synaptic proteins associated to the function of BDNF. Brain Res. 1070, 124–130 (2006).

    CAS  Article  Google Scholar 

  40. 40

    Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006).

    CAS  Article  Google Scholar 

  41. 41

    Newton, S.S., Dow, A., Terwilliger, R. & Duman, R. A simplified method for combined immunohistochemistry and in situ hybridization in fresh-frozen, cryocut mouse brain sections. Brain Res. Brain Res. Protoc. 9, 214–219 (2002).

    CAS  Article  Google Scholar 

  42. 42

    Koo, J.W. et al. The postnatal environment can counteract prenatal effects on cognitive ability, cell proliferation, and synaptic protein expression. FASEB J. 17, 1556–1558 (2003).

    CAS  Article  Google Scholar 

Download references


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.

Author information




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.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hunsberger, J., Newton, S., Bennett, A. et al. Antidepressant actions of the exercise-regulated gene VGF. Nat Med 13, 1476–1482 (2007).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing