Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice

Authors

  • Jaewon Lee,

    1. Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
    2. Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA
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  • Wenzhen Duan,

    1. Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
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  • Mark P. Mattson

    1. Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
    2. Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA
    3. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Address correspondence and reprint requests to Mark P. Mattson, National Institute on Aging, GRC 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. E-mail: mattsonm@grc.nia.nih.gov

Abstract

To determine the role of brain-derived neurotrophic factor (BDNF) in the enhancement of hippocampal neurogenesis resulting from dietary restriction (DR), heterozygous BDNF knockout (BDNF +/–) mice and wild-type mice were maintained for 3 months on DR or ad libitum (AL) diets. Mice were then injected with bromodeoxyuridine (BrdU) and killed either 1 day or 4 weeks later. Levels of BDNF protein in neurons throughout the hippocampus were decreased in BDNF +/– mice, but were increased by DR in wild-type mice and to a lesser amount in BDNF +/– mice. One day after BrdU injection the number of BrdU-labeled cells in the dentate gyrus of the hippocampus was significantly decreased in BDNF +/– mice maintained on the AL diet, suggesting that BDNF signaling is important for proliferation of neural stem cells. DR had no effect on the proliferation of neural stem cells in wild-type or BDNF +/– mice. Four weeks after BrdU injection, numbers of surviving labeled cells were decreased in BDNF +/– mice maintained on either AL or DR diets. DR significantly improved survival of newly generated cells in wild-type mice, and also improved their survival in BDNF +/– mice, albeit to a lesser extent. The majority of BrdU-labeled cells in the dentate gyrus exhibited a neuronal phenotype at the 4-week time point. The reduced neurogenesis in BDNF +/– mice was associated with a significant reduction in the volume of the dentate gyrus. These findings suggest that BDNF plays an important role in the regulation of the basal level of neurogenesis in dentate gyrus of adult mice, and that by promoting the survival of newly generated neurons BDNF contributes to the enhancement of neurogenesis induced by DR.

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