Enhanced Adult Neurogenesis and Angiogenesis and Altered Affective Behaviors in Mice Overexpressing Vascular Endothelial Growth Factor 120

Vascular endothelial growth factor (VEGF) is implicated as a molecular mediator for adult neurogenesis and behavioral effects of antidepressant drugs. However, these potential roles of VEGF in the CNS have not been clarified in model animals. Here we have created transgenic mice overexpressing a sho...

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Bibliographic Details
Published in:The Journal of neuroscience 2008-12, Vol.28 (53), p.14522-14536
Main Authors: Udo, Hiroshi, Yoshida, Yuka, Kino, Takako, Ohnuki, Koichiro, Mizunoya, Wataru, Mukuda, Takao, Sugiyama, Hiroyuki
Format: Article
Language:English
Subjects:
Adult Stem Cells - physiology
Age Factors
Aggression - physiology
Animals
Bromodeoxyuridine - metabolism
Cell Differentiation - genetics
Cell Proliferation
Conditioning (Psychology) - physiology
Exploratory Behavior - physiology
Fear - physiology
Female
Magnetic Resonance Imaging
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity - genetics
Neovascularization, Physiologic - genetics
Neurogenesis - genetics
Pain Threshold - physiology
Phosphopyruvate Hydratase - metabolism
Prosencephalon - cytology
Prosencephalon - physiology
Statistics, Nonparametric
Swimming
Vascular Endothelial Growth Factor A - genetics
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Summary:Vascular endothelial growth factor (VEGF) is implicated as a molecular mediator for adult neurogenesis and behavioral effects of antidepressant drugs. However, these potential roles of VEGF in the CNS have not been clarified in model animals. Here we have created transgenic mice overexpressing a short active variant of VEGF-A (VEGF120) in forebrain. Expression of VEGF120 significantly enhanced cell proliferation and angiogenesis, as exemplified by the formation of an enlarged reddish brain. Adult neurogenesis in hippocampus was markedly stimulated without affecting cell differentiation of neural progenitor cells. Hippocampal neurogenesis was particularly robust in young adult animals, but it declined with age and reduced to control levels by 20 weeks under continuous expression of VEGF120. Thus, VEGF alone is not sufficient to support the long-term enhancement of adult neurogenesis, and VEGF-induced vascularization per se does not necessarily predict increased neurogenesis. In transgenic mice, we observed significant changes in affective behaviors. VEGF was found to have not only antidepressant effects but also anxiolytic effects. In addition, we found that VEGF significantly reduced fear and aggression. In contrast, basal activities under natural conditions were not affected much. Unexpectedly, these characteristic behaviors were maintained in older transgenic mice undergoing a reduced level of cell proliferation in hippocampus, suggesting that there is potential dissociation between adult neurogenesis and mood regulation. Our data indicate that VEGF exerts strong neurogenic and angiogenic effects in postnatal brain and influences different forms of affective behaviors.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.3673-08.2008