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The Journal of Neuroscience, December 31, 2008, 28(53):14522-14536; doi:10.1523/JNEUROSCI.3673-08.2008

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

Hiroshi Udo,¹ Yuka Yoshida,¹ Takako Kino,² Koichiro Ohnuki,² Wataru Mizunoya,³ Takao Mukuda,⁴ and Hiroyuki Sugiyama¹

¹Department of Biology, Faculty of Science, and ³Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan, ² Evaluation and Management Department, User Science Institute, Kyushu University, Fukuoka 815-8540, Japan, and ⁴Department of Human Science, Faculty of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan

Correspondence should be addressed to Dr. Hiroshi Udo, Department of Biology, Faculty of Science, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. Email: hudouscb{at}mbox.nc.kyushu-u.ac.jp

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.

Key words: growth factor; neurogenesis; hippocampus; depression; anxiety; fear; aggression

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Received Aug. 4, 2008; revised Nov. 11, 2008; accepted Nov. 13, 2008.

Correspondence should be addressed to Dr. Hiroshi Udo, Department of Biology, Faculty of Science, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. Email: hudouscb{at}mbox.nc.kyushu-u.ac.jp

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