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The Journal of Neuroscience, May 13, 2009, 29(19):6379-6387; doi:10.1523/JNEUROSCI.4829-08.2009

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Behavioral/Systems/Cognitive
A New Role for FGF2 as an Endogenous Inhibitor of Anxiety

Javier A. Perez, Sarah M. Clinton, Cortney A. Turner, Stanley J. Watson, and Huda Akil

Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109

Correspondence should be addressed to Javier A. Perez, Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Email: perezja{at}umich.edu

Human postmortem studies have demonstrated that fibroblast growth factor-2 (FGF2) expression is decreased in the brain of depressed individuals. It remained unclear, however, whether this is a consequence of the illness or whether FGF2 plays a primary role in the control of mood and emotions. In this series of studies, we first ask whether endogenous FGF2 expression correlates with spontaneous anxiety, a trait associated with vulnerability to severe mood disorders in humans. This is tested in two genetically distinct groups of rats selectively bred to differ dramatically in their response to novelty and anxiety-provoking conditions (HRs = low anxiety/high response to novelty vs LRs = high anxiety/low response to novelty). We demonstrate that high-anxiety LRs have significantly lower levels of hippocampal FGF2 mRNA relative to low-anxiety HRs. We then demonstrate that FGF2 expression is modifiable by environmental factors that alter anxiety—thus, environmental complexity reduces anxiety behavior and induces FGF2 expression in hippocampus, particularly in high-anxiety LRs. Finally, we directly test the role of FGF2 as an anxiolytic and show that a 3 week treatment regimen of peripherally administered FGF2 is highly effective at blunting anxiety behavior, specifically in high-anxiety LRs. This treatment is accompanied by an increase in survival of adult-born hippocampal cells, both neurons and astrocytes, most clearly in LRs. These findings implicate hippocampal FGF2 as a central integrator of genetic and environmental factors that modify anxiety, point to hippocampal neurogenesis and gliogenesis as key in this modulation, and underscore FGF2's potential as a new target for treatment of depression and anxiety disorders.

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Received Oct. 7, 2008; revised March 16, 2009; accepted April 2, 2009.

Correspondence should be addressed to Javier A. Perez, Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Email: perezja{at}umich.edu

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