An unexpected role for fibroblast growth factor-2 in modulating anxiety and hippocampal stem cells

Strong evidence supports the role of genetic endowment conferring either vulnerability or protection to mood disorders. However, environmental factors are also known to play a critical modulating role in such vulnerability. Recent reports revealed decreased levels of Fibroblast Growth Factor-2 (FGF-2) gene expression in several post-mortem brain regions of subjects with a history of major depression. One of the regions showing profound alterations was the hippocampus of these severely depressed subjects. These reports implicated FGF-2 in depression, however they did do not address whether the observed dysregulation in FGF-2 expression represents a predisposing factor to the illness or a consequence of the disease process. Given that altered anxiety is observed in mood disorders such as depression we examined the potential contribution of FGF-2 in two genetically distinct groups of rats selectively bred to differ dramatically in their response to novelty and to anxiety-provoking conditions (HRs= Low Anxiety/High Response to Novelty vs. LRs= High Anxiety/Low Response to Novelty). We demonstrate that the Low-Anxious HRs have significantly elevated levels of hippocampal FGF-2 mRNA relative to the High-Anxious LR's, and that there exists a highly significant inverse correlation between FGF-2 levels and anxiety behavior. Interestingly, FGF-2 expression is modulatable by environmental factors that alter anxiety and enhance neurogenesis---thus environmental complexity (EC) reduces anxiety behavior induces FGF-2 expression and promotes neurogenesis in the hippocampus, particularly in the High Anxious LR's. Moreover, a 3-week treatment regimen of administered FGF-2 is highly effective at blunting anxiety behavior, specifically in the High Anxious LR's. This anxiolytic effect is accompanied by an increase in the survival of hippocampal adult stem cells, both neurons and astrocytes, again specifically in the LR's. Furthermore, we show that the impact of EC on hippocampal cell genesis is dependent on the FGF system as FGF blockade disrupted the effects of EC on increasing cell proliferation and new cell survival. This suggests that hippocampal cell genesis might contribute to modulating the anxiolytic effects of FGF-2 and EC. Taken together, these findings implicate hippocampal FGF-2 as a novel modulator of anxiety behavior and underscore its potential as a new target for the treatment of mood and anxiety disorders.