The exponential growth rate of the elderly population necessitates strategies to prevent age-related physiological declines. Notably, hippocampal neurogenesis, important for cognitive performance, decreases during aging. Similarly, ERKs, crucial regulators of cellular processes seen during neurogenesis, also decrease during aging and are associated with hippocampally-related cognition, thus ERKs could mediate hippocampal cognition by modulating neurogenesis. Furthermore, both ERK activation and neurogenesis depend on growth factor mediation, which also decreases during aging. Since increasing dietary intake of fruits and vegetables and particularly, blueberries, has proven effective at ameliorating age-related cognitive deficits associated with the hippocampus, we speculated that behavioral improvements seen in aged blueberry-supplemented animals results from improvements in neurogenesis mediated by blueberry potentiation of growth factors and corresponding ERK activation. Therefore, in this study, we examined whether blueberry-supplementation in rats modulated neurogenesis, ERK activation, growth factor (IGF-1, NGF) and receptor (IGF-1R, TRK-A) expression and whether these were associated with improved RAWM performance as well as one another. Further, in vitro, we examined whether blueberry extract could modulate proliferation in neuroblastoma cells, and whether this was ERK-specific and fit a proliferation-like pattern of ERK activation. Finally, we determined whether blueberries potentiated ERK-dependent processes, namely NGF-induced differentiation and trophic factor withdrawal. Our results indicate that blueberry-supplementation significantly increased cell proliferation in dentate gyrus and this was negatively associated with RAWM errors. Moreover, both ERK and IGF-1 and IGF-1R levels were significantly increased by blueberry treatment and were negatively correlated with RAWM errors. Nevertheless, while ERK and growth factor levels were positively correlated, no significant correlation between ERK or growth factors and neurogenesis was seen, suggesting that growth factor-dependent ERK activation and neurogenesis may improve cognition independently. In vitro results demonstrated that neuroblastoma proliferation is ERK-specific and that blueberries dose-dependently increase proliferation by specific ERK activation patterns. Moreover, blueberries dose-dependently potentiated NGF-induced differentiation and protected cells from NGF withdrawal, demonstrating that blueberries are also capable of modulating cellular processes, ERK activation, and growth factor activity in vitro. These studies provide mechanistic insights into the effects of blueberries on cognitive performance and neurogenesis.
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