Basic fibroblast growth factor-enhanced neurogenesis contributes to cognitive recovery in rats following traumatic brain injury

Abstract

Stem/progenitor cells reside throughout the adult CNS and are actively dividing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. This neurogenic capacity of the SVZ and DG is enhanced following traumatic brain injury (TBI) suggesting that the adult brain has the inherent potential to restore populations lost to injury. This raises the possibility of developing strategies aimed at harnessing the neurogenic capacity of these regions to repair the damaged brain. One strategy is to enhance neurogenesis with mitogenic factors. As basic fibroblast growth factor (bFGF) is a potent stem cell mitogen, we set out to determine if an intraventricular administration of bFGF following TBI could affect the levels of injury-induced neurogenesis in the SVZ and DG, and the degree to which this is associated with cognitive recovery. Specifically, adult rats received a bFGF intraventricular infusion for 7 days immediately following TBI. BrdU was administered to animals daily at 2–7 days post-injury to label cell proliferation. At 1 or 4 weeks post-injury, brain sections were immunostained for BrdU and neuronal or astrocytic markers. We found that injured animals infused with bFGF exhibited significantly enhanced cell proliferation in the SVZ and the DG at 1 week post-TBI as compared to vehicle-infused animals. Moreover, following bFGF infusion, a greater number of the newly generated cells survived to 4 weeks post-injury, with the majority being neurons. Additionally, animals infused with bFGF showed significant cognitive improvement. Collectively, the current findings suggest that bFGF-enhanced neurogenesis contributes to cognitive recovery following TBI.

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

“…Because neither study examined neuroprotection within the dentate gyrus, it is possible that the cognitive improvements accompanying FGF-2 administration were related to a reduction in cell death or enhancement of neurogenesis within the dentate. In a 2009 study, Sun et al [114] demonstrated enhanced post-traumatic neurogenesis in the hippocampus and SVZ using a FGF-2 treatment paradigm that also improved cognitive function after TBI in rats. Similarly, overexpression of FGF-2 in hippocampal cells achieved through stereotactic injection of FGF-2 expressing viral vectors enhanced neurogenesis and reduced granule cell layer cell loss in mice after CCI brain injury [110].…”

Compensatory Neurogenesis in the Injured Adult Brain

“…However, several studies have examined the effect of administering neurogenic agents to rodent models of TBI to assess the effect on neuronal replacement and functional recovery. Administration of EGF or FGF-2 into the lateral ventricles following FPI has been shown to increase the rate of memory recovery in the Morris Water Maze, and produce a concomitant increase in the number of new hippocampal neurons co-labeled with BrdU and NeuN (Sun, et al, 2009, Sun, et al, 2010. Interestingly, intraventricular administration of the calcium-binding protein S100 following TBI has also been shown to increase the percentage of newly generated hippocampal neurons expressing NeuN and improve cognitive recovery in the Morris water Maze [for review see (Kleindienst, et al, 2007)].…”

Sustained Survival and Maturation of Adult Neural Stem/Progenitor Cells after Transplantation into the Injured Brain

“…The optical fractionator method was used to estimate the total number of BrdU-positive cells following our previously described method (Sun et al, 2009). This design-based stereological method to estimate cell numbers has been widely used by our lab.…”

“…To estimate the total number of transplanted BrdU-labeled cells that were present at 2 or 4 weeks after injection, six 50-lm-thick coronal sections through the injection site spaced 300 lm apart were quantified using an unbiased stereological optical fractionator method as previously described (Sun et al, 2009. A total of 8 · 10 4 cells (4 · 10 4 · 2 lL) were injected initially.…”