Inhibition of injury-induced cell proliferation in the dentate gyrus impairs cognitive recovery following traumatic brain injury

• Main Author: Daniels, Teresa
• Format: Others
• Published: VCU Scholars Compass 2012
• Subjects: Neurogenesis; lateral fluid percussion injury; Ara-C; bFGF; Morris Water Maze; Anatomy; Medicine and Health Sciences; Nervous System
• Online Access: http://scholarscompass.vcu.edu/etd/2800; http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=3799&context=etd

Traumatic brain injury (TBI) induces a robust cellular proliferative response among neural stem/progenitor cells (NS/NPCs) in the dentate gyrus of the hippocampus. This proliferative effect is thought to contribute to the innate cognitive recovery observed following TBI. Inhibition of hippocampal neurogenesis impairs cognitive function. Furthermore, enhancement of injury-induced hippocampal neurogenesis via intraventricular administration of basic fibroblast growth factor (bFGF) improves cognitive function in animals following TBI. In this experiment, we investigated the direct association between injury-induced hippocampal neurogenesis and cognitive recovery utilizing an antimitotic agent, arabinofuranosyl cytidine (Ara-C). In this study, adult rats received a moderate lateral fluid percussion injury (LFPI). Immediately following injury, Ara-C with or without bFGF was infused into the lateral ventricle via an osmotic mini-pump for 7 days. To label dividing cells animals received daily single injections of 5-bromo-2'-deoxyuridine (BrdU) at 2-7 days post-injury. To examine the effect of Ara-C on cell proliferation, a group of animals was sacrificed at 1 week following injury. Brain sections were immunostained for BrdU and cell type specific markers, and the number of BrdU+ cells in the hippocampus was assessed by stereology. To examine the effect of inhibition of injury-induced cell proliferation on cognitive recovery, animals were assessed on Morris water maze tasks (MWM) either at 21 to 25 days or 56-60 days post-injury. We found that post-injury Ara-C treatment significantly reduces injury-induced cell proliferation in the DG and abolishes the innate cognitive recovery on MWM performance at 56-60 days post-injury. Additionally, Ara-C diminishes bFGF enhanced cell proliferation in the DG and cognitive recovery following TBI. These results support the causal relationship between injury-induced hippocampal neurogenesis and cognitive functional recovery. Our studies suggest that the post-TBI neurogenic response is an endogenous repair mechanism that contributes to the restoration of hippocampal function post-injury.