Adult hippocampal neurogenesis, or the process of creating new neurons in the dentate gyrus (DG) of the hippocampus, underlies learning and memory capacity. This cognitive ability is essential for humans to operate in their everyday lives, but cognitive disruption can occur in response to traumatic insult such as brain injury. Previous findings in rodent models have characterized the effect of moderate traumatic brain injury (TBI) on neurogenesis and found learning and memory shortfalls correlated with limited neurogenic capacity. While there are no substantial changes after one mild TBI, research has yet to determine if neurogenesis contributes to the worsened cognitive outcomes of repetitive mild TBI. Here, we examined the effect of neurogenesis on cognitive decline following repetitive mild TBI by utilizing AraC to limit the neurogenic capacity of the DG. Utilizing a BrdU fate-labeling strategy, we found a significant increase in the number of immature neurons that correlate learning and memory impairment. These changes were attenuated in AraC-treated animals. We further identified endothelial cell (EC)-specific EphA4 receptor as a key mediator of aberrant neurogenesis. Taken together, we conclude that increased aberrant neurogenesis contributes to learning and memory deficits after repetitive mild TBI. / Doctor of Philosophy / In the United States, millions of people experience mild traumatic brain injuries, or concussions, every year. Patients often have a lower ability to learn and recall new information, and those who go on to receive more concussions are at an increased risk of developing long-term memory-associated disorders such as dementia and chronic traumatic encephalopathy. Despite the high number of athletes and military personnel at risk for these disorders, the underlying cause of long-term learning and memory shortfalls associated with multiple concussions remains ill defined. In the brain, the hippocampus play an important role in learning and memory and is one of only two regions in the brain where new neurons are created from neural stem cells through the process of neurogenesis. Our study seeks to address the role of neurogenesis in learning and memory deficits in mice. These findings provide the foundation for future, long-term mechanistic experiments that uncover the aberrant or uncontrolled processes that derail neurogenesis after multiple concussions. In short, we found an increase in the number of newborn immature neurons that we classify as aberrant neurogenesis. Suppressing this process rescued the learning and memory problems in a rodent model of repeated concussion. These findings improve our understanding of the processes that contribute to the pathophysiology of TBI.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/94329 |
| Date | 02 October 2019 |
| Creators | Greer, Kisha |
| Contributors | Graduate School, Theus, Michelle H., Gourdie, Robert G., He, Jia-Qiang, Eyestone, Willard H., Chappell, John C. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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