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"EFFECT OF PHYSICAL IMPACT RISE TIMES AND ALTERED NEUROGENESIS ON TEMPORAL EVOLUTION OF NEUROPATHOLOGY AFTER TRAUMATIC BRAIN INJURY"

by
Eric Joseph Neuberger
Interdisciplinary Biomedical Sciences Program
B.S. 2007, State University of New York at New Paltz, New Paltz, NY
A.A. 2000, SUNY Orange, Middletown, NY


Thesis Advisor: Viji Santhakumar, Ph.D.
Associate Professor
Department of Pharmacology, Physiology & Neuroscience

Thursday, May 5, 2016
1:00 P.M., MSB H609


Abstract

The anatomical and physiological effects of traumatic brain injury (TBI) which occur in sports, automobile accidents and combat are important for understanding the underlying pathological processes and determining patient management strategies. Differences in the rate of rise to peak injury pressure in civilian and military brain injuries are likely to produce different types of stresses and damage to brain tissue. However, consequences of different injury rates on the cellular and network function are yet to be examined. Thus, whether rate of rise to peak pressure influences outcomes independent of peak pressures remains an open question. Studies in this thesis used a programmable Fluid Percussion Injury (FPI) device and demonstrated that the rate of rise to peak pressure modifies the immediate neurobehavioral and early cellular response to concussive brain injury. The results identified that, despite a better immediate neurological outcome following fast injury, the long term cellular and physiological pathology after injuries with fast- and slower-rising waveforms are not different indicating dissimilar progression of cellular pathology after fast- and slow-rising injuries.
The hippocampal dentate gyrus, the site of neuronal degeneration following FPI, is a prominent locus of adult neurogenesis. Generation of new neurons in the adult dentate is believed to play an important role in hippocampus -dependent learning and memory. Slow-rate but not fast-rate FPI selectively dentate neurogenesis 7 days injury indicating rate-dependent perturbation of neurogenesis by injury waveforms. Further analysis of the temporal progression of neurogenesis after slow-rate standard FPI identified a significant decline in neurogenesis 30 and 90 days after FPI indicative of a delayed depression of neurogenesis after brain injury. The decrease in neurogenesis was associated with depletion of neural precursor and blast cells 90 days after FPI consistent with exhaustion of neural precursor cells. These findings lead to the hypothesis that the early post-injury increase in neurogenesis contributes to the exhaustion of neural precursor cells, and that suppression of the post-injury increase in neurogenesis would rescue long-term deficits in neurogenesis. Since the Vascular Endothelial Growth Factor receptor 2 (VEGFR2) is known to regulate neurogenesis, VEGFR2 antagonist was used to suppress excessive neurogenesis after TBI. Results presented herein show that post-injury intra-ventricular treatment with a VEGFR2 antagonist (SU1498) blocks early TBI-induced increase in neurogenesis without completely eliminating baseline levels of adult dentate neurogenesis. As predicted, this treatment rescued the proliferative capacity of the neural precursor cells and proliferation rates return to normal at later time points. In addition, blocking the early increase in neurogenesis resulted in prolongation of the latency to chemically evoked seizures in head-injured rats. Together the work presented in this thesis provides the first experimental evidence that the initial increase in neurogenesis after brain injury may contribute to post-traumatic neuropathology rather than be beneficial to the network as previously proposed.


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