Defense Date

2019

Document Type

Thesis

Degree Name

Master of Science

Department

Anatomy & Neurobiology

First Advisor

Dong Sun

Second Advisor

Raymond Colello

Third Advisor

Kirsty Dixon

Fourth Advisor

Qinglian Liu

Abstract

Traumatic brain injury (TBI) is a devastating problem which stands as a leading cause of death and disability. The elderly is significantly affected by TBI, typically as the result of falls, and recovery is especially limited. This, in part, is associated with decreased tissue-specific stem cell regeneration and replacement of damaged cells in the aged brain. The diminished ability of the aged brain to recover is especially devastating after TBI, likely leading to permanent loss of sensory, motor, and cognitive functions. Studies have shown that the mature mammalian brain contains Neural Stem Cells (NSCs), found in specific regions of the brain, which can generate functional neurons during normal and pathological conditions. Two of those regions, the Dentate Gyrus (DG) of the hippocampus as well as the Subventricular Zone (SVZ) of the lateral ventricles, have proven to be niches for these multipotent NSCs. A key regulator in the maintenance of these NSCs is the Notch signaling pathway, shown to control proliferation, differentiation, and apoptosis of NSCs during development and throughout adulthood. In the current study, we assessed the regulatory mechanisms that drive the regenerative functions of NSCs in a neuropathological state following TBI. Using the Lateral Fluid Percussion Injury model, we analyzed the diffuse effects of the injury response on 3-month old male Sprague-Dawley rats. Immediately following TBI, Notch agonist, antagonist or vehicle was infused into the lateral ventricle for 7 days to assess the role of Notch signaling on neural stem cell proliferation/survival and neurogenesis at 30 days post-TBI. Dividing cells during infusion time were labeled with BrdU via single daily intraperitoneal injections for 7 days. Animals were sacrificed at 30 days post-injury and brain tissues were processed then immunolabeling for BrdU and Doublecortin. We found a higher number of BrdU-positive cells in the FPI+Notch1 agonist group when compared to Sham and FPI+Jagged-1 Fc antagonist groups in the contralateral granular zone. A significant increase in proliferation/survival was also seen in FPI+Notch1 versus Sham/FPI+Jagged-1 Fc and for FPI+Vehicle versus Sham animals in both the ipsilateral and contralateral hilus. DCX immunolabeling did not establish a significant difference in FPI+Notch1 compared to Sham animals, nor across any other groups, which is consistent with what we know of activation of the Notch pathway. Our results demonstrate that Notch1 signaling is directly involved in cellular proliferation/survival of NSCs in the DG following TBI at 30 days post-injury, but further work must be done to understand the fate of these cells. Thus, drug treatment targeting Notch1 signaling could serve as a potential therapeutic target following TBI to preserve NSCs and limit long-term cognitive deficits.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-9-2019

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