DOI

https://doi.org/10.25772/A8JT-WZ07

Defense Date

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Dong Sun

Second Advisor

Kirsty Dixon

Third Advisor

Linda Phillips

Fourth Advisor

Thomas Reeves

Fifth Advisor

Aron Lichtman

Abstract

Traumatic Brain Injury (TBI) is a prevalent problem with an estimated 5 million people suffering from chronic cognitive impairments long after the injury. Following TBI there is a series of pathophysiological changes in the brain including neurogenesis, an important response linking endogenous repair and regeneration. The dentate gyrus (DG) of the hippocampus is a primary neurogenic region within the adult brain where neural stem and progenitor cells (NS/NPCs) reside. Studies using rodent models have shown that cognitive recovery after TBI is associated with new neurons generated from the DG. Thus far, in studies examining post-injury neurogenesis, the regulatory mechanisms, functional integration, and morphological development of NS/NPCs are among the key aspects that are poorly understood. A critical regulatory mechanism that may play a role in injury-induced neurogenesis is Notch1 signaling. Studies have shown that the Notch1 pathway is a key mediator for neurogenesis in developing and adult brains, as it has essential roles in regulating stem cell proliferation and fate determination. The formation of neuronal dendritic processes post-mitotically is another critical role of Notch1, as it facilitates complexity in branching patterns of cells that are in direct association with memory performance. Notch1 has a strong association with CREB signaling and synaptic plasticity, specifically in regions critical for cognitive functions and learning such as the hippocampus. As the hippocampus is the most vulnerable region to TBI, the morphological development and synaptic plasticity of new neurons generated in the DG of the hippocampus following TBI may serve an important role in the cognitive recovery process. In this series of studies, we have characterized the role of Notch1 in injury-induced new neuron population dynamics. Additionally, we have discovered that Notch1 does play an essential role for proper dendritic arbor morphology development after TBI, and this is directly associated with an inability to recover learning and memory capabilities at the time of innate cognitive recovery after injury. This series of studies provides fundamental support that injury-induced populations of new neurons contribute to recovery after injury, and Notch1 signaling is crucial for this process to occur in these new neurons.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-3-2022

Available for download on Thursday, August 03, 2023

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