Defense Date

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

John T Povlishock

Abstract

Traumatic axonal injury (TAI) is a consistent feature of (TBI) and is responsible for much of its associated morbidity. TAI is now recognized to result from progressive/secondary axonal injury, though much remains unknown in regards to the pathobiology and the long-term consequences of axonal injury. TAI has been described in the perisomatic domain, located within the neocortex following mild TBI, and within this domain has been linked to neuronal recovery, not neuronal cell death in the acute setting. Due to technical limitations, our understanding of the long-term fate of this neuronal population and the mechanisms responsible for permitting neuronal survival, recovery and axon regeneration following injury are unknown. The studies presented in this thesis are centered upon the hypothesis that injury within the perisomatic domain is unique, and may allow for enhanced neuronal recovery and axonal regeneration. To address many of these questions, we have utilized a novel model of diffuse brain injury in mice, allowing for the use of transgenic mice to overcome previous limitations in the study of TAI. To address this hypothesis, we first assessed the impact of genetic deletion of cyclophilin D (CypD), a regulator of the mitochondrial permeability transition pore (mPTP), upon TAI within the perisomatic domain. Via this approach it was determined that CypD deletion reduced the number of injured axons by ~50%, indicating that CypD and mPTP formation contribute to TAI in the perisomatic domain. Next, using a fluorescent-based approach, we assessed the temporospatial events associated with TAI, acutely. Here it was determined that the axon initial segment (AIS) is uniquely susceptible to TAI following mild TBI (mTBI) and injury within this domain progresses rapidly to axon disconnection. Last we assessed the long-term fate of axotomized neurons and their associated axonal processes. We report that over a chronic time frame, TAI induces no overt cell death, instead results in significant neuronal atrophy with the simultaneous activation of a somatic program of axon regeneration and recovery of the remaining axonal processes. Taken together, the findings of this work reveal that TAI results in a unique axonal injury that results in a persistent axon regenerative attempt.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

August 2012

Included in

Neurosciences Commons

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