DOI

https://doi.org/10.25772/XS21-NP14

Author ORCID Identifier

0000-0003-2204-4832

Defense Date

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Kimberle M. Jacobs

Second Advisor

John Povlishock

Third Advisor

John Greer

Fourth Advisor

Rory McQuiston

Fifth Advisor

Jose Miguel Eltit

Sixth Advisor

Jeffrey Dupree

Abstract

The pathognomonic sequela of traumatic brain injury is traumatic axonal injury, the

burden of which correlates with less favorable outcomes. Elucidation of

the intrinsic variables that endow delineated neuronal subgroups and microanatomical domains with outsized vulnerability to injury represents a critical domain of inquiry toward the successful translation of disease-modifying therapeutics. To this end, we studied mild traumatic brain injury (mTBI) within the central fluid percussion model to examine the consequences of mTBI on the morphology and functional integrity of the axon initial segment (AIS) and the relative contributions to network homeostasis mediated by distinct populations of inhibitory interneurons. One day after injury, we discovered that trauma-induced functional derangement of the AIS exists on a continuum, from subtle aberration within intact neurons to abolition within severely axotomized neurons. Moreover, we found that somatostatin-expressing interneurons were resilient to axonal injury and exhibited enhanced intrinsic excitability and synaptic efficacy within the network, an adaptation which may function to compensate for the release from inhibition secondary to disproportionate axonal injury among parvalbumin-expressing interneurons. Because the AIS is disrupted in the experimental autoimmune encephalomyelitis model of multiple sclerosis, we compared the functional consequences at the AIS in trauma to this model of neuroinflammation. We found that while AIS morphology by ankyrin-G is disrupted, the functional efficacy of the AIS is enhanced, a divergent result emphasizing the complexity and seeming non-linearity of AIS function. We propose that examination of differential vulnerability of neuronal subtypes within diverse pathological states represents a fruitful domain of investigation.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-18-2025

Download

Share

COinS