Abstract

Pediatric mild traumatic brain injury (mTBI) is a major public health concern with the potential to produce long-lasting cognitive, adaptive, and socio-behavioral outcomes. However, our understanding of how TBI pathophysiology evolves in the developing brain is lacking. Our central hypothesis was that pediatric mTBI results in evolving microstructural dysregulation that leads to functional and structural deficits late in life. To test this hypothesis, we first sought to assess the influence of pediatric mTBI on white matter (WM) dysregulation in early adulthood. To accomplish this, we investigated the effects of single and repeated pediatric mTBI on white matter, focusing on the anterior commissure (AC), a white matter structure distant from the injury site. We demonstrated that mTBI leads to myelin-related diffusion changes in white matter and abnormal oligodendrocyte (OL) development in the AC which are accompanied by behavioral deficits two months after the initial injury. Second, we sought to examine the lifespan evolution of pediatric mTBI. To accomplish this, we investigated the long-term effects of pediatric mTBI at postnatal day 17 and mapped the temporal evolution of the long-term behavioral and associated structural deficits up to late adulthood (18 m) using clinically relevant in-vivo diffusion tensor imaging (DTI) in mice. We demonstrated that a single exposure to a pediatric mTBI in childhood can result in early temporally evolving structural deficits detectable through early diffusion neuroimaging and are correlated to spatial learning and memory impairments late in life. Our results suggest that early in life mTBIs elicit long-term behavioral alterations and OL-associated white matter dysregulation in the developing brain and that such early injuries have the potential to elicit temporally-evolving behavioral and structural deficits late in life. This dissertation provides new insights into how post-pediatric mTBI deficits are manifested both in early adulthood and later in life and describe how such injury evolves over a lifespan resulting in modified tissue characteristics and behavioral profile following pediatric mTBI. Such information will not only provide a deeper understanding of the complex pediatric mTBI pathophysiological development but can serve as the basis for long-term outcome prediction in pediatric mTBI.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Andre Obenaus

Second Advisor

Erik J. Behringer

Third Advisor

Johnny Figueroa

Fourth Advisor

Jerome Badaut

Fifth Advisor

Shu-Wei Sun

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level

Ph.D.

Year Degree Awarded

2020

Date (Title Page)

7-2020

Language

English

Library of Congress/MESH Subject Headings

Brain Concussion; Cerebellar White Matter - injuries; Mice

Type

Dissertation

Page Count

xi, 108 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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