Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Subhra Mohapatra, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Bala Chandran, Ph.D.

Committee Member

Robert Frisina, Ph.D.

Committee Member

Kevin Nash, Ph.D.

Keywords

Auditory Brainstem Response, CCL20, Hearing Loss, Optoacoustic Tomography, Pioglitazone, Spiral Ganglion

Abstract

Traumatic brain injury (TBI) affects over 2.87 million people in the US each year. The large majority of these injuries can be classified as mild. However, evidence suggests that even mild TBIs can lead to long-lasting symptoms that greatly impact quality of life. This is particularly true when an individual sustains multiple TBIs (repetitive TBI, rTBI). Much of the damage caused by rTBI is due to secondary injury mechanisms that cause the initial injury site to spread and worsen over time. No therapies currently exist which can mitigate secondary injury, and monitoring this phase of rTBI is difficult. Development of therapeutic strategies for rTBI requires more research into underlying mechanisms that cause secondary injury as well as new tools for testing therapeutic efficacy. In this dissertation, we evaluate the use of a new noninvasive imaging method for monitoring rTBI and describe the effect of rTBI on the auditory system. We have previously characterized a mouse model of rTBI that recapitulates many of the pathological sequelae observed in TBI patients. We have shown that C-C motif chemokine ligand 20 (CCL20), a small chemokine which has been implicated in T cell infiltration, is upregulated after rTBI, and that reduction of CCL20 can mitigate a variety of rTBI-induced pathology and behavioral symptoms. In Chapter 2, we describe the use of multispectral optoacoustic tomography (MSOT) for monitoring neurovascular changes in this model. Using MSOT, we observed a transient increase in oxygenated hemoglobin ratio at 5 days post-injury (dpi) that returned to baseline by 7 dpi. We also detected acute blood-brain barrier disruption 24 hours post-injury using indocyanine green. Treatment with pioglitazone, an anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARγ) agonist that causes reduction of CCL20, prevented the increase in oxygenated hemoglobin, suggesting that this phenomenon may be tied to rTBI-induced inflammation and showing that MSOT can be a useful tool for evaluating therapeutic intervention. In Chapter 3, we characterize auditory pathology in our rTBI model. Hearing loss is a common long-term symptom of TBI, even in the absence of direct damage to the ear or auditory pathway. The mechanisms that underlie hearing loss in these cases are unclear. We observed deficits in auditory brainstem responses and auditory temporal processing that persisted up to 60 dpi. Hearing loss was accompanied by loss of spiral ganglion neurons at timepoints as early as 14 dpi. This model has potential to be a useful tool for elucidating the causes of rTBI-induced hearing loss and developing strategies to mitigate damage to the auditory system after brain injury. We believe that these studies will help facilitate future research toward the development of new rTBI therapies.

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