Biological Systems Engineering
EFFECT OF INJURY MECHANISM AND SEVERITY ON THE MOLECULAR PATHOPHYSIOLOGY OF TRAUMATIC BRAIN INJURY
Date of this Version
Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. However, approximately 80% suffer from milder injuries. Thus, examining pathophysiological changes associated with mild TBI is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Through this work, we developed models of TBI, ranging in both injury mechanism and severity, using an electromagnetic controlled cortical impact (CCI) device. First, we characterized and optimized a closed head, mild TBI model (DTBI) to determine the clinical translatability and practicality of producing repeated mild injuries. Interestingly, we determined that impact speed was highly dependent on both input velocity and depth. Indeed, impact conditions differed from input parameters, and we suggest researchers characterize closed head models using CCI devices to ensure data is interpreted based on the true impact conditions. Additionally, we investigated how impact speeds influenced pathophysiology, specifically autophagic flux. Our results show that autophagic flux was impaired acutely in the hippocampus, regardless of impact speed, providing rationale for evaluating autophagic flux following mild, diffuse impacts. Thus, we continued investigating pathophysiological changes associated with a spectrum of TBI, including severe CCI, modified mild TBI (MTBI), and previously characterized DTBI. Following impacts, we observed distinct differences in gross neuropathology, which corresponded with changes in the progression of cell death. Indeed, severe CCI resulted in dramatic increases in oncosis, while mild models differed regarding apoptotic response, suggesting injury mechanism and severity shift the progression of cell death. Interestingly, each of the three impact models resulted in impaired autophagic flux, which coincided with changes in both oncotic and apoptotic cell death. Thus, these results provide evidence that the pathophysiological mechanisms affiliated with TBI heterogeneity may be linked through common upstream events, namely impaired autophagic flux and lysosomal dysfunction. Therefore, therapeutic strategies designed to intervene in the amelioration of these consequences may alleviate molecular dysfunction, in addition to the cognitive and behavioral deficits observed following TBI.
Advisor: Forrest M. Kievit
Analytical, Diagnostic and Therapeutic Techniques and Equipment Commons, Bioresource and Agricultural Engineering Commons, Other Medicine and Health Sciences Commons
A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Master of Science, Major: Agricultural and Biological Systems Engineering, Under the Supervision of Professor Forrest Kievit. Lincoln, Nebraska: July, 2022
Copyright © 2022 Brandon Z. McDonald