Date of Graduation

2016

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Jason D Huber

Committee Co-Chair

James A Bibb

Committee Member

Rae R Matsumoto

Committee Member

Diane B Miller

Committee Member

Charles L Rosen

Abstract

Neuropsychiatric symptoms and cognitive deficits are common among victims of a traumatic brain injury (TBI), and currently, there are no effective treatments to improve outcome. We first developed a clinically-relevant blast TBI model based on lung scaling parameters to elucidate mechanisms of neuronal cell death. In order to discover effective treatments to improve outcome, we had to validate our novel preclinical model of TBI. TBI is an external force that can cause damage to the neurovascular unit (NVU), which can lead to secondary effects, cell death and behavioral dysfunction. In our first study we observed that our model damaged the NVU, increased neuronal cell death, and produced cognitive deficits in young adult Sprague-Dawley rats. The link between damage to the NVU and neurobehavioral dysfunction following TBI is poorly understood. Recently secondary injury cascades, such as endoplasmic reticulum (ER) stress and neuroinflammation, have been hypothesized to be early indicators for the development of neurobehavioral dysfunction. Therefore, we examined the regional and temporal profile of these secondary injury cascades using our validated rodent TBI model. We also measured neurobehavioral dysfunction using a variety of functional assays at various time points post-TBI. Tissues from brain regions associated with the behavioral sequelae of TBI were evaluated for biochemical changes. Furthermore, we investigated the neurophysiological response in brain slice recordings at various time points after TBI. We discovered that TBI produced spatial memory deficits in the rats and altered synaptic firing rates in the hippocampus. In our next study, we revealed a robust increase in markers of ER stress and neuroinflammation within the frontal cortex after TBI. Interestingly, we observed impulsive-like behavior in rats after TBI, which is indicative of damage to the frontal cortex. After characterization of the injury response, we investigated the role of ER stress modulation in mediating secondary injury cascades and neurobehavioral dysfunction following TBI. Salubrinal, an ER stress modulator, attenuated markers of neuroinflammation and neuronal cell death. Most importantly, ER stress modulation ameliorated impulsive-like behavior in rats after TBI. The final portion of this study was to elucidate a link between ER stress and the development of Chronic Traumatic Encephalopathy (CTE). We revealed a potential link between repetitive blast injury and neuropsychiatric symptoms associated with CTE. Tau phosphorylation and aggregation are considered hallmarks of CTE development. We observed an increase in marker of tau phosphorylation and conformational change in rats exposed to repetitive blast. We also observed spatial memory deficits and impulsive-like behavior after repetitive TBI. Together, these results suggest that repetitive blast exposure may lead to tauopathy and the behavioral sequelae associated with CTE. Future studies should aim to causally link secondary injury cascades to tauopathy in order to elucidate new drug targets to improve patient outcome after TBI.

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