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Quantify Physiological and Structural Changes After a Convulsive Sub-Lethal Dose of Soman Using MRI and Oxygen Sensors in Rats

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Quantify Physiological and Structural Changes After a Convulsive Sub-Lethal Dose of Soman Using MRI and Oxygen Sensors in Rats University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2020-08-31 Quantify Physiological and Structural Changes After a Convulsive Sub-lethal Dose of Soman using MRI and Oxygen Sensors in Rats Lee, Seung-Hun (Kevin) Lee, S.-H. (2020). Quantify Physiological and Structural Changes After a Convulsive Sub-lethal Dose of Soman using MRI and Oxygen Sensors in Rats (Unpublished doctoral thesis). University of Calgary, Calgary, AB. http://hdl.handle.net/1880/112485 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Quantify Physiological and Structural Changes After a Convulsive Sub-lethal Dose of Soman using MRI and Oxygen Sensors in Rats by Seung-Hun (Kevin) Lee A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN NEUROSCIENCE CALGARY, ALBERTA AUGUST, 2020 © Seung-Hun (Kevin) Lee 2020 Abstract Chemical weapons including nerve agents pose an ongoing issue in global conflicts, terrorism, and assassination plots. The current treatment protocol against nerve agents include atropine sulfate, HI-6 oxime, and benzodiazepine, which have been successful in prolonging survival after nerve agent exposure. However, the treatments are unable to prevent neurological damage associated with nerve agent-induced seizures. The objective of this thesis is to use imaging modalities to improve our understanding of the physiological and structural changes in the brain following a sub-lethal dose of nerve agent (soman) exposure. First, we investigated changes in oxygenation using chronically implanted oxygen sensors in awake and freely moving rats. We were able to measure oxygenation before, during, and after soman exposure. We found distinct oxygen profiles that oscillated based on seizure onset, which may be due to abnormal hemodynamics. Additionally, hyperoxygenation was detected during status epilepticus and remained elevated at 24 hours. Next, in order to validate the results, we measured cerebral blood flow using continuous arterial spin labelling (CASL) MRI. We found global hypoperfusion at 1 hour and hypoperfusion in the piriform network at 18-24 hours in isoflurane anaesthetized rats. Following this, we combined a way to simultaneously measure cerebral blood flow using CASL MRI and oxygenation using oxygen sensors in isoflurane anaesthetized rats. Here, we found hypoperfusion but normoxia in the cortex, suggesting a decrease in metabolism. Further investigation of whether changes are due to neurological damage was explored by correlating quantitative T2 (qT2) MRI to a histological marker of neurodegeneration. No changes in qT2 or neurodegeneration was found at 1 hour after soman, suggesting hypoperfusion and hypometabolism may be mediated through oxidative stress. At 18-24 hours after soman exposure, changes in qT2 MRI correlated with neurodegenerative markers, with the strongest ii correlation being in the piriform cortex. This suggests hypoperfusion in the piriform network at 18-24 hours, which may be the result of damage to the neurovascular unit. Overall, this thesis identifies impairment of vasodynamics following soman exposure as a potential therapeutic target and the use of qT2 MRI to guide efficacy of these therapies. iii Preface Chapter 1 provides a general introduction on nerve agents and Canada’s interests towards the research. Chapter 2 is a literature review. Chapter 3 is an empirical data chapter outlining the changes in brain oxygenation and is published in Neurotoxicology: Lee, K., Bohnert, S., Wu, Y., Vair, C., Mikler, J., Teskey, G. C., & Dunn, J. F. (2018). Assessment of brain oxygenation imbalance following soman exposure in rats. Neurotoxicology, 65, 28-37. doi:10.1016/j.neuro.2018.01.007 Chapter 4 is an empirical data chapter outlining the changes in cerebral hemodynamics and is published as a special issue manuscript in Toxicological Letters: Submitted Chapter 5 is an empirical data chapter outlining the sensitivity of quantitative T2 MRI in detect neurodegeneration following soman and is published in Scientific Reports: Accepted Chapter 6 is a general discussion which describes the progression of the thesis and future directions. iv Acknowledgements First and foremost, I would like to show my deepest appreciation and gratitude to Dr. Jeff F. Dunn. Jeff accepted me into his lab despite my brief research experience in petroleum microbiology. Thank you for putting me on the most exciting project I could have ever asked for. Although the journey was bumpy at times, his guidance and leadership has helped me along the way. I will always cherish and appreciate his love for science. I thank Jeff for having so much faith in me and creating an environment where I could grow. I would like to thank my collaborator Sara Bohnert for providing the funding and being an excellent collaborator. It has been a pleasure to work together on this project. I am grateful for your patience and understanding. I have learned a tremendous amount about nerve agents. Thank you for always being there to discuss science. I would also like to thank my committee members Dr. Cam Teskey and Dr. Bruce Pike for your guidance and insights. Thank you, Cam, for opening up your lab to me where I was able to collaborate with members in your lab. Their support and guidance were of great help. Thank you to my internal examiner, Dr. Pierre Levan and external examiner, Dr. Alon Friedman, for taking their time to be examiners for my thesis defense. A special thanks to the Dunn lab. Thank you for all the help and scientific discussions over the years. The time that was spent together have been interesting and fun. I could not have asked for a better lab family. v Thank you to members of the Defence Research and Development Canada-Suffield Research Centre, Dr. John Mikler and Cory Vair. Thank you for making the long journey to bring up the soman. Thank you to Dave Rushforth and Tad Foniok in the Experimental Imaging Centre. I will always appreciate the openness of Dave and Tad for sharing their expertise. It was a pleasure hanging out by the 9.4T MRI. I would like to give a special thanks to my bestie and office mate, Dr. Lia Maria Hocke. You were the best office mate anyone could have. I will always cherish our time watching Doctor Who and eating fish sticks and custard. Congratulations again, I can’t wait to meet little Branick. I also want to thank Nikola Yee. Thank you for believing in me when I didn’t. I could not have done this without your constant support. I can only hope to repay a fraction of the support you have given me. Last, but not least, I would like to thank my family. Thank you to my mother, Dr. Woonyoung Baik, who gave up everything in South Korea to come to Canada, raising me as a single-mother, and giving me this opportunity. Thank you to my father, Choongsun Lee, who cheered me on from South Korea. Finally, thank you to my sister, Suyeon Lee, for bothering me with your love. vi Dedication I dedicate this thesis to my incredible family- Dr. Woonyoung Baik, Choongsun Lee, and Suyeon Lee. They have taught me the virtue of perseverance. A small token of appreciation for their guidance, support, and unconditional love. vii Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iv Acknowledgements ....................................................................................................................... v List of Tables ................................................................................................................................ xi List of Figures and Illustrations ................................................................................................ xii List of Symbols, Abbreviations and Nomenclature ................................................................ xiv Chapter 1: General Introduction ................................................................................................ 1 1.1 Nerve Agents and Canada: General Overview ......................................................................... 1 1.2 Objective and Aims ................................................................................................................... 2 Chapter 2: Literature Review ...................................................................................................... 4 2.1 Pesticide use and OP compounds .............................................................................................. 4 2.2 Nerve Agents ............................................................................................................................. 8 2.2.1 History ....................................................................................................................................................... 8 2.2.2 Types of Nerve Agents ..........................................................................................................................
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