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Chronic Neurovascular Dysfunction in a Preclinical Model of Repeated Mild Traumatic Brain Injury

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Chronic Neurovascular Dysfunction in a Preclinical Model of Repeated Mild Traumatic Brain Injury Chronic Neurovascular Dysfunction in a Preclinical Model of Repeated Mild Traumatic Brain Injury by Conner Adams A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Medical Biophysics University of Toronto © Copyright by Conner Adams 2018 Chronic Neurovascular Dysfunction in a Preclinical Model of Repeated Mild Traumatic Brain Injury Conner Adams Master of Science Department of Medical Biophysics University of Toronto 2018 Abstract: Outcomes associated with repeated mild traumatic brain injury (mTBI) are considerably worse than those of a single mTBI. Despite higher prevalence relative to moderate injuries, the repeated mTBI’s pathological progression has been understudied. For moderate-to-severe TBI, metabolic mismatch has been identified as a key component in pathological progression, and hence amenable to therapeutic targeting. Here, I present a mouse model of repeated mTBI induced via three controlled cortical impacts delivered at three day intervals for purpose of probing the aspects of the neurovascular coupling in chronic repeated mTBI in Thy1-ChR2 mice. Resting cerebral blood flow and cerebrovascular reactivity were investigated via arterial spin labelling MRI, and intracranial electrophysiological measurements of evoked neuronal responses to optogenetic photostimulation were performed. Immunohistochemistry revealed alterations in vascular organization and astrocyte reactivity. This work provided the first insights into the neurophysiological alterations post repeated mTBI and enables new understanding of the associated cerebrovascular deficits. ii Acknowledgements I would like to thank Bojana for demonstrating true leadership throughout my time in the lab. As my supervisor, she taught me a great deal about science and enforced the importance of character and dedication in all facets of life. For that, I am forever grateful. I am also thankful for the constructive criticism and guidance provided by Dr. Greg Stanisz, Dr. JoAnne McLaurin, and Dr. Lothar Lilge. I would also like to acknowledge all members of the Stefanovic, Stanisz, and McLaurin labs, as well as all contributors to this project for making its completion possible. To Raafy, Grant, and Laura I am grateful for making my life outside the lab fun and fulfilling, throughout even the most trying times. Finally, as always I am grateful for the endless love and support from my parents, Mike and Shelley, as well as my sister Ali. iii Table of Contents Acknowledgements ................................................................................................................ iii Table of Contents ................................................................................................................... iv Table of Figures ....................................................................................................................... v Glossary of Terms .................................................................................................................. vi 1. Introduction ......................................................................................................................... 1 1.1 Brain networks ............................................................................................................................ 2 1.1.1 - Cortical Neuronal Organization: ......................................................................................... 2 1.1.2 - Cortical Cerebrovascular network: ...................................................................................... 3 1.1.3 - Cerebral Blood Flow Regulation: ........................................................................................ 4 1.2 Traumatic Brain Injury ............................................................................................................. 7 1.2.1: Repeated Mild TBI ............................................................................................................... 7 1.2.2: Animal Models of Repeated mTBI: ...................................................................................... 9 1.3 Magnetic Resonance Imaging of Cerebral Blood Flow ......................................................... 12 1.3.1: pCASL - labeling: ............................................................................................................... 12 1.3.2: fMRI.................................................................................................................................... 20 1.4 Electrophysiological Recording of Evoked Neuronal Activity ............................................. 23 1.4.1 - Electrophysiology of repeated mTBI ................................................................................ 23 1.4.2 - Optogenetics: ..................................................................................................................... 23 1.5 The Present Work ..................................................................................................................... 26 2. Paper: ................................................................................................................................. 27 Abstract: .......................................................................................................................................... 28 Introduction: ................................................................................................................................... 29 Materials & Methods: ..................................................................................................................... 32 Results: ............................................................................................................................................. 38 Discussion: ....................................................................................................................................... 44 Supplementary Material: ............................................................................................................... 47 References: ....................................................................................................................................... 48 3. Discussion & Future Work: ............................................................................................. 52 3.0 Discussion .................................................................................................................................. 52 3.1 Summary of Major Findings: .................................................................................................. 56 BIBLIOGRAPHY ................................................................................................................. 57 iv Table of Figures Figure A1: Flow driven adiabatic inversion. Figure A2: Diagram of radiofrequency and gradient waveforms of pCASL labelling process. Figure A3: ASL signal amplitude due to labelling. Figure A4: Model Hemodynamic Response Function (HRF). Figure A5: Schematic of Regressors for functional pCASL experiment. Figure A6: Expression of ChR2-YFP in coronal section of Thy1-ChR2 mouse. Figure 1: Experimental timeline for induction of repeated mTBI and imaging. Figure 2: Assessment of cerebral blood flow and arterial transit time via multi Post Label Delay pCASL. Figure 3: Reduced Cerebrovascular Reactivity to 10% inhaled CO2. Figure 4: Reduction of neuronal response to photostimulation. Figure 5: Immunohistochemical assessment of chronic phase of injury. Figure S1: Example of ROIs selected via logistic regression. Figure S2: Channelrhodopsin expression in Thy1-ChR2 mouse. v Glossary of Terms AD Alzheimer’s Disease AFNI Analysis of Functional Neuroimages ASL Arterial Spin Labelling ATP Adenosine Triphosphate ATT Arterial Transit Time BOLD Blood Oxygen Level Dependent CASL Continuous Arterial Spin Labelling CBF Cerebral Blood Flow CBV Cerebral Blood Volume CCI Controlled Cortical Impact ChR2 Channelrhodopsin CMRO2 Cerebral Metabolic Rate of Oxygen CPP Cerebral Perfusion Pressure CTE Chronic Traumatic Encephalopathy CVR Cerebrovascular Reactivity DWI Diffusion Weighted Imaging EPI Echo Planar Imaging fMRI Functional Magnetic Resonance Imaging FPI Fluid Percussive Injury GABA Gamma-Aminobutyric Acid GCS Glasgow Coma Scale GFAP Glial Fibrillary Acid Protein GLM General Linear Model HRF Hemodynamic Response Function mFPI Mild Fluid Percussive Injury mPLD Multi Post Label Delay vi MRI Magnetic Resonance Imaging mTBI Mild Traumatic Brain Injury NO Nitric Oxide NVC Neurovascular Coupling pCASL Pseudo-Continuous Arterial Spin Labelling pCO2 Partial Pressure of CO2 PaCO2 Arterial Pressure of CO2 PCS Post Concussive Syndrome PFA Paraformaldehyde PGE2 Prostaglandin E2 PLD Post Label Delay RARE Rapid Acquisition with Refocused Echoes RF Radiofrequency ROI Region Of Interest S1FL Somatosensory 1, Forelimb Region TBI Traumatic Brain Injury vSMC Vascular Smooth Muscle Cell YFP Yellow Fluorescent Protein vii 1. Introduction Interruption of blood supply to the brain can terminate brain activity within seconds and have permanent consequences on brain function (Moskowitz, Lo, and Iadecola 2010). This is in part due to the brain’s high metabolic activity and presence of toxic glutamate (Choi 1992). Given the dearth of internally stored metabolites, brain additionally depends critically on the tight coupling between neuronal activity and the corresponding local increases in cerebral blood flow (Iadecola 2004). This relation, often referred to as neurovascular coupling (NVC) forms
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