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Metformin Pretreatment Rescues Subependymal Zone Neurogenesis and Long-Term Olfactory Memory in a Juvenile Model of Cranial Irradiation

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Metformin Pretreatment Rescues Subependymal Zone Neurogenesis and Long-Term Olfactory Memory in a Juvenile Model of Cranial Irradiation Metformin Pretreatment Rescues Subependymal Zone Neurogenesis and Long-Term Olfactory Memory in a Juvenile Model of Cranial Irradiation by Daniel Derkach A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Sciences University of Toronto © Copyright by Daniel Derkach 2019 Metformin Pretreatment Rescues Subependymal Zone Neurogenesis and Long-Term Olfactory Memory in a Juvenile Model of Cranial Irradiation Daniel Derkach Master of Science Institute of Medical Sciences University of Toronto 2019 Abstract Neural stem cells (NCSs) in the mammalian brain contribute to neurogenesis throughout life and in response to brain injuries to promote neurorepair. Cranial irradiation (IR), used as an adjuvant therapy in the treatment of childhood brain tumors, results in cognitive deficits associated with long-term impairments to neurogenesis in rodent models. Metformin is an antidiabetic drug that enhances functional neurogenesis under physiological conditions and in response to brain injuries. Herein, we investigated metformin’s potential to rescue deficits to neurogenesis and long-term olfactory memory (LTOM) following cranial IR. Juvenile mice displayed acute and persistent deficits in periventricular neurogenesis following 8 Gy cranial IR. We show that metformin pretreatment was sufficient to enhance the recovery of proliferating neuroblasts and completely restore LTOM. This study is the first to report that metformin pretreatment promotes neurogenesis and functional recovery following juvenile cranial IR and supports its consideration as a therapeutic intervention to enhance neurorepair. ii Acknowledgements This Master’s thesis is the product of three years of research and support from my mentors, colleagues, friends, and family. This experience has greatly contributed to my self- development as a scientist, student, and educator, and has also provided me with a sense of both humility and reward. I am extremely grateful to my mentors Dr. Cindi Morshead, Dr. Rebecca Ruddy, and Master’s student Ashkan Azimi for the training, support, and critical feedback. Your guidance and insights expedited the learning process and helped me improve my critical thinking and reasoning skills. Your enthusiasm in helping me succeed has motivated me to work with passion and instilled a desire to pay it forward through dedicated mentoring of other undergraduate students. You have imparted with me the notion that success is not only found in personal accomplishment, but through the accomplishments of those who have learned from or have been influenced by you. I would like to acknowledge all my colleagues who have shared with me the experiences of wonder, confusion, frustration, perseverance, failure, and success. To Dr. Rebecca Ruddy, Dr. Emily Gilbert, Dr. Jessica Livingston-Thomas, Ashkan Azimi, and Kelsey Adams, your technical expertise and extensive understanding of neural stem cell biology has been immensely helpful in developing relevant and meaningful questions, as well as the experiments to address these questions. You’ve encouraged me to constantly learn and ask questions until there are no remaining answers. To Stasja Drecun, Nancy Liu, and Fil Stojic, your roles as devil’s advocates and source of philosophical discussion have continuously challenged me to think critically and through multiple perspectives, and to argue effectively and with humility. To Elana Sefton, Clara Bourget, Nishanth Lakshman, Rehnuma Islam, Stephanie Iwasa, Ilan Vonderwalde, Tom Enbar, and Dr. Erica Scott, thank you for your enduring friendship and for promoting a sense of family within the lab. To the undergraduate students that I have had the pleasure of mentoring, you’ve taught me just as much as I have hopefully taught you. Most importantly, I am eternally thankful for the unconditional support, sacrifice, and love of my family and my partner Katie. You’ve been my greatest source of inspiration and emotional support, and have instilled values within me that have guided every aspect of my life. iii Statement of Contributions Artificial cerebrospinal fluid (aCSF) and serum-free media (SFM) used for tissue culturing were prepared by lab manager Venkateswaran Subramaniam. Assistance with transcardial perfusions was provided by lab technician Ricky Siu and Master’s student Ashkan Azimi. Assistance with genotyping GFAP::GFP mice was provided by lab technician Ricky Siu. Eight GFAP::GFP mice that were used to establish a colony were provided by Dr. Maryam Faiz’s lab. The fluorescence-activated cell sorting (FACS) protocol was provided by Dr. Fiona Doetsch’s lab. Doctoral student Kelsey Adams and Master’s student Elana Sefton assisted with optimizing the FACS protocol for the Morshead lab. Undergraduate student Mohsen Heidari assisted in sectioning brains. Undergraduate student Tarlan Kehtari assisted in the execution and analysis of conditioned media experiments. Undergraduate student Matthew Renaud assisted in sectioning brains, food restriction of mice, and the execution of the long-term olfactory memory (LTOM) task. Training with the neurosphere assay and on the cesium-137 gamma irradiator (Best Theratronics, Gamacell 40 Exactor) was provided by doctoral student, and more recently, Dr. Rebecca Ruddy. Principal Investigator Dr. Cindi Morshead provided thesis manuscript feedback. Program Advisory Committee (PAC) members Dr. Rebecca Laposa, Dr. Freda Miller, and Dr. Cindi Morshead advised on project viability and experimental design. This research was supported by funding from the Canadian Institutes of Health Research (CIHR), Brain Canada (via the Hospital for Sick Children, Toronto, Canada), the Stem Cell Network (SCN), and the Carlton and Marguerite Smith Medical Research Fellowship (Division of Anatomy within the Department of Surgery, University of Toronto). iv Table of Contents Acknowledgements......................................................................................................................... iii Statement of Contributions ............................................................................................................ iv Table of Contents .............................................................................................................................v List of Abbreviations ....................................................................................................................... ix List of Figures ................................................................................................................................. xv List of Appendices ......................................................................................................................... xvi 1. Literature Review .................................................................................................................... 1 1.1. Regenerative Medicine ................................................................................................... 1 1.2. Neural Stem and Progenitor Cells ................................................................................... 1 1.2.1. Initial characterization of neural stem cells ............................................................ 1 1.2.2. Existence of NSCs in the postnatal human and rodent brain ................................. 2 1.2.3. Neural stem cells during development ................................................................... 3 1.2.4. Neural stem cells during adulthood........................................................................ 5 1.3. The role of adult SEZ NSCs under baseline conditions ................................................... 7 1.3.1. Neural stem and progenitor pool maintenance ..................................................... 8 1.3.2. In vivo NSC lineage and olfactory bulb neurogenesis ........................................... 10 1.3.3. The role of neurogenesis in olfactory behaviour .................................................. 12 1.3.4. Neurogenesis vs. gliogenesis ................................................................................ 14 1.4. The SEZ NSC Niche ........................................................................................................ 15 1.4.1. Cytoarchitecture ................................................................................................... 15 1.4.2. Ependymal Cells and Cerebrospinal Fluid ............................................................. 17 1.4.3. Microglia ............................................................................................................... 19 1.4.4. Vasculature ........................................................................................................... 21 v 1.4.5. Extracellular matrix (ECM) .................................................................................... 22 1.4.6. Neurotransmitters ................................................................................................ 23 1.5. Postnatal NSC-niche heterogeneity and endogenous response to injury .................... 24 1.5.1. Regional heterogeneity within the SEZ ................................................................. 24 1.5.2. Temporal heterogeneity within the SEZ ............................................................... 26 1.5.3. Changes to NSC and niche dynamics following injury .......................................... 29 1.6. Assaying for NSCs .......................................................................................................... 32
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