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Related Behaviour in Mice Genetic, molecular, and neurobiological determinants of post-traumatic stress disorder- related behaviour in mice Kristie Leigh Smith A thesis submitted in fulfilment of the requirements of the degree of Doctor of Philosophy Faculty of Medicine and Health University of Sydney 2020 ii Statement of originality This thesis is submitted to the University of Sydney in fulfilment of the requirements for the degree of Doctor of Philosophy. I certify that, to the best of my knowledge, the content of this thesis is original and assert that any assistance received in preparing this thesis has been acknowledged. I have not submitted this material, either in full or part, for a degree at this or any other institution. Kristie Leigh Smith iii Author attribution statement I, Kristie Leigh Smith, completed the majority of work in this thesis, and any assistance that I received is outlined in detail below. Investigations were carried out at the Brain and Mind Centre at the University of Sydney. All experimental work was completed under the direction of my supervisor, Associate Professor Jonathon Arnold who, as corresponding author of the three manuscripts that compose the body of this thesis, has granted permission for the use of materials herein. For the publication in Chapter 2, under the supervision of A/Prof Arnold I designed and conducted all behavioural and immunohistological experiments and analysed all experimental data. I acknowledge Stephanie Todd, David Clarke, and Mustafa Kassem who provided training and continued guidance for certain behavioural and histological experiments. I further acknowledge Dr Michael Kuligowski who provided critical microscopy support, and Dr Miguel Bedoya-Perez in providing statistical analysis assistance. I solely composed the manuscript for publication with editing assistance from A/Prof Arnold. For the publication in Chapter 3 I shared first authorship with Natalia Brzozowska having contributed equally to the publication of this manuscript. I helped design experiments with A/Prof Arnold and Dr Brzozowska and performed behavioural experiments, histology processing, and microglial cell density and morphology analyses. I acknowledge Natalia Brzozowska, Peter Waters, Sarah Abelev, and Ligia Menezes Cavalcante who assisted in running behavioural testing and histology processing. I solely conducted glucocorticoid histology staining and contributed to both the statistical analyses and composition of the manuscript with Natalia Brzozowska and A/Prof Arnold. For the publication in Chapter 4 I acknowledge Stephanie Todd and Dr Aurelie Boucher for their role in running the behavioural testing. I performed immunohistological staining, and solely quantified c-Fos and microglial cell histological preparations. I conducted all statistical analyses and solely composed the manuscript with A/Prof Arnold. Kristie Leigh Smith Supervisor: Associate Professor Jonathon Arnold iv Table of contents Acknowledgements ................................................................................................. vi Publications, presentations, and awards ............................................................. vii Additional publications ........................................................................................ viii List of figures and tables ......................................................................................... ix List of abbreviations .............................................................................................. xii Abstract ................................................................................................................... xv Chapter 1 - Introduction .......................................................................................... 2 1.1. Stress and stress related disorders ................................................................... 2 1.1.1. What is stress? ..................................................................................................... 2 1.1.2. Post-traumatic stress disorder ........................................................................ 4 1.1.3. The modern picture of PTSD .......................................................................... 6 1.1.4. Current treatment of PTSD ............................................................................. 8 1.2. Advancing the understanding of neurobiological and genetic bases of PTSD and stress disorders ...................................................................................... 12 1.2.1. PSTD neurobiology: fear circuits and loss of grey matter ............................ 12 1.2.2. Animal models of PTSD ................................................................................. 15 1.2.3. Face, construct and predictive validity of an animal model of PTSD .......... 17 1.2.4. Positive and negative neuroadaptive consequences of stress.................. 20 1.3. PTSD and neuroinflammation: Is there a link between loss of synaptic connectivity and microglia? ................................................................................... 23 v 1.3.1. A brief history of microglia ........................................................................... 24 1.3.2. Structure and function of microglia ............................................................. 26 1.3.3. The complement system and microglia ....................................................... 28 1.3.4. Stress and microglia....................................................................................... 30 1.4. Could genetic factors predispose or confer resilience to PTSD? .............. 33 1.4.1. Development of novel serenic agents for PTSD and beyond ...................... 36 1.5. Aims .............................................................................................................. 38 Chapter 2 - Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD. ................... ..41 Chapter 3 - Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice ….................................................................................53 Chapter 4 - P2X7 rececptor knockout mice display less aggressive biting behaviour correlating with increased brain activation in the piriform cortex..............................65 Chapter 5 – General discussion .............................................................................. 73 5.1. Conclusion ................................................................................................... 92 6. References ....................................................................................................... 94 7. Supplementary material ................................................................................ 127 vi Acknowledgements Firstly, I would like to acknowledge Associate Professor Jonathon Arnold for his role as my primary supervisor. I entered this degree with no laboratory experience and appreciate the extra effort that was required on his part to prepare me for my research and guide me to the end of this PhD. I would also like to express my thanks and appreciation to Professor Jim Lagopoulos who dragged me into the research world. You reminded me of the importance of remaining resilient in the face of adversity. I would additionally like to thank Professor Maxwell Bennett who both provided invaluable support and guidance. I would like to acknowledge the staff at the Australian Centre of Microscopy and Microanalysis. Particularly, thanks to Dr Michael Kuligowski for his time and patience. I’d also like to thank my friend Dr Steve Kassem who helped experimentally and also provided moral support throughout this whole journey. Thanks to Trudy Stone who, as postgraduate coordinator at the BMC, supported me through both the Masters of Brain and Mind Sciences degree and my PhD. I would like to thank members of the Arnold lab, both past and present. From the ghetto to greener pastures, we’ve always maintained a jovial and supportive environment. Thanks to the staff and students at the Lambert Initiative for Cannabinoid Therapeutics, particularly our lab manager Cheryl Handford for her tireless work. The network of support that exists in this lab is unprecedented. Special thanks to A/Prof Elizabeth Scott who has guided me professionally and personally for almost a decade. Without your help my academic success would be non- existent. To all my friends who watched me go through this journey these many years, thank you for your patience and support. A special mention to Adamina Drazkiewicz who has supported me from the beginning literally feeding and clothing me. I appreciate everything. Lastly, but most importantly, I’d like to thank my mother, Gayle. From a very young age you taught me importance of resilience, particularly as a woman. You have never doubted my ability to achieve anything and have always had complete unconditional love for me. Dedicated to Marcus Kapitza. vii Publications, presentations, and awards Smith, K. L., Kassem, M. S., Clarke, D. J., Kuligowski, M. P., Bedoya-Pérez, M. A., Todd, S. M., Arnold, J. C. (2019). Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD. Brain Behav Immun. doi:10.1016/j.bbi.2019.05.042 Brzozowska, N. I.*, Smith, K. L.*, Zhou, C., Waters, P. M., Cavalcante, L. M.,
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