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Contributions of the Renin Angiotensin System to Fear Memory and Fear Conditioned Cardiovascular Responses

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Contributions of the Renin Angiotensin System to Fear Memory and Fear Conditioned Cardiovascular Responses by Adam Swiercz B.S. in Biology, May 2006, The George Washington University M.P.S. in Molecular Biotechnology, May 2009, The George Washington University M.S. in Physiology, May 2011, Georgetown University A Dissertation submitted to The Faculty of The Columbian College of Arts & Sciences of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy January 10, 2020 Dissertation co-directed by Paul J. Marvar Associate Professor of Pharmacology and Physiology and David Mendelowitz Professor of Pharmacology & Physiology The Columbian College of Arts and Sciences of The George Washington University certifies that Adam Swiercz has passed the Final Examination for the degree of Doctor of Philosophy as of October 2nd, 2019. This is the final and approved form of the dissertation. Contributions of the Renin Angiotensin System to Fear Memory and Fear Conditioned Cardiovascular Responses Adam Swiercz Dissertation Research Committee: Paul J. Marvar, Associate Professor of Pharmacology & Physiology, Dissertation Co-Director David Mendelowitz, Professor of Pharmacology & Physiology, Dissertation Co-Director Abigail Polter, Assistant Professor of Pharmacology & Physiology, Committee Member Colin Young, Assistant Professor of Pharmacology & Physiology, Committee Member ii © Copyright 2020 by Adam Swiercz All rights reserved iii Acknowledgements I would like to thank and acknowledge Dr. Paul Marvar, whose mentorship has made this dissertation possible. It has been a pleasure working in your lab, and I am truly grateful for your support and encouragement throughout the years. Thanks to the current and former members of the Marvar lab who have made my time at GW a rewarding and enjoyable experience. I would also like to thank my co-mentor, Dr. David Mendelowitz, as well as my committee members: Dr. Narine Sarvazyan, Dr. Colin Young, and Dr. Abigail Polter. You have all been very generous with your time, and your guidance has been incredibly helpful. To Dr. Leo Chalupa and Dr. Peter Nemes, thank you for your help during the defense process. Dr. Vincent Chiappinelli, thank you for your support during my time in the department of pharmacology and physiology. I would also like to thank Dr. Linda Werling and Marc Wittlif, who I had the pleasure of working with during my first few years in the IBS program. I am especially grateful for my parents, who instilled in me the determination required to accomplish my personal and academic goals. To my wife, Kelly, thank you for your endless patience, optimism, and support. iv Abstract of Dissertation Contributions of the Renin Angiotensin System to Fear Memory and Fear Conditioned Cardiovascular Responses Anxiety disorders, such as Posttraumatic stress disorder (PTSD), are associated with an increased risk of developing cardiovascular disease. While the exact mechanisms underlying this relationship are not entirely clear, recent evidence suggests that a hormonal system involved in the maintenance of blood pressure and fluid balance may play an integral role. The renin angiotensin system (RAS), which modulates autonomic nervous system activity and cardiovascular function, also influences learning processes such as fear memory formation and maintenance. Pharmacologically targeting the RAS may be effective in reducing symptoms of fear and anxiety disorders. This dissertation seeks to improve our understanding of the relationship between fear memory and cardiovascular reactivity, as well as the involvement of the RAS in fear learning processes. The first study examines the effects of extinction learning on cardiovascular responses to conditioned auditory stimuli. Through simultaneous recording of freezing behavior, blood pressure, and heart rate, it is shown that blood pressure responses are attenuated by repeated conditioned stimulus exposure. In the second study, the role of the angiotensin II type 1 receptor (AT1R) in the reconsolidation of auditory fear memory is investigated. Our findings suggest that blockade of AT1R during reconsolidation leads to long-term reductions in freezing behavior. Results from this study also indicate that treatment with the AT1R antagonist losartan following memory retrieval leads to differential gene expression patterns in the v amygdala. The final study identifies the functional properties of central angiotensin II type 2 receptors (AT2R) in fear expression and extinction. The regional distribution and characteristics of AT2R+ cells within the amygdala are examined in detail. Furthermore, pharmacological activation of AT2R in the central amygdala was used to determine how these receptors might contribute to fear learning and expression. Finally, AT2R-expressing neurons in the central amygdala are shown to project to the periaqueductal grey, a brain region responsible for mediating freezing behavior. The studies in this dissertation are the first to incorporate acute cardiovascular responses such as blood pressure into the assessment of extinction and reconsolidation, which are important clinical targets for the treatment of anxiety and fear. Furthermore, evidence is provided that AT1R contributes to the reconsolidation of auditory fear memories, and that AT2R-expressing neurons in the central amygdala modulate fear expression and extinction. These findings advance our understanding of the physiological and neurobiological systems that regulate fear learning, and suggest that compounds targeting the RAS may be useful in the treatment of fear-related psychiatric conditions. vi Table of Contents Acknowledgements ......................................................................................................... .iv Abstract of Dissertation .....................................................................................................v Table of Contents ............................................................................................................ vii List of Figures .................................................................................................................. .ix List of Tables ................................................................................................................... .xi List of Abbreviations ...................................................................................................... xii Chapter 1: General Introduction ........................................................................................................1 Posttraumatic Stress Disorder .................................................................................2 Posttraumatic Stress Disorder and Cardiovascular Disease Risk ...........................3 The Renin Angiotensin System ..............................................................................5 AT1R ...........................................................................................................7 AT2R ...........................................................................................................8 The Renin Angiotensin System and the Sympathetic Nervous System .....9 The Brain Renin Angiotensin System....................................................... 11 Anxiety and the Brain Renin Angiotensin System ................................... 14 Angiotensin II in Learning and Memory .................................................. 15 Emotion and Memory ........................................................................................... 16 Fear Memory ......................................................................................................... 18 Pavlovian Fear Conditioning .................................................................... 19 Circuitry of Fear Conditioning.................................................................. 21 Fear-Conditioned Physiological Responses .............................................. 24 Extinction of Fear Memory ....................................................................... 26 A Role for the Renin Angiotensin System in PTSD ................................. 29 Memory Reconsolidation .......................................................................... 30 Genetic Markers of Reconsolidation ........................................................ 32 Summary and Specific Aims ................................................................................ 34 References ............................................................................................................. 40 Chapter 2: Extinction of Fear Memory Attenuates Conditioned Cardiovascular Fear Reactivity Abstract ................................................................................................................ 60 Introduction .......................................................................................................... 61 Materials and Methods ......................................................................................... 63 vii Results .................................................................................................................. 67 Discussion ............................................................................................................ 73 References ............................................................................................................ 88 Chapter 3: Evaluation of an Angiotensin Type 1 Receptor Blocker on the Reconsolidation of Fear Memory Abstract
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