Sex Differences in Retrieval of Context Fear: Behavioral and Neural Mechanisms by Ashley Alta Keiser A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Psychology) in the University of Michigan 2018 Doctoral Committee: Assistant Professor Natalie C. Tronson, Chair Professor Jill B. Becker Assistant Professor Jacek Debiec Professor Martin Sarter Ashley Alta Keiser [email protected] ORCID iD: 0000-0003-4042-0336 Ashley Alta Keiser DEDICATION In loving memory of the amazing women who raised me, my mom Michelle Lynn Schmeling and my grandma Carol Marguerite Winn. You always deserved the world but you gave it to me instead, this is for you. ii ACKNOWLEDGEMENTS I have been incredibly fortunate to be a part of an enriching, collaborative, intellectual and supportive environment at The University of Michigan. I would like to thank the faculty, staff and my colleagues whom have all played a large role in creating this positive scientific community. First and foremost, I would like to thank my graduate advisor, Dr. Natalie Tronson for being a strong source of support throughout this entire process. Not only has Natalie directly trained me on many behavioral and molecular techniques in her lab, but she has also provided me with many professional opportunities and has taught and me to think critically. Her mentorship has no doubt shaped me into a better scientist and writer and for that, I will be forever grateful. I am also very grateful to Dr. Jill Becker who has been very influential to me from the moment she first met with me as an undergrad at SfN and throughout my time at Michigan. I am grateful to Jill for believing in me and presenting me with many great opportunities during my training. Additionally, I would like to thank my other committee members Drs. Martin Sarter and Jacek Debiec for their insightful comments on my dissertation work, ongoing support and involvement in my training. As the Tronson lab has grown over the past 5 years, I’ve had the pleasure of working with many very talented individuals who have shaped our lab into a fun and productive environment including: Dr. Elissa Donzis, Dr. Katie Collette, Ian Speirs, Lacie Turnbull, Daria Tchessalova, Brynne Raines, and Caitlin Posillico. I would like to thank Dr. Elissa Donzis for answering my many questions when I first began graduate school, her help with the MANY iii perfusions and for all of her advice throughout the years, Ian for helping to teach me techniques early in my training and for his humor, Lacie for her cheerful spirit and for being my lunch buddy, Daria for being one of the nicest people I know and always being supportive, Caitlin for “getting me” and being a great friend, Dr. Katie Collette for being a huge source of support and guidance and Brynne for always being there for me when I needed help, even when I didn’t ask. Beyond this group of amazing individuals, I have been extremely lucky to have worked with a number of fantastic undergraduate research assistants. First, I would like to thank my honors thesis students. I would like to thank Pauline Pan for being extremely reliable and for her consistent help with my experiments, even when I did not ask for help she was there, Dana Feldman for sticking with me since the beginning and helping me with everything along the way, Mara Darian for your kindness and assistance on my earlier projects. I would also like to thank many other undergraduates in the lab that have helped me along the way including Rosa Garcia- Hernandez, Ilana Bruckman, Annie Minns, Iris Song, George Lu, and Allie Rubin. Last but not least I would also like to thank many other Tronson lab undergrads including Alexandra Stevens, Rachel Fenberg, Eric Nicolau, and Brianna Schwarz. I will 100% miss all of my lab mates, you have all made lab a fun place to be. There are many other people that have contributed to my success and development as a scientist. First, I would like to thank my undergraduate mentor Dr. Adam Prus for taking me into his lab and giving me the independence to undertake my own research project. I have no doubt that I wouldn’t be where I am today if it wasn’t for his support and for all of the opportunities he provided me. A huge thanks to Dr. Todd Hillhouse who first took me under his wing as his assistant and exposed me to research for the first time; thank you both for giving me that chance. A huge thank you also goes out to the McNair Scholars program at Northern Michigan iv University who provided me with invaluable knowledge and support that have helped me to succeed in graduate school. Additionally, there are many others to whom I owe thanks. A huge thanks to the DNA sequencing core and Bioinformatics team at The University of Michigan whom helped with RNA sequencing experiments; specifically, I would like to thank Rebecca Tagett, Dr. Rich Mc Eachin, Dr. Bob Lyons and Judy Opp. A special thanks goes to Dr. Shigeki Iwase and the members of his lab for welcoming me into their space through my RNA-sequencing experiments. I would especially like to thank Christina Vallianatos for teaching me qPCR and sharing many protocols along the way. Also thank you to Daria and Pauline for helping me with those experiments. I would like to thank my funding source from the Department of Defense for providing me with a NDSEG graduate fellowship which has allowed me the funds to pursue my dream of getting a PhD and for affording me great opportunities to present my work. A huge thank you goes to Chris Fitzpatrick for holding a workshop that made me aware of this amazing opportunity and for providing critical feedback. I would also like to acknowledge Brian Wallace, Tina Griffith, and Shamilya Williams as well as many others for their helpful guidance in graduate school. Outside of lab I have been fortunate to be surrounded by so many wonderful people. First, I want to thank my amazing cohort: Kyra Phillips, Shelley Warlow, Katie Yoest, and Alex Kawa. You guys are truly the best and I’ve been so fortunate to go through the hurdles of graduate school with you. There are many others I would like to thank that have helped make graduate school enjoyable including but not limited to: Dr. Liz Cogan, Dr. Daniel Castro, Dr. Shannon Cole, Dr. Natalie Nevarez, Dr. Morgan Gustison, Dr. Katy Goldey, Cassie Avila, Jonte Jones, Dr. Kirsten Porter-Stransky, Dr. Lindsay Yager, Hannah Baumgartner, Rosemary Bettle, v Crystal Carr, Sofia Carrera, Ilena Morales, Erin Naffziger, Pavlo Popov, Jacqueline Quigley, Anne Sabol, Sarah Westrick and many others I have met along the way. Last but most certainly not least I would like to thank my family. First, I would like to thank my incredibly supportive and loving husband and best friend Richard Keiser. I truly mean it when I say that I could not have done this without your support through it all. You have encouraged me to pursue research from the very beginning. I could go on for many paragraphs but I will spare my committee from reading more of this ever-growing dissertation. A special thanks goes to my mother and father in law Sandra and Scott Keiser and Sister in law Holly Keiser, your support means everything. A huge thanks to Elma Subhan and Sarah Williams, you guys are like sisters to me, thank you for being there since the beginning. And most importantly, I want to thank the two most strong and loving women I know, my parents my grandma Carol Winn and mom Michelle Schmeling. You taught me that I could do anything I put my mind to and I could not have done this if not for the love, strength and support you instilled in me. You left this world far too young but I will continue to do my best to make you proud. You all mean the world. vi TABLE OF CONTENTS Dedication .......................................................................................................................... ii Acknowledgements .......................................................................................................... iii List of Tables .................................................................................................................... ix List of Figures .....................................................................................................................x Abstract ............................................................................................................................ xii Chapter I. Introduction .....................................................................................................1 Introduction ..............................................................................................................1 Sex Differences in Natural Environment .................................................................2 Sex Differences in Memory .....................................................................................3 Studying Fear Memory ............................................................................................5 Role of Hippocampus and Amygdala in Context Fear Memory .............................7 Molecular Mechanisms Underlying Memory Formation ......................................11 Sex Differences in Molecular Mechanisms ...........................................................14 Conclusion .............................................................................................................21 Summary of Current Studies ..................................................................................22 Figures....................................................................................................................28