CONTRIBUTIONS OF THE MEDIAL PREFRONTAL CORTEX TO MANAGING MEMORY AND RESOLVING MNEMONIC INTERFERENCE A Dissertation Presented to the Faculty of the Department of Psychology of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Psychology by Gregory Joseph Peters February 2016 © 2016 Gregory Joseph Peters CONTRIBUTIONS OF THE MEDIAL PREFRONTAL CORTEX TO MANAGING MEMORY AND RESOLVING MNEMONIC INTERFERENCE Gregory Joseph Peters Cornell University, 2016 Abstract Mnemonic interference is the failure to retrieve a target memory due to the presence of other memories. Interference indicates underlying principles of memory organization, most notably that there is an interdependent structure to memories. Interference is potentially problematic for retrieval in systems that store many memories, yet there is substantial evidence for neural mechanisms dedicated to managing interference in support of memory retrieval. This evidence indicates that the prefrontal cortex (PFC) is a critical structure for combatting interference. However, the majority of this evidence is derived from human imaging studies and behavior studies involving human subjects with non-specific PFC damage, which lack the experimental control to examine the precise neural operations that manage interference. Surprisingly, few animal models exist that explicitly examine the role of the PFC in managing mnemonic interference. This discrepancy may be due to a diverse literature on the functional contribution of the PFC, including its involvement in a variety of processes that fall under the broad category of executive control. Animal studies have modeled some of these other executive functions, particularly the PFC role in behavioral flexibility and task switching. This thesis argues that many executive functions attributed to the PFC and modeled in animals involve an underlying need to resolve conflict in neural representations developed over learning. This view may reduce the number of attributes needed to characterize PFC function. I test this hypothesis by examining the role of PFC in resolving mnemonic interference in rats and comparing this evidence to other animal models of PFC function. These studies provide strong evidence that the PFC is critical for the normal management of interference in rats, which is consistent with the human literature. Together this evidence indicates a fundamental role for PFC in managing mnemonic competition, which opens the door for detailed investigations of neural mechanisms of interference resolution in animal models of memory. BIOGRAPHICAL SKETCH Greg was born and raised in rural Connecticut. His parents, Joe and Ursula Peters, encouraged freethinking, inquiry and debate, and they always insisted that both of their sons spend the majority of their time exploring the natural world. Greg attended Edwin O. Smith High School in Storrs, Connecticut, which borders the main campus of the University of Connecticut. Always influenced by the nearby flagship, Greg made the short trip over to UConn as an undergraduate, which he soon realized was a familiar place with so much more to offer than he ever knew. Greg credits the diverse opportunities and a few great mentors at UConn for cultivating his academic potential, and for teaching him to channel a longstanding curiosity in the behavior of the creatures of our world. It was in Dr. Etan Markus’ course in learning and memory that Greg realized his appreciation for the fundamental importance of memory to living things. In Dr. Markus’ research lab, Greg learned that it was possible to observe neural activity that directly reflected memory, and he began to believe he might be able to make a career out of asking questions that came naturally to him. Greg graduated from UConn with a degree in Psychology and Neuroscience and took a technician job with Dr. Amy Griffin at the University of Delaware, where he helped her start up her neurophysiology lab. Seeing a lab grow from the ground up was a valuable experience, and Greg learned about the many little things that make a lab tick. Prior to graduate school, Greg focused mostly on research concerning hippocampal processing and its relation to memory. Both of Greg’s prior mentors, Dr. Markus and Dr. Griffin, embraced the perspective that the rat hippocampus is essential for aspects of memory that go well beyond the more predominant spatial memory processing theories. Dr. David Smith’s contextual view of hippocampal processing offered a perspective that Greg admired and believed in, and he was thrilled to be given the opportunity to pursue a graduate degree studying the neurobiology of memory at a Cornell University. Greg will be forever grateful that he was fortunate enough to land in such a great academic environment located in a beautiful college town, and to have gained so many wonderful friends and colleagues along the way. iv Acknowledgements First and foremost, I would like to thank my advisor, Dr. David Smith, for his indispensable guidance throughout my graduate career. My work will always benefit from unavoidable thoughts of how David would criticize it, and I have gained so much from all the lessons he has passed to me along the way. Most of all, I am grateful to have found an advisor that truly cares about his role as mentor, and who clearly strives for the right balance of providing guidance while preaching self-sufficiency. I would also like to thank my committee members for taking time out of their busy schedules to review my work, and for all of their insightful comments and suggestions that help support my research. Looking back, I have no idea where I would be without the support and encouragement of Dr. Etan Markus. He introduced me a world of science that I knew little of, and his continued generosity and guidance sets an example that I hope I can adopt and return to budding minds someday. I also owe a debt of gratitude to my undergraduate advisor and friend, Dr. John Rickards. I will never forget our many long chats, where we spoke like equals. I thank him for trying to instill in me the confidence that I think he knew I needed. I would like to convey my deepest appreciation to my beautiful wife, Marcela, who regularly manages to be more patient than she should be. I know how lucky I am to have her, and I am thankful this will be the only time we will write our dissertations together while taking care of our infant daughter and saying goodbye to the place where we fell in love. I also owe a special thanks to my little Lia, who made me laugh and smile each and every day I spent writing these pages. I worried it would be hard to work while also looking after her, but she truly made it so much easier. Most of all, I thank my parents, who have had an incomparable and extraordinary influence on my life. Words cannot express how grateful and lucky I am to have had their unwavering support on this journey. Their generosity, encouragement and sacrifice has always propped me up, but maybe more importantly, they allowed themselves to let me choose my own way and make my own mistakes, which will forever benefit my life, my work and the philosophy on life that I pass to others. v TABLE OF CONTENTS BIOGRAPHICAL SKETCH ................................................................................. IV ACKNOWLEDGEMENTS .................................................................................... V CHAPTER 1 INTRODUCTION ................................................................................................... 1 INTERFERENCE AND MEMORY ................................................................................. 2 NEUROBIOLOGY OF INTERFERENCE RESOLUTION ..................................................... 3 ANIMAL MODELS OF PFC FUNCTION ......................................................................... 7 FUNCTIONAL ANATOMY OF THE PFC ........................................................................ 8 SUMMARY AND THESIS OVERVIEW ........................................................................ 10 CHAPTER 2 THE MEDIAL PREFRONTAL CORTEX IS CRITICAL FOR MANAGING MEMORY RETRIEVAL AND RESOLVING INTERFERENCE ........................... 17 INTRODUCTION ................................................................................................... 17 EXPERIMENT 1 .................................................................................................... 20 Acquisition of the concurrent discrimination task ........................................... 20 Acquisition of blocked discrimination problems ............................................. 24 EXPERIMENT 2 - MANAGING PROACTIVE INTERFERENCE ......................................... 26 EXPERIMENT 3 – LONG-TERM INFLUENCE FROM INITIAL LEARNING .......................... 30 DISCUSSION ....................................................................................................... 33 METHODS ........................................................................................................... 39 CHAPTER 3 THE MEDIAL PREFRONTAL CORTEX MANAGES WORKING MEMORY INTERFERENCE INDEPENDENT OF CHANGES IN STRATEGY .................... 52 INTRODUCTION ................................................................................................... 52 RESULTS ............................................................................................................ 57 Repeated items in a continuous match to sample task cause interference .. 57 Differential involvement of the mPFC during varying levels