UNIVERSITY OF CALIFORNIA, IRVINE Mapping brain networks engaged by spaced learning DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Neurobiology by Carley Karsten Dissertation Committee: Professor Christine Gall, Chair Professor Gary Lynch Professor Michael Yassa Professor John Guzowski 2017 © 2017 Carley Karsten DEDICATION To Grandma Dolores, The original “Dr. Carley”, You’ve been with me every step of the way. ii TABLE OF CONTENTS LIST OF FIGURES ............................................................................................................................................ v ACKNOWLEDGMENTS ................................................................................................................................. vii CURRICULUM VITAE ................................................................................................................................... viii ABSTRACT OF THE DISSERTATION ............................................................................................................... xi INTRODUCTION ............................................................................................................................................. 1 Localization of memory............................................................................................................................. 1 Evidence for synaptic consolidation ......................................................................................................... 1 Evidence for systems consolidation .......................................................................................................... 3 Spaced training enhances OLM ................................................................................................................ 6 Mechanisms thought to underlie the spaced training effect ................................................................... 7 CHAPTER ONE ............................................................................................................................................. 10 Brain-wide Fos activity mapping reveals a novel learning circuit engaged by spaced training .............. 10 Summary ............................................................................................................................................. 11 Introduction ........................................................................................................................................ 12 Materials and Methods ....................................................................................................................... 15 Results ................................................................................................................................................. 18 Discussion ............................................................................................................................................ 21 Acknowledgements ............................................................................................................................. 23 Figures ................................................................................................................................................. 24 CHAPTER TWO ............................................................................................................................................ 28 Orbital frontal cortex is critical for effects of spaced training on long-term object location memory .. 28 Summary ............................................................................................................................................. 29 Introduction ........................................................................................................................................ 30 Materials and Methods ....................................................................................................................... 32 Results ................................................................................................................................................. 35 Discussion ............................................................................................................................................ 40 Figures ................................................................................................................................................. 43 CHAPTER THREE .......................................................................................................................................... 45 Synaptic activity mapping reveals septal-temporal “activation zones” across all hippocampal fields .. 45 Summary ............................................................................................................................................. 46 Introduction ........................................................................................................................................ 47 iii Materials and Methods ....................................................................................................................... 50 Results ................................................................................................................................................. 54 Discussion ............................................................................................................................................ 57 Acknowledgements ............................................................................................................................. 58 Figures ................................................................................................................................................. 59 CHAPTER FOUR ........................................................................................................................................... 62 Increasing TrkB signaling offsets social learning deficits in Fmr1-KO mice ............................................ 62 Summary ............................................................................................................................................. 63 Introduction ........................................................................................................................................ 64 Materials and Methods ....................................................................................................................... 67 Results ................................................................................................................................................. 72 Discussion ............................................................................................................................................ 77 Acknowledgements ............................................................................................................................. 79 Figures ................................................................................................................................................. 80 CHAPTER FIVE ............................................................................................................................................. 83 Leveraging behavioral structure to predict learning .............................................................................. 83 Summary ............................................................................................................................................. 84 Introduction ........................................................................................................................................ 85 Materials and Methods ....................................................................................................................... 87 Results ................................................................................................................................................. 91 Discussion ............................................................................................................................................ 96 Acknowledgements ............................................................................................................................. 98 Figures ................................................................................................................................................. 99 DISCUSSION ............................................................................................................................................... 105 REFERENCES .............................................................................................................................................. 109 iv LIST OF FIGURES Figure 1.1 Representative Fos images 38 Figure 1.2 Spaced training activates different brain regions than massed 39 Figure 1.3 Spaced learning activates a different neuronal network than massed 40 Figure 1.4 Spaced training network is most active after the second training trial 41 Figure 2.1 OFC is needed for long-term OLM with spaced training 57 Figure 2.2 Inactivation of OFC alters neuronal activity in BLA 58 Figure 2.3 BLA is needed for long-term OLM with spaced training 58 Figure 2.4 OFC inactivation before vs. after massed training 59 Figure 3.1 Anatomical divisions used for regional synaptic analysis 74 Figure 3.2 Massed OLM training increases synaptic pERK in CA3 sr 75 Figure 3.3 Spaced OLM training increases synaptic pERK after