MODELING THE HIPPOCAMPUS: FINELY CONTROLLED MEMORY STORAGE USING SPIKING NEURONS ______________________________________________________ A Dissertation presented to The Faculty of the Graduate School University of Missouri – Columbia ______________________________________________________ In Partial Fulfillment of the Requirement for the Degree Doctor of Philosophy ______________________________________________________ by Ali Hummos Dr. Satish S. Nair, Dissertation Supervisor May 2018 The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled MODELING THE HIPPOCAMPUS: FINELY CONTROLLED MEMORY STORAGE USING SPIKING NEURONS presented by Ali Hummos, a candidate for the degree of doctor of philosophy of Informatics, and hereby certify that, in their opinion, it is worthy of acceptance. Professor Carmen Chicone Professor Chi-Ren Shyu Professor Dong Xu Professor Satish Nair ACKNOWLEDGEMENTS I would like to thank my family for their encouragement throughout this long journey. This work could not have been, without their love, support, and patience. I think all my colleagues and fellow scientists, their interactions helped shape my character and polish my knowledge. I would like to thank my advisor Dr. Nair, who guided through this journey me with his kindness and knowledge. I would like to thank my committee members for their direction and consideration, and taking that time to review my research. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ................................................................................................ ii LIST OF FIGURES ............................................................................................................ v LIST OF TABLES ............................................................................................................ vii ABSTRACT ..................................................................................................................... viii CHAPTER 1: INTRODUCTION AND OBJECTIVES ..................................................... 1 1.1 Background and Motivation ..................................................................................... 1 1.2 Chapter Overview and Objectives ............................................................................ 3 CHAPTER 2: Intrinsic mechanisms stabilize encoding and retrieval circuits differentially in a hippocampal network model ........................................................................................ 5 Abstract ........................................................................................................................... 5 Introduction ..................................................................................................................... 7 Methods........................................................................................................................... 9 Results ........................................................................................................................... 23 Discussion ..................................................................................................................... 31 Conclusions ................................................................................................................... 36 Figures........................................................................................................................... 38 CHAPTER 3: An Integrative Model of the Intrinsic Hippocampal Theta Rhythm ......... 57 Abstract ......................................................................................................................... 57 Introduction ................................................................................................................... 58 Results ........................................................................................................................... 60 Discussion ..................................................................................................................... 71 Methods......................................................................................................................... 79 Tables ............................................................................................................................ 90 Figures........................................................................................................................... 91 iii CHAPTER 4: Interplay of resonant and synchronizing generators in a hippocampal theta model............................................................................................................................... 102 Abstract ....................................................................................................................... 102 Introduction ................................................................................................................. 103 Results ......................................................................................................................... 105 Discussion ................................................................................................................... 109 Methods....................................................................................................................... 115 Tables .......................................................................................................................... 126 Figures......................................................................................................................... 129 CHAPTER 5 − SUMMARY, CONTRIBUTIONS, AND FUTURE WORK ................ 136 REFERENCES: .............................................................................................................. 139 VITA ............................................................................................................................... 156 iv LIST OF FIGURES Figure 1 Matching neurons to biological recordings ........................................................ 38 Figure 2 Network 3D structure and CA3 local circuitry. .................................................. 39 Figure 3 Matching short-term plasticity to experimental recordings. ............................... 41 Figure 4 Pattern completion and separation in CA3 and DG. .......................................... 43 Figure 5 The effects of recurrent connections on excitation within CA3. ........................ 45 Figure 6 Effects of BC interneurons on the stability of CA3 pyramidal cells. ................. 48 Figure 7 OLM interneurons stabilize CA3 and control burst size. ................................... 50 Figure 8 Recurrent connections short-term depression stabilizes CA3 activity. .............. 52 Figure 9 The encoding circuit is stabilized by OLM inhibition and the retrieval circuit is stabilized by short-term depression at the recurrent CA3 connections. ............................ 53 Figure 10 Distinct patterns of excitation during encoding and retrieval levels of ACh. .. 54 Figure 11 Summary of stabilizing mechanisms in low, med and high cholinergic states. 56 Figure 12: Network synaptic connections, titration of external input synapses, and the dynamics of short-term plasticity. ..................................................................................... 92 Figure 13 Model network displayed theta rhythmicity. .................................................... 93 Figure 14 Disconnected pyramidal cells show theta spiking oscillations. ........................ 94 Figure 15 Divergent projections from EC to CA3 produced theta oscillations. ............... 95 Figure 16 Recurrent connections produced theta oscillations. ......................................... 96 Figure 17 Pyramidal-OLM cells network generates theta through two mechanisms. ...... 97 Figure 18 The role of BCs in theta rhythm generation. .................................................... 98 Figure 19 Relative contributions of individual theta generators across cholinergic states. ......................................................................................................................................... 100 Figure 20: Multiple generators of theta oscillations in the hippocampal CA3 network. 130 Figure 21: Pyramidal cells slow currents and OLM-pyramidal cells loop are the two resonant mechanisms. ..................................................................................................... 131 Figure 22: Resonant mechanisms can substitute for and compete with each other. ....... 132 v Figure 23: Functional separation at the extremes of cholinergic modulation minimizes interference between resonating mechanisms. ................................................................ 133 Figure 24: Synchronizing mechanisms can substitute for or interfere with one another 133 vi LIST OF TABLES Table 1: Model cells parameter values ............................................................................. 90 Table 2: Summary of synaptic properties used in the CA3 network model. .................... 90 Table 3: Summary of inactivation studies ...................................................................... 126 Table 4: Classification of theta rhythm mechanisms as resonant, synchronizing, or both. ......................................................................................................................................... 128 vii ABSTRACT The hippocampus, an area in the temporal lobe of the mammalian brain, participates in the storage