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CREB-Mediated Enhancement of Hippocampus-Dependent Memory Consolidation and Reconsolidation

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CREB-Mediated Enhancement of Hippocampus-Dependent Memory Consolidation and Reconsolidation CREB-mediated enhancement of hippocampus-dependent memory consolidation and reconsolidation by Melanie Jay Sekeres A thesis submitted in conformity with the requirements for the degree of Doctorate of Philosophy (PhD) Department of Physiology University of Toronto © Copyright by Melanie Jay Sekeres, 2012 CREB-mediated enhancement of hippocampus-dependent memory consolidation and reconsolidation Melanie Jay Sekeres PhD Department of Physiology University of Toronto 2012 Abstract Memory stabilization following encoding (synaptic consolidation) or memory reactivation (reconsolidation) requires gene expression and protein synthesis. Although consolidation and reconsolidation may be mediated by distinct molecular mechanisms, disrupting the function of the transcription factor CREB (cAMP responsive element binding protein) impairs both processes. We use a gain-of-function approach to show that CREB (and CREB-coactivator CRTC1) can facilitate both synaptic and systems consolidation and reconsolidation. We first examine whether acutely increasing CREB levels in the dorsal hippocampus is sufficient to enhance spatial memory formation in the watermaze. Locally and acutely increasing CREB in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions which do not normally support consolidation, weakly-trained wild-type (WT) mice and strongly-trained mutant mice with brain-wide disrupted CREB function. ii CRTCs (CREB regulated transcription co-activators) are a powerful co-activator of CREB, but their role in memory is virtually unexplored. We show, for the first time, that the novel CREB co-activator CRTC1 enhances memory consolidation. Locally increasing CRTC1 (or CREB) in the dorsal hippocampus of WT mice prior to weak context fear conditioning facilitates consolidation of precise context memory. Last, we show that CREB or CRTC1 facilitates precise and enduring memory consolidation and reconsolidation. Acute enhancement of hippocampal CREB or CRTC1 during initial synaptic consolidation can maintain precision of remote context memory, while increasing CREB or CRTC1 just prior to reactivation of a weak remote context memory enhances context memory reconsolidation. These gain-of-function manipulations indicate that increasing CRTC1 or CREB function is sufficient to enhance the strength of new, as well as reactivated established, memories without compromising memory specificity. Together with previous results, these findings indicate that CREB is both necessary and sufficient for hippocampal-dependent memory formation, and underline its pivotal role in the hippocampal molecular machinery underlying long-term memory consolidation and reconsolidation. iii Acknowledgments I would like to acknowledge my PhD supervisor, Dr. Sheena Josselyn for her continuous mentorship throughout my graduate program. She is one of the toughest women scientists I have known, and she has been a tremendous example of dedication to science, and to pop culture. The contributions of Dr. Paul Frankland have also been an invaluable part of my graduate program, both as a collaborator and as a sports fan. Life in the lab was always a fun and supportive environment thanks to the motley crew of graduate students and post-doctoral fellows in the Josselyn and Frankland labs. I would especially like to acknowledge Alonso Martinez-Cannabal, Anne Wheeler, Katherine Akers, Maithe Arruda-Carvalho, Christy Cole, Adelaide Yiu, Scellig Stone, and Catia Teixiera for years of collaboration, entertainment and enabling. I also acknowledge the in-vitro work done by Valentina Mercaldo and Derya Sargin (Chapter 4). Daily life in the lab would not have been nearly as smooth without the contributions of our outstanding lab manager Toni Decristofaro, and technicians Mika Yamamoto and Russell Braybon. I thank Dr. Martin Wojtowicz and Dr. Zhengping Jia for their suggestions and guidance on my graduate supervisory committee. I also acknowledge the contributions of Dr. Gordon Winocur for his ongoing advice and constructive criticism, and Jeff Winocur for his sharp eye and wit, and for his tolerance. Funding of my graduate program was provided by CIHR Frederick Banting and Charles Best Canada Graduate scholarship - Master’s and Doctoral awards, Sick Kids Research Institute (Restracomp), the University of Toronto’s School of Graduate Studies (SGS), the University of Toronto’s Faculty of Medicine, and the University of Toronto Neuroscience Program (UTNP). iv Table of Contents Acknowledgments ........................................................................................................... iv Table of Contents ............................................................................................................. v List of Figures ................................................................................................................ xii List of Abbreviations ....................................................................................................... xv 1 INTRODUCTION ......................................................................................................... 1 1.1 Consolidation ........................................................................................................ 2 1.1.1 Synaptic consolidation ................................................................................ 3 1.2 Transcription factors .............................................................................................. 5 1.2.1 Transcriptional regulation by CREB............................................................ 6 1.2.2 CREB co-activators .................................................................................. 11 1.3 CREB’s role in regulating behaviour ................................................................... 15 1.3.1 Identification of CREB as a key mediator of memory consolidation ......... 16 1.3.2 Methods of genetically manipulating CREB function in the mammalian brain ......................................................................................................... 19 1.3.3 A role for CRTCs in memory consolidation? ............................................. 27 1.4 Introduction to Systems Consolidation ................................................................ 29 1.4.1 The hippocampus ..................................................................................... 31 1.4.2 Theories of systems consolidation of remote memory.............................. 41 1.4.3 Reconsolidation ........................................................................................ 44 1.4.4 Time-dependent reorganization of remote memories ............................... 45 1.5 Putting it all together: CREB is both necessary and sufficient for memory consolidation ....................................................................................................... 48 1.5.1 CREB is necessary for memory consolidation .......................................... 48 1.5.2 CREB is sufficient for memory consolidation ............................................ 54 v 1.5.3 CREB is necessary for memory reconsolidation ...................................... 58 1.6 The role of CREB co-activators in memory consolidation ................................... 62 1.6.1 CBP/p300 disruption impairs memory consolidation ................................ 62 1.6.2 What is the role of CRTCs in memory consolidation? .............................. 63 1.7 Goals of this thesis: Hypotheses and predictions ................................................ 64 2 GENERAL METHODS............................................................................................... 66 2.1 Mice .................................................................................................................... 66 2.1.1 Wild-type (WT) ......................................................................................... 66 2.1.2 CREBαΔ−/− mice ......................................................................................... 66 2.2 Preparation of HSV Vectors ................................................................................ 66 2.3 Surgery................................................................................................................ 68 2.4 General behavioural procedures ......................................................................... 68 2.4.1 Spatial watermaze experiments ............................................................... 68 2.4.2 Context fear conditioning experiments ..................................................... 72 2.5 Statistical analyses .............................................................................................. 74 2.6 Histology ............................................................................................................. 74 2.7 Immunohistochemistry ........................................................................................ 76 3 Dorsal hippocampal CREB is both necessary and sufficient for spatial memory ....... 77 3.1 Abstract ............................................................................................................... 77 3.2 Introduction ......................................................................................................... 77 3.2.1 Experiment 1: Effects of increasing or suppressing CREB on the consolidation of spatial memory that is only weakly acquired in control mice. ........................................................................................................
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