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Using IEG's to Uncover Pathways for Spatial Learning in The Using IEG’s to uncover pathways for spatial learning in the rat A thesis submitted for the degree of doctor of philosophy Katherine L. Shires Department of Psychology/Biosciences, Cardiff University July 2006 UMI Number: U584126 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U584126 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Declaration This work has not previously been accepted in substance for any degree and is not concurrently submittedTr! candidature for any degree. Signed ...................................... Date ............. Statement 1 This thesis is being ed in partial fulfillment of the requirements for the degree of PhD Signed.. Date ijfi.J Statement 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other SourceSafe acknowledged by footnotes giving explicit references. Signed... .............................. Date............... P . j l . J . 0 .7........ Statement 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisation Abstract This thesis concentrates on the induction of the immediate early genes zif268 and c-fos in a functional and dysfunctional brain network. Initial studies focused on the creation of a task to allow the study of immediate early gene activation after working memory. Previous studies using such a paradigm have compared the animals performing the experimental task with poorly matched control groups. Experiments in this thesis attempted to rectify this. A group of experiments using the water maze found decreases in Zif268 activation in the experimental group as compared to control groups, mainly in the hippocampus and some parahippocampal areas. This was believed to have arisen because of a streamlining of the brain network in the Working Memory group. An increase in c-Fos immunoreactivity was seen in the Working Memory group as compared to controls in prefrontal regions. Structural equation modelling analysis was performed, which allows immediate early gene counts to be used to analyse networks of brain regions. In the Working Memory group connections were seen between the parahippocampal regions and the subiculum that progressed via the hippocampus, indicating that the hippocampus was still engaged by the task. In the control group analysed no such hippocampal pathway was found. This water maze task was then used to study zif268-EG¥Y* activation in a novel transgenic rodent model, where the Zif268 promoter drives the expression of a fluorescent protein EGFP. Activation of both EGFP and Zif268 immunoreactivity was seen in the CA1 region of the animals performing the control task. No EGFP activation was seen in this region in the Working Memory group even though EGFP expression was seen in other regions. The GFP protein was also able to be seen under direct visualisation in the CA1 and dentate gyrus region of control animals. Concerning the dysfunctional brain, gene expression was analysed in the retrosplenial cortex after NMDA lesions of the anterior thalamic nuclei. Previous research has shown that lesions produce a dramatic hypoactivity in the protein products of the immediate early genes c-fos and zif268. Microarray analysis of retrosplenial tissue revealed that as well as decreases in expression of genes related to repair and cell adhesion/neurogenesis, an increase in c-fos mRNA was seen in the lesion hemisphere of the brain. This pattern of expression is opposite to that of the protein. Possible reasons for this are discussed. Acknowledgements First, I would like to thank both of my supervisors John Aggleton and David Carter. Their guidance, support and reassurance has been invaluable during my PhD. It has been a pleasure to work with you both. Huge thanks are also due to Eman Amin who as “super RA” helped with many aspects of this thesis and most valuably kept me sane during many hours of microscope work and section mounting. Also thanks go to Guillaume Poirier for being a sounding board and good friend, I couldn’t have asked for a better collaborator. Thanks too to Laura Peronace for stats help, shopping and Starbucks. Thanks to Penny Mann, for teaching me all about transgenics and answering my many questions, also to James Futter and Seralynne Vann for showing patience whilst teaching me stereotaxic surgery. Also thanks to Trish Jenkins for helping me find my feet at the start of my PhD. Thanks go to all those that cared for and helped me with my animals; Lyn Hill, Kerry Housler, Mike Underwood and Clive Mann. Thanks to Val Pearce and Jeff Lewis, for all their help sorting out anything lab related, and for putting up with me being a ‘pest’. Thanks to all the computing staff, and particularly Dave Griffiths, for the many hours sorting out our problems. Thanks to Lucy Thomson, Sarah Sumner (Sanderson) and David Sanderson for being the best housemates I could have asked for and particularly Dave for reassuring me that I would finish my thesis. Thanks too to all other friends I have made during my PhD that made this such an enjoyable experience. Thanks to my family, Louise Shires, John Shires and Norman and Mary Bath, for putting up with and supporting me. This thesis is dedicated to the memory of Christopher Shires who I got my aptitude and love of science from. Publications Shires, K.L. and Aggleton, J.P. (2005) Decreases in Immediate Early Gene Activation Following Spatial Learning in the Watermaze by Rats: Use of a Novel Control. (European Brain and Behaviour Society Abstract). Poirier,G; Shires, K.L.; Carter, D.A. and Aggleton, J.P. (2004) Transcriptome Analysis of Granular Retrosplenial Tissue Following Anterior Thalamic Excitotoxic Lesions in the Rat Reveal a Distal Effect (Society for Neuroscience Abstract) Shires, K.L. and Aggleton, J. P. (2004) Immediate Early Gene Expression Following Learning in the Water Maze: Comparison with a Novel Control (Society for Neuroscience Abstract) Abbreviations Neuroanatomy Aca anterior cingulate cortex AD anterodorsal nucleus AM anteromedial nucleus Atn anterior thalamic nuclei AV anteroventral nucleus LD lateral dorsal nucleus Bfd barrel fields DG dentate gyrus ENTI lateral entorhinal cortex ENTm medial entorhinal cortex IL infralimbic cortex Mop motor cortex MTL medial temporal lobe Peri perirhinal cortex PL prelimbic cortex Por/Post postrhinal cortex Rga retrosplenial granular a Rgb retrosplenial granular b rRSP rostral retrosplenial cortex Ssp somatosensory cortex Subd dorsal subiculum Genes AP-1 activating protein 1 Chgb Chromogranin B CREB cyclic AMP response element binding protein EGFP enhanced green fluorescent protein ERE Egr response element EST expressed sequence tag Fral Fos related antigen 1 Fra2 Fos related antigen 2 GFP green fluorescent protein Hsdllbetal Hydroxysteroid dehydrogenase 11 beta type 1 IEG immediate early gene Klf5 kruppel-like factor 5 Lsamp Limbic system associated membrane protein MAPK mitogen-activated protein kinase Mmp9 matrix metalloproteinase 9 Nrxnlb non-processed neurexin 1 -alpha 01fm3 Olfactomedin 3 PKA protein kinase A RTF regulatory transcription factor SCN1B voltage-gated sodium channel subunit beta 1 - A Usp3 Ubiquitin specific protease 3 YFP yellow fluorescent protein ZFP91 zinc finger protein 91 Pharmacology and chemistry AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AS-ODN antisense oligodeoxynucleotides DAB diaminobenzidine DEPC Diethylpyrocarbonate GABA gamma-aminobutyric acid LTD long term depression LTP long term potentiation NMD A jV-methyl-D-aspartic acid PBS phosphate buffered saline PBST PBS with 0.2% Triton-X PCR polymerase chain reaction PFA paraformadehyde QPCR quantitative polymerase chain reaction Others AGF1 adjusted goodness of fit index EEG electroencephalogram fMRl functional magnetic resonance imaging GFI goodness of fit index ICM implied covariance matrix MCI mild cognitive impairment OCM observed covariance matrix PET positron emission tomography RAM radial arm maze ROS reactive oxygen species SEM structural equation modelling Contents Declaration ........................................................................................................... i Abstract................................................................................................................ ii Acknowledgements ...............................................................................................iii Publications .......................................................................................................... iv Abbreviations ........................................................................................................v Chapter one .................................................................................................. 1 GENERAL INTRODUCTION.............................................................................1 1.1 What are Immediate Early Genes?.................................................................1
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