Sensitivity of the Retrosplenial Cortex to Distal Damage in a Network Associated with Spatial Memory

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Sensitivity of the Retrosplenial Cortex to Distal Damage in a Network Associated with Spatial Memory Sensitivity of the retrosplenial cortex to distal damage in a network associated with spatial memory: Evidence from lesion and gene expression studies in the rat. GUILLAUME POIRIER Thesis submitted to Cardiff University For the Degree of Doctor of Philosophy September 2006 UMI Number: U584894 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 U584894 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 CANDIDATE’S ID NUMBER 0 7 2 5 ^ CANDIDATE’S SURNAME Please circle appropriate value Mr / Miss 1 Ms / Mrs / Rev / Dr 1 Other please specify ..../felfcfcpL CANDIDATE’S FULL FORENAMES DECLARATION This work has not previousjy been accepted in substance for any degree and is not concurrently submitted in candidature for any dec^re ~ ^ Signed .................. (candidate) Date ... 'E/fcfiffX? STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of fht>..................(insert MCty^Md, MPhil, PhD etc, as appropriate) Signed ... (candidate) Date ... STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged-by are acknowledged-by foot footnotes giving explicit references.;es Signed . ... (candidate) D ate.. 25fc!>£& 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 bdTmade available to outside organisations. Signed. (candidate) Date.. STATEMENT 4 - BAR ON ACCESS APPROVED I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access apqreveaapproved bvdv the tne Graduateuraauate Developmentueveiopmeni Committee.uomminee. Signed $ C rrrr> ..................... (candidate) Date Sensitivity of the retrosplenial cortex to distal damage in a network associated with spatial memory: Evidence from lesion and gene expression studies in the rat. T ab le of contents Acknowledgments ................................................................................................................iii Sum m ary............................................................................................................................. iv Publications ..........................................................................................................................v Abbreviations ..................................................................................................................... vi Chapter 1: General introduction ......................................................................................1 Chapter 2 : Spatial memory, regional plasticity and limbic network interactions ........................................................................................................................3 3 Chapter3 : Retrosplenial cortex vulnerability to afferent damage: A Fos imaging study in the rat .......................................................................................8 6 Chapter4 : Effects of anterior thalamic nuclei lesions on retrosplenial cortex immediate-early gene activity: Time course, cell characteristics, and association with corticosterone levels ..............................................................................................119 Chapter5 : Using microarray techniques to target the impact of anterior thalamic nuclei lesions in rats upon retrosplenial cortex function: Why might anterior thalamic damage cause covert pathology in the retrosplenial cortex? ...............................................................................................................................164 Chapter6 : General discussion ....................................................................................2 3 7 References ........................................................................................................................2 5 4 -Acknowledgments I would like to thank my supervisor, John Aggleton, a wonderful mentor, for taking a chance on me. I am grateful that you made me part of your research group and for the lengths you have gone to help me along the way. Very special thanks go to Laura Peronace, without whom I probably would not have made it in one piece. I am grateful for your understanding, especially when the research came first. I would also like to express my gratitude to Dave Mumby, who set the ball in motion. I wish to thank Melissa Glenn for teaching me the basics, and to Trisha Jenkins for the work that laid the foundations for my thesis. Numerous people have provided invaluable assistance towards the completion of this thesis and related work, and Dave Carter, Kerrie Thomas, Jon Erichsen, Leslie-Anne Strabel, Matthew Mundy, Anthony McGregor, Peter Jones, Jeff Lewis, and Val Pearce deserve particular mention. Eman Amin deserves credit for never being daunted by the crazy schemes and mountains of work I created. I particularly wish to thank Kate Shires, for constant support during the course of this thesis, and other friends and colleagues who made me enjoy life in and out of the lab. Alex Johnson and Steve Chambers, amongst others, certainly deserve a few pints for their antics, as does Rachel Kyd for introducing me to surf in the Gower. The encouragement and reassurances provided by Elsa Pioli and Helen Pothuizen were well appreciated in the last stretch. The humour and enthusiasm of Mathieu Albasser, contrary to what he may think, have been great in helping me stay focused. Finally, I wish to acknowledge the guidance of my family who has demonstrated the value of hard work. Most of all, I would like to acknowledge the unrelenting support of my parents, Carole Marcoux and Michel Poirier, who have always believed in me and encouraged me to reach for my dreams. um m ary This thesis explores the influence of brain regions in the extended hippocampal system on the activity of the retrosplenial cortex in the rat. The primary motivation of the experiments presented in this thesis is to improve the understanding of the vulnerability of the retrosplenial cortex, especially in the context of diencephalic amnesia and Alzheimer’s disease. Using molecular imaging, it is shown that discernible networks of brain regions are active even at different training levels of the same spatial memory task, not just between different tasks. I provide evidence that multiple brain regions exhibit a relationship with memory. Importantly, these regions display associations with different memory components, which change according to the experience and the performance level of the subjects. The lesion studies provide information about the vulnerability of granular b retrosplenial cortex to distal damage in certain regions. The pattern of the terminations of the projections from each region to the retrosplenial cortex does not appear to be predictive of the impact that damage to each will have on immediate-early gene activity in the latter. In addition to the anterior thalamic nuclei, the retrosplenial cortex is vulnerable to damage in the entorhinal cortex and in the hippocampus, but not in the laterodorsal thalamic nucleus. I show that retrosplenial cortex dysfunction can occur as early as one week after anterior thalamic nuclei lesions. Evidence is also shown to suggest that both granular and dysgranular subregions of the retrosplenial cortex are affected as a result of anterior thalamic nuclei lesions. Finally, the presence of hormonal alterations in dysfunctional retrosplenial cortex tissue and evidence from a microarray analysis suggest that this region exhibits widespread alterations in cellular function after anterior thalamic nuclei lesions. The effects presented and the mechanisms that are proposed contribute to our understanding of the vulnerability of the retrosplenial cortex to neurological insults. P ublications Poirier G., Thomas K.L., Mundy M.E., McGregor A. Jones P.M., & Aggleton J.P. (2006). Retrosplenial cortex immediate-early gene reactivity after lesions to its afferents: Selective vulnerability to distal damage. Abstract. Federation of European Neuroscience Societies, Vienna. Poirier G., Albasser M., & Aggleton J.P. (2006). Immediate-early gene hypoactivity in the rat retrosplenial cortex after different lesions: An evaluation of the retrosplenial vulnerability to afferent damage. Abstract. Molecular and Cellular Cognition Society, Vienna. Albasser M., Warburton E.C., Poirier G., & Aggleton J.P. (2006). Hippocampal lesions in rats markedly reduce retrosplenial cortex activity as measured by c-Fos gene expression. Abstract. Federation of European Neuroscience Societies, Vienna. Poirier G. & Aggleton J.P. (2005). The retrosplenial cortex and immediate-early gene reactivity following deafferentation in the rat. Abstract. Experimental Psychology Society, London. Poirier, G., Bloom, Z., & Aggleton, J.P. (2005). Temporal characterization of the effect of anterior thalamic nuclei lesions on immediate-early gene activation in retrosplenial
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