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Extinction of Conditioned Fear in the Developing Rat

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Extinction of Conditioned Fear in the Developing Rat G G EXTINCTION OF CONDITIONED FEAR IN THE DEVELOPING RAT Jee Hyun Kim Bachelor of Psychology (Hons) March 2008 Doctor of Philosophy Thesis School of Psychology The University of New South Wales PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Kim First name: Jee Hyun Other name/s: Abbreviation for degree as given in the University calendar: PhD School: Psychology Faculty: Science Title: Extinction of Conditioned Fear in the Developing Rat Abstract 350 words maximum: (PLEASE TYPE) The present thesis examined extinction of conditioned fear in the developing rat. In the adult rat, the hippocampus is thought to be important for the context-specificity of extinction. Because the hippocampus is a late-maturing structure, it was hypothesised that context-modulation of extinction may be different across development. The first series of experiments investigated reinstatement of extinguished fear in the developing rat (Chapter 2). The results showed that P24 rats exhibited context-specific reinstatement. On the other hand, P17 rats did not exhibit reinstatement of extinguished fear following a US reminder treatment. The failure to see reinstatement in P17 rats was not due to the reminder treatment being ineffective in these rats because the same treatment alleviated spontaneous forgetting in rat this age. The second series of experiments then examined the renewal effect and GABAergic involvement in extinction in P24 and P17 rats (Chapter 3). It was observed that P24 rats displayed renewal whereas P17 rats did not. Also, pre-test injection of FG7142 recovered extinguished fear in P24 rats but not in P17 rats, even across a range of doses. This failure to see any FG7142 effect on extinction in P17 rats was not due to the lack of responsiveness to this drug in these rats because FG7142 was found to be effective in alleviating spontaneous forgetting in rats this age. The third series of experiments then examined the effect of temporary inactivation of the amygdala on extinction and re-extinction in the developing rat (Chapter 4). It was observed that extinction retention is impaired in both P24 and P17 rats if the amygdala is inactivated during extinction training. Interestingly, when a CS that had been previously extinguished and then re-trained was re-extinguished, re-extinction was amygdala-independent if initial extinction occurred at 24 days of age but amygdala-dependent if initial extinction occurred at 17 days of age. That is, amygdala involvement in re-extinction was dissociated across development. Taken together, these experiments provide strong evidence for fundamental differences in mechanisms underlying fear extinction across development. The implications of the findings were discussed in light of the theoretical and neural models of extinction. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...…….… Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS G G Abstract The present thesis examined extinction of conditioned fear in the developing rat. In the adult rat, the hippocampus is thought to be important for the context-specificity of extinction. Because the hippocampus is a late-maturing structure, it was hypothesised that context-modulation of extinction may be different across development. The first series of experiments investigated reinstatement of extinguished fear in the developing rat (Chapter 2). The results showed that P24 rats exhibited context-specific reinstatement. On the other hand, P17 rats did not exhibit reinstatement of extinguished fear following a US reminder treatment. The failure to see reinstatement in P17 rats was not due to the reminder treatment being ineffective in these rats because the same treatment alleviated spontaneous forgetting in rat this age. The second series of experiments then examined the renewal effect and GABAergic involvement in extinction in P24 and P17 rats (Chapter 3). It was observed that P24 rats displayed renewal whereas P17 rats did not. Also, pre-test injection of FG7142 recovered extinguished fear in P24 rats but not in P17 rats, even across a range of doses. This failure to see any FG7142 effect on extinction in P17 rats was not due to the lack of responsiveness to this drug in these rats because FG7142 was found to be effective in alleviating spontaneous forgetting in rats this age. The third series of experiments then examined the effect of temporary inactivation of the amygdala on extinction and re-extinction in the developing rat (Chapter 4). It was observed that extinction retention is impaired in both P24 and P17 rats if the amygdala is inactivated during extinction training. Interestingly, when a CS that had been previously extinguished and then re-trained was re-extinguished, re- extinction was amygdala-independent if initial extinction occurred at 24 days of age but G G amygdala-dependent if initial extinction occurred at 17 days of age. That is, amygdala involvement in re-extinction was dissociated across development. Taken together, these experiments provide strong evidence for fundamental differences in mechanisms underlying fear extinction across development. The implications of the findings were discussed in light of the theoretical and neural models of extinction. G G Table of Contents Abstract ii Certificate of Originality vii Acknowledgements viii Publications and Proceedings ix Care and Use of Animals xii List of Tables xiii List of Figures xiv Abbreviations xvii Chapter 1. Introduction 1 1.1 Pavlovian Conditioned Fear 4 The neural model of conditioned fear: a summary 6 The ontogeny of conditioned fear 11 1.2 Extinction of Conditioned Fear 16 Reinstatement 18 Renewal 20 Spontaneous recovery 21 Pharmacological studies 22 1.3 Neurobiology of Extinction 27 The amygdala 28 The medial prefrontal cortex 33 The role of the hippocampus in extinction of conditioned fear 39 1.4 Contextual Learning in the Developing Rat 42 1.5 Experimental Rationale 43 Chapter 2. Reinstatement of extinguished fear in the developing rat 46 Reinstatement of forgotten fear following infantile amnesia 47 General Methods 52 Experiment 1 58 Experiment 2 62 Experiment 3.1 67 G G Experiment 3.2 68 Experiment 3.3 70 Discussion 73 Chapter 3. Renewal and the effect of pre-test FG7142 injection on 78 extinguished fear in the developing rat GABAergic inhibition and fear 79 General Methods 83 Experiment 4 86 Experiment 5.1 91 Experiment 5.2 93 Experiment 5.3 96 Experiment 6.1 100 Experiment 6.2 102 Discussion 104 Chapter 4. Amygdala involvement in extinction and re-extinction in the 108 developing rat General Methods 111 Experiment 7.1 115 Experiment 7.2 119 Re-extinction of conditioned fear 122 Experiment 8.1 125 Experiment 8.2 128 Experiment 9 132 Discussion 140 Extinction in the 17-day-old rat and current models of extinction 143 Chapter 5. General Discussion 147 5.1 Extinction is Fundamentally Different Across Development – 150 Theoretical Accounts Extinction may be unlearning in 17-day-old rats 150 Extinction may be ‘deepened extinction’ in 17-day-old rats 153 5.2 Extinction is Fundamentally Different Across Development – Neural 159 Accounts Extinction memory may be stored in the amygdala in 17-day-old rats 167 G G Extinction may be erasure in 17-day-old rats 168 5.3 Concluding Remarks 175 References 178 Appendices 197 A. Raw Data 197 Chapter 2 197 Chapter 3 204 Chapter 4 210 B. Summary Tables of Statistical Analyses 215 Chapter 2 215 Chapter 3 219 Chapter 4 224 G G Certificate of Originality ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. G G Acknowledgements I thank Jesus Christ, the lover of my soul. You love me despite how nothing in my life is hidden from You. That unconditional love is the source of my unrelenting confidence, courage, and hope. You carried me throughout this journey. Rick Richardson, you are the most amazing and selfless supervisor in the world. I am deeply grateful of your trust and love. Your passion for research and life inspires me, and without your guidance I cannot be what I am today.
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