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Elucidating Mechanisms That Lead to Persistent Anxiety-Like Behavior In ELUCIDATING MECHANISMS THAT LEAD TO PERSISTENT ANXIETY-LIKE BEHAVIOR IN RATS FOLLOWING REPEATED ACTIVATION OF CORTICOTROPIN-RELEASING FACTOR RECEPTORS IN THE BASOLATERAL AMYGDALA Denise Gaskins Submitted to the faculty of the Graduate School in partial fulfillment of the requirements for the degree Master of Science in the Program of Medical Neuroscience, Indiana University August 2011 i Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Master of Science. Anantha Shekhar, M.D., Ph.D., Chair Robert A. Harris, Ph.D. Master’s Thesis Committee _ Cynthia M. Hingtgen, M.D., Ph.D. May 23, 2011 William A. Truitt, Ph.D. ii © 2011 Denise Gaskins All Rights Reserved iii ACKNOWLEDGEMENTS First, I would like to thank my family and friends for their support and patience. Above all, I would like to thank my husband Ron who supported me throughout this whole process and was a continual source of encouragement on many different levels. Without his support I would not have been able to complete my studies. Next, I would like to thank Dr. Anantha Shekhar for his help and guidance throughout my graduate career. I am further grateful for the financial support and opportunity that presented itself under his tutelage. I would also like to thank the other members of my research committee, Bill Truitt, Ph.D., Bob Harris, Ph.D. and Cynthia Hingtgen, M.D, Ph.D. for their encouraging words, guidance, and constructive criticism. Specific thanks to Bill for his time and efforts in teaching me molecular techniques, how to structure presentations and how to write. I would also like to thank Dr. Harris for advocating on my behalf. I have great respect for Dr. Harris and his support meant a lot. I emphatically believe that it takes innumerable advisors as well as administrative support to guide a graduate student towards the completion of his/her academic endeavors. I appreciate all help given by many. I would like to specifically thank Younglim Lee, Ph.D., Tammy Sajdyk, Ph.D., Philip Johnson, Ph.D., Sonal Sanghani, Ph.D., Jay Simon, Ph.D., Jim Troffater, Ph.D., Michael Kubeck, Ph.D., and Edwin Harper, Ph.D. for their time, advice, and instruction over the years. Thanks also to Amy Dietrich, Pam Minick, and Stephanie Fitz for their efforts that directly contributed to my training and data collection and to iv fellow graduate student John Spence for his camaraderie and advice during the completion of this dissertation. I am also grateful for the personal awards and grants that provided financial support over the course of my studies for traveling expenses (Hingtgen Award and IUSM grant) and salary support (Scottish Rite Fellowship and the Department of Psychiatry). v ABSTRACT Denise Gaskins ELUCIDATING MECHANISIMS THAT LEAD TO PERSISTENT ANXIETY-LIKE BEHAVIOR IN RATS FOLLOWING REPEATED ACTIVATION OF CORTICOTROPIN-RELEASING FACTOR RECEPTORS IN THE BASOLATERAL AMYGDALA Anxiety disorders are estimated to impact 1 in 4 individuals within their lifetime. For some individuals, repeated episodes of the stress response leads to pathological anxiety and depression. The stress response is linked to increased levels of corticotropin-releasing factor (CRF) in the basolateral nucleus of the amygdala (BLA), a putative site for regulating anxiety and associative processes related to aversive emotional memories, and activation of CRF receptors in the BLA of rats produces anxiety-like behavior. Mimicking repeated episodes of the stress response, sub-anxiogenic doses of urocortin 1 (Ucn1), a CRF receptor agonist, are microinjected into the BLA of rats for five consecutive days, a procedure called priming. This results in 1) behavioral sensitization, such that a previously non-efficacious dose of Ucn1 will elicit anxiety-like response after the 3rd injection and 2) the development of a persistent anxiety-like phenotype that lasts at least five weeks after the last injection without any further treatment. Therefore, the purpose of this thesis was to identify mechanisms involved in the Ucn1-priming-induced anxiogenesis. The first a set of experiments revealed that the anxiety-like behavior was not due to aversive conditioning to the context or partner cues of the testing environment. Next, Ucn1-priming-induced gene expression changes in the BLA vi were identified: mRNA expression for Sst2, Sst4, Chrna4, Chrma4, and Gabrr1 was significantly reduced in Ucn1-primed compared to Vehicle-primed rats. Of these, Sst2 emerged as the primary receptor of interest. Subsequent studies found that antagonizing the Sstr2 resulted in anxiety-like behavior and activation of Sstr2 blocked acute Ucn1-induced anxiety-like responses. Furthermore, pretreatment with a Sstr2 agonist delayed the behavioral sensitization observed in Ucn1-induced priming but did not stop the development of persistent anxiety- like behavior or the Ucn1-priming-induced decrease in the Sstr2 mRNA. These results suggest that the decrease in Sstr2 mRNA is associated with the expression of persistent anxiety-like behavior but dissociated from the mechanisms causing the behavioral sensitization. Pharmacological studies confirmed that a reduced Sstr2 mediated effect in the BLA is likely to play a role in persistent anxiety and should be investigated further. Anantha Shekhar, M.D., PhD. vii TABLE OF CONTENTS LIST OF TABLES ................................................................................................ xii LIST OF FIGURES ............................................................................................. xiii 1 INTRODUCTION .............................................................................................. 1 1.1 Stress and Anxiety Overview .............................................................. 1 1.1.1 Neuroanotomy overview of the stress/anxiety response ....... 2 1.1.2 Neurochemical overview of the stress/anxiety response ....... 5 1.2 Corticotrophin-Releasing Factor (CRF) ............................................... 7 1.3 Amygdala and Anxiety ...................................................................... 12 1.3.1 Subnuclei of the amygdala .................................................. 15 1.3.2 Basolateral amygdala (BLA) and anxiety ............................ 17 1.3.3 Anatomical connections of the BLA ..................................... 19 1.3.3.1 Afferent connections to the BLA ............................ 19 1.3.3.2 Efferent connections from the BLA ........................ 20 1.3.4 Internal circuitry of the BLA ................................................. 21 1.3.5 BLA inhibitory interneurons exist as a network .................... 22 1.3.6 Summary of BLA role in anxiety .......................................... 23 1.4 Priming of the BLA with Urocortin 1 (Ucn1) as a Model of Persistent Pathological Anxiety ................................................................ 24 1.5 Specific Aims, Rationale, and Working Hypotheses ......................... 27 1.5.1 Specific Aim 1 ..................................................................... 28 1.5.1.1 Working Hypothesis 1 ............................................ 28 1.5.1.2 Rationale 1 ............................................................ 28 1.5.1.3 Objective 1 ............................................................ 29 1.5.2 Specific Aim 2 ..................................................................... 30 1.5.2.1 Working Hypothesis 2 ............................................ 30 1.5.2.2 Rationale 2 ............................................................ 31 1.5.2.3 Objective 2 ............................................................ 32 1.5.3 Specific Aim 3 ..................................................................... 32 1.5.3.1 Working Hypothesis 3a .......................................... 33 1.5.3.2 Working Hypothesis 3b .......................................... 32 1.5.3.3 Rationale 3 ............................................................ 33 1.5.3.4 Objective 3 ............................................................ 35 1.5.4 Specific Aim 4 ..................................................................... 35 1.5.4.1 Working Hypothesis 4 ............................................ 35 1.5.4.2 Rationale 4 ............................................................ 35 1.5.4.3 Objective 4 ............................................................ 36 viii 2 METHODS AND MATERIALS ........................................................................ 37 2.1 General Methods .............................................................................. 37 2.1.1 Animals ............................................................................... 37 2.1.2 Cannulae placement surgery procedure ............................. 37 2.1.3 Intracranial drug microinjections .......................................... 39 2.1.4 Experimental drugs/compounds .......................................... 39 2.1.5 Placement verification ......................................................... 40 2.1.6 Social interaction (SI) test ................................................... 41 2.1.7 Exclusion criteria data analysis ........................................... 43 2.2 Experimental Protocols ..................................................................... 43 2.2.1 Experiment 1 Protocol: Determine if the persistent anxiety-like phenotype of rats observed following Ucn1-priming is the result of adverse conditioning to the SI arena (context) and/or the presence of a novel partner ........................................
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