LLooyyoollaa UUnniivveerrssiittyy CChhiiccaaggoo LLooyyoollaa eeCCoommmmoonnss Dissertations Theses and Dissertations 2012 FFoorreebbrraaiinn NNoorraaddrreenneerrggiicc AAlltteerraattiioonnss aanndd AAnnxxiieettyy AAfftteerr MMyyooccaarrddiiaall IInnffaarrccttiioonn Jaimee Glasgow Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Neurosciences Commons RReeccoommmmeennddeedd CCiittaattiioonn Glasgow, Jaimee, "Forebrain Noradrenergic Alterations and Anxiety After Myocardial Infarction" (2012). Dissertations. 417. https://ecommons.luc.edu/luc_diss/417 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 2012 Jaimee Glasgow LOYOLA UNIVERSITY CHICAGO FOREBRAIN NORADRENERGIC ALTERATIONS AND ANXIETY AFTER MYOCARDIAL INFARCTION A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN CELL BIOLOGY, NEUROBIOLOGY, AND ANATOMY BY JAIMEE ELIZABETH GLASGOW CHICAGO, ILLINOIS AUGUST 2012 ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Karie Scrogin, for her boundless knowledge and patience. Throughout my training, she has encouraged and challenged me to grow as a scientist, and in all areas of my life. I would also like to thank the other members of my dissertation committee, Dr. EJ Neafsey, Dr. Kuei Tseng, Dr. George Battaglia, Dr. Wendy Kartje, and Dr. Thackery Gray, for their time and thoughtful input throughout my studies. Finally, I would like to thank my friends and family for their contribution to this research through their unconditional love and support. I would especially like to thank my mother, Peggy Glasgow, for her unwavering encouragement until her final days. i TABLE OF CONTENTS ACKNOWLEDGEMENTS ...................................................................................... i LIST OF TABLES ................................................................................................. iv LIST OF FIGURES ............................................................................................... v LIST OF ABBREVIATIONS ................................................................................. vii CHAPTER 1: INTRODUCTION ............................................................................ 1 CHAPTER 2: REVIEW OF RELATED LITERATURE ......................................... 10 Anxiety and Depression after MI and in Heart Failure ................................... 10 Assessments of Depression and Anxiety ...................................................... 12 Neural Control of the Normal and Failing Heart ............................................ 17 Normal Cardiac Function ......................................................................... 17 Autonomic Nervous System: Overview .................................................... 19 Myocardial Infarction and Heart Failure ................................................... 22 Autonomic Nervous System in MI and Heart Failure ............................... 23 The Endocrine System in MI and Heart Failure ....................................... 24 Arrhythmia Generation After MI ..................................................................... 26 Emotional Stressors, Sympathetic Activation, and Arrhythmia ...................... 27 Cortical and Subcortical Control of Heart Rhythms ....................................... 29 Central Nervous System Pathways Mediating Stress Responses ................ 30 Amygdala ................................................................................................. 30 Central Nucleus ....................................................................................... 31 Intercalated Cell Masses .......................................................................... 32 Intra-Amygdala Circuitry in Conditioned Fear .......................................... 33 Prefrontal Cortex: Anatomy and Regulation of Stress Responses ................ 34 Medial Prefrontal Cortex: Anatomy and Role in Stress Responses ......... 34 Insular Cortex .......................................................................................... 38 Orbitofrontal Cortex ................................................................................. 39 Prefrontal Cortex-Amygdala Interactions....................................................... 40 Central Noradrenergic Regulation of Stress Responses and Circulation ...... 41 Locus Coeruleus ...................................................................................... 41 Central Noradrenergic Control of Circulation................................................. 43 Noradrenergic Modulation of Stress Responses ........................................... 45 ii CHAPTER 3: NEOPHOBIA, ARRHYTHMIA, AND ALTERED FOREBRAIN METABOLIC ACTIVITY AFTER MYOCARDIAL INFARCTION .................... 49 Abstract: ........................................................................................................ 49 Introduction: .................................................................................................. 50 Materials and Methods: ................................................................................. 54 Results: ......................................................................................................... 65 Discussion ..................................................................................................... 88 CHAPTER 4: ALTERATIONS IN BETA-ADRENERGIC RECEPTORS AFTER MYOCARDIAL INFARCTION...................................................................... 100 Abstract: ...................................................................................................... 100 Introduction: ................................................................................................ 101 Materials and Methods: ............................................................................... 105 Discussion ................................................................................................... 127 CHAPTER 5: ALTERATIONS IN EXPRESSION AND EXTINCTION OF CONDITIONED FEAR AFTER MYOCARDIAL INFARCTION .................... 134 Abstract ....................................................................................................... 134 Introduction ................................................................................................. 135 Materials and Methods ................................................................................ 139 Results ........................................................................................................ 148 Discussion ................................................................................................... 172 GENERAL DISCUSSION ................................................................................. 181 REFERENCE LIST ........................................................................................... 190 VITA ................................................................................................................. 216 iii LIST OF TABLES Table 1. Cytochrome oxidase activity (NS). 87 Table 2. Specific 125ICYP binding in prefrontal cortical and amygdala regions. 125 Table 3. Isoproterenol inhibition of 125ICYP binding. 126 iv LIST OF FIGURES Figure 1. Coronary artery ligation surgery 69 Figure 2. Left ventricular function (Specific Aim 1) 70 Figure 3. Locus coeruleus stimulation parameters 72 Figure 4. Terminal measures of congestion and remodeling (Specific Aim 1) 73 Figure 5. Open field test for anxiety and neophobia 74 Figure 6. Blood pressure and heart rate responses to locus coeruleus stimulation 75 Figure 7. Representative arrhythmia waveforms 77 Figure 8. ECG and arterial pressure during locus coeruleus stimulation 78 Figure 9. Sequential ECG waveforms 79 Figure 10. Quantification of locus coeruleus stimulation-associated arrhythmias 80 Figure 11. Incubation curve for cytochrome oxidase histochemistry 81 Figure 12. Representative sections showing cytochrome oxidase staining 82 Figure 13. Cytochrome oxidase activity 84 Figure 14. Cytochrome oxidase activity: ipsi- vs. contralateral infralimbic cortex 86 Figure 15. Schematics of incubations to determine specific binding 116 Figure 16. Schematics of 125ICYP solutions to determine agonist inhibition of β AR binding 118 1 Figure 17. Left ventricular function (Specific Aim 2) 120 Figure 18. Terminal measures of congestion and remodeling (Specific Aim 2) 121 v Figure 19. Typical 125ICYP autoradiograms used to determine βAR binding in the prefrontal cortex 122 Figure 20. Standard curves relating specific activity and optical density 123 Figure 21. Typical 125ICYP autoradiograms used to determine βAR binding in the amygdala 124 Figure 22. Left ventricular function (Specific Aim 3) 153 Figure 23. Terminal measures of congestion and remodeling (Specific Aim 3) 155 Figure 24. Freezing responses during fear conditioning 156 Figure 25. Freezing responses during fear extinction 158 Figure 26. Blood pressure responses during extinction 161 Figure 27. Change in blood pressure during extinction 162 Figure 28. Heart rate responses during extinction 163 Figure 29. Change in heart rate during extinction 164 Figure 30. Freezing responses during extinction recall 165 Figure 31. Blood pressure responses during extinction recall 167 Figure 32. Change in blood pressure in extinction recall 168 Figure 33. Heart rate responses during extinction recall 169 Figure 34. Change in heart rate during extinction recall 170 Figure 35. Defecation response during extinction and extinction recall 171 Figure 36. Conclusions and model 188 vi LIST OF ABBREVIATIONS α AR Alpha2-adrenergic receptor 2 AP Arterial pressure AV Atrioventricular ACE Angiotensin-converting enzyme ACTH Adrenocorticotropic hormone AVP Arginine vasopressin βAR Beta-adrenergic receptor β AR Beta1-adrenergic receptor 1 β AR Beta2-adrenergic receptor 2 BLAc Basolateral complex of the amygdala BLA Basolateral nucleus of the amygdala cAMP Cyclic adenosine monophosphate CAL Coronary artery ligation CeA Central nucleus of the amgydala CeL Central amygdala: lateral division CeM Central amygdala: medial division Cg Anterior cingulate cortex CN Central nervous system CO Cytochrome oxidase vii CS Conditioned stimulus DPM Decays per minute ECG Electrocardiogram EPM Elevated plus maze FO Fractional occupancy FS Fractional shortening Gαi G inhibitory protein Gαs G stimulatory protein GABA Gamma-aminobutyric acid GPCR G protein-coupled receptor HPA Hypothalamic-pituitary-adrenal HPLC High-performance liquid chromatography HR Heart rate ICM Intercalated cell masses 125ICYP 125-Iodocyanopindolol IL Infralimbic cortex Ins Insular cortex LVDD Left ventricular diastolic diameter M Motor cortex MAP Mean arterial pressure OF Orbitofrontal cortex PKA Protein kinase A viii
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