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Astrocyte Sensitivity to Dopamine in Culture and Ex Vivo

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Astrocyte Sensitivity to Dopamine in Culture and Ex Vivo University of South Carolina Scholar Commons Theses and Dissertations Summer 2019 Astrocyte Sensitivity to Dopamine in Culture and Ex Vivo Ashley L. Galloway Follow this and additional works at: https://scholarcommons.sc.edu/etd Part of the Biomedical Commons, and the Medicine and Health Sciences Commons Recommended Citation Galloway, A. L.(2019). Astrocyte Sensitivity to Dopamine in Culture and Ex Vivo. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5465 This Open Access Dissertation is brought to you by Scholar Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. ASTROCYTE SENSITIVITY TO DOPAMINE IN CULTURE AND EX VIVO by Ashley L. Galloway Bachelor of Science University of Tennessee at Chattanooga, 2014 Master of Science University of South Carolina, 2016 Submitted in Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Biomedical Science School of Medicine University of South Carolina 2019 Accepted by: Pavel I. Ortinski, Major Professor Ana Pocivavsek; Chairman, Examining Committee Norma Frizzell, Committee Member Fabienne Poulain, Committee Member Robert L. Price, Committee Member Cheryl L. Addy, Vice Provost and Dean of the Graduate School © Copyright by Ashley L. Galloway, 2019 All Rights Reserved. ii DEDICATION I would like to dedicate this work to my best friend, Garrett B. Hutchison, for being by my side throughout this humbling journey. He has been irreplaceable in his efforts towards “feeding and care” of his graduate student. It is my hope that we will continue to collaborate on this journey that is life, sharing adventures and memories for the remainder of our days. I would also like to dedicate this manuscript to my mother, Diane Galloway, who has, without fail, supported me in every possible way throughout life and most importantly, through my academic endeavors. Truly, it is to my mother that my sincerest thanks must go, for I would not have achieved such a goal without her unyielding support, understanding, and encouragement. iii ACKNOWLEDGEMENTS I would like to thank everyone from the PPN department that I have known during my time here. Every single one has contributed in some way to this thesis. Foremost I would like to thank my mentor, Dr. Pavel Ortinski, for his patience and encouragement throughout this project; for providing me with limitless opportunity and for opening up the world of neuro(science) to me. I have grown substantially, both as a scientist and a person, throughout our time together. May my future professional endeavors reflect the exemplary mentorship and guidance you gave me through my graduate career. I would also like to extend a special thank you to those I regard as “graduate-school survival” mentors: Dr. Larry Reagan, Dr. Jill Turner, and Dr. David Mott. Your wisdom and guidance have helped me navigate the many twists and turns along the path to becoming a Ph.D. To Dr. Robert (Bob) Price, thank you for teaching me the imaging techniques, without which, this dissertation would not have been possible. Your patience and enthusiasm in mentoring me on techniques of microscopy and presentation are invaluable. I was not only able to learn a challenging and rewarding scientific approach, but I was also given the opportunity to discover a creative outlet for my passion in science. iv To my committee, Dr. Norma Frizzell, Dr. Robert Price, Dr. Fabienne Poulain, and Dr. Ana Pocivavsek. I am extremely grateful for your mentorship and guidance throughout my time as a Ph.D student. v ABSTRACT Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. This thesis illustrates effects of dopamine on cultured astrocytes and astrocytes in brain slices (ex vivo). In striatal cultures, extracellular dopamine triggered changes in astrocytic Ca2+ signaling and rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation, but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. To isolate possible mechanisms underlying these structural and functional changes, whole- genome RNA sequencing was used in identifying prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. Specifically, results show that cultured astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. To examine astrocyte response to behaviorally relevant dopamine signals, astrocyte morphological and molecular profiles in ventral striatum (nucleus accumbens core; NAcC) and dorsolateral striatum were characterized following cocaine self-administration training on an extended access schedule. Findings illustrate that extended cocaine experience resulted in decreased numbers of GFAP+ cells and primary process number in the ventral striatum. This was vi associated with an increase in connexin 30 mRNA, an astrocyte-astrocyte interaction gene. In the dorsolateral striatum, there was an observed increase in length of GFAP+ primary processes and downregulation of SPARC (astrocyte- neuron interaction gene) mRNA. vii TABLE OF CONTENTS DEDICATION ........................................................................................................... iii ACKNOWLEDGMENTS .............................................................................................. iv ABSTRACT ............................................................................................................. vi LIST OF TABLES ......................................................................................................xii LIST OF FIGURES ................................................................................................... xiii LIST OF SYMBOLS .................................................................................................. xv LIST OF ABBREVIATIONS .........................................................................................xvi CHAPTER 1: GENERAL INTRODUCTION ....................................................................... 1 1.1 DOPAMINERGIC NEUROTRANSMISSION ...................................................... 3 1.2 MOTIVATION, REWARD, AND MEMORY ....................................................... 4 1.3 ROLES OF THE HIPPOCAMPUS AND STRIATUM: IMPLICATIONS IN DISEASE ................................................................................................... 5 1.4 STRIATUM: SUBREGION DISTINCTIONS IN COGNITION AND MOTOR FUNCTION .................................................................................................... 8 1.5 DOPAMINE AND SUBSTANCE ABUSE IN THE STRIATUM: EVOLUTION OF ADDICTION ............................................................................................. 10 1.6 ASTROCYTE MORPHOLOGY .................................................................... 11 1.7 ASTROCYTE REGIONAL HETEROGENEITY ................................................. 13 1.8 ASTROCYTE PLASTICITY AND HOMEOSTATIC CONTROL OF NEUROTRANSMISSION ............................................................................. 14 1.9 DOPAMINERGIC SIGNALING IN ASTROCYTES ............................................. 17 1.10 ASTROCYTE-SYNAPSE RELATIONSHIPS .................................................. 19 viii 1.11 ALTERATIONS IN ASTROCYTE-SYNAPSE RELATIONSHIPS: IMPLICATIONS FOR SUBSTANCE USE DISORDERS ........................................... 25 1.12 CONCLUSION ...................................................................................... 28 CHAPTER 2: METHODS .......................................................................................... 34 2.1 IN VITRO MODEL OF ELEVATED EXTRACELLULAR DOPAMINE ....................... 34 2.2 INTRAVENOUS CATHETER IMPLANTATION FOR COCAINE SELF-ADMINISTRATION ................................................................................. 35 2.3 ANIMAL MODEL OF ELEVATED EXTRACELLULAR DOPAMINE SIGNALING ........ 36 2.4 IMMUNOCYTOCHEMISTRY AND IMMUNOHISTOCHEMISTRY .......................... 37 2.5 IMMUNOFLUORESCENT IMAGING AND ANALYSIS: DENSITY AND MORPHOLOGY ......................................................................... 39 2.6 WESTERN BLOT PROCEDURE AND ANALYSIS OF PRIMARY CULTURED ASTROCYTES .............................................................................. 40 2.7 GENETIC CHARACTERIZATION: RNA-SEQUENCING AND RT-QPCR ................ 41 2.8 CALCIUM IMAGING OF CULTURED ASTROCYTES ........................................ 44 2.9 ELECTROPHYSIOLOGY OF CULTURED ASTROCYTES .................................. 45 2.10 STATISTICAL ANALYSIS ........................................................................ 46 CHAPTER 3: EFFECTS OF ELEVATED EXTRACELLULAR DOPAMINE EXPOSURE ON ASTROCYTES IN VITRO ........................................................... 52 3.1 INTRODUCTION ..................................................................................... 52 3.2 CHARACTERIZATION OF PRIMARY CULTURES ............................................ 55 3.3 ELEVATED DOPAMINE LEADS TO STELLATION OF ASTROCYTE PROCESSES IN VITRO .................................................................................. 55 3.4 ASTROCYTE STELLATION
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