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Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption

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Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2018 Molecular Brain Adaptations to Ethanol: Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption Andrew D. van der Vaart Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Molecular and Cellular Neuroscience Commons, Pharmacology Commons, and the Psychiatry and Psychology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/5510 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. ©Andrew van der Vaart 2018 All Rights Reserved Molecular Brain Adaptations to Ethanol: Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Andrew Donald van der Vaart Bachelor of Arts, University of Virginia, 2009 Director: Michael F. Miles, M.D., Ph.D., Professor, Departments of Pharmacology and Toxicology, Neurology Virginia Commonwealth University, Richmond, Virginia, February 2018 i Acknowledgments I would like to sincerely thank all of the people in my life who have provided support, guidance, and contributions to this endeavor. I thank the VCU M.D.-Ph.D. program and the NIAAA for giving me the opportunity to practice research without fear of mistakes for long enough to learn something. I must thank my mentor Dr. Michael Miles. An intrepid captain, Dr. Miles navigated me through my first grant, first first-author paper, and countless fretful nights. His reassurances and ability to calmly cut through the noise has been instrumental. I could not have imagined how much I would grow in this environment. To study under his keen scientific mind has been so gratifying. I also owe a special thank-you to Dr. Kenneth Kendler. Dr. Kendler took a risk on a youth with his head in the clouds when he recruited me to VIPBG. Since then we have had many expansive conversations which have never failed to inspire me. Thank you for showing me that to study psychiatry is to study humanity. And to my committee members: Dr Negus for patiently ensuring I learn the fundamentals of pharmacology, Dr Brunzell for her insight into cellular signaling and Dr. McQuiston for keeping my neuroscience knowledge anchored by the appropriate scaffolds. Thank you all. I could not have traversed this road without the support of my friends and family. Ellen, you really were on the frontlines. Thank you for holding me up, even when the winds were cold. Thank you Mom, Dad, and Rob, all of whom have supported me since before I was self-aware. Thank you to Guy who was the greatest lab partner a ii sentimental fool could ask for. And to the rest of the Miles lab- Rory, Kristin, Jessica, Jim, Jennifer—thank you for the memories, they are vivid ones! iii Table of Contents Clarification of Contributions ..................................................................................... vii List of Tables ................................................................................................................ ix List of Figures ............................................................................................................... x List of Abbreviations .................................................................................................. xiii Abstract ........................................................................................................................ xv Chapter 1 – Introduction ............................................................................................... 1 Chapter 2 – Background and Significance ................................................................. 8 2.1 Primary Binding Sites of Ethanol ............................................................................... 8 2.1.1 GABAA Receptors ..................................................................................... 10 2.1.2 NMDA Receptors ...................................................................................... 12 2.1.3 Intracellular Signaling Enzymes ................................................................ 15 2.2 Glycogen Synthase Kinase 3 ................................................................................... 18 2.2.1 GSK3B and Plasticity ................................................................................ 18 2.2.2 GSK3B in Addiction and Neuropsychiatric Disorders ................................ 25 2.3 Modeling Alcohol Use Disorder ................................................................................ 31 Chapter 3 – Effects of Acute and Chronic Ethanol on the Genome........................ 36 3.1 Introduction .............................................................................................................. 36 3.2 Materials and Methods ............................................................................................ 40 3.3 Results .................................................................................................................... 52 3.4 Discussion ............................................................................................................... 78 Chapter 4 – Effects of Acute and Chronic Ethanol on GSK3B Activity, Downstream Targets, and Behaviors ........................................................................ 88 4.1 Introduction .............................................................................................................. 88 iv 4.2 Materials and Methods ............................................................................................ 92 4.3 Results .................................................................................................................. 102 4.3.1 Acute Ethanol .......................................................................................... 102 4.3.2 Chronic Ethanol ...................................................................................... 112 4.3.3 Acute-on-Chronic Ethanol ....................................................................... 122 4.4 Discussion ............................................................................................................. 129 Chapter 5 – Genetic Modulation of Gsk3b and Ethanol Drinking ......................... 135 5.1 Introduction ............................................................................................................ 135 5.2 Materials and Methods .......................................................................................... 138 5.2.1 Viral-mediated overexpression ................................................................ 138 5.2.2 Viral-mediated deletion ........................................................................... 144 5.2.3 Tamoxifen-inducible Cre ......................................................................... 148 5.3 Results .................................................................................................................. 150 5.2.1 Viral-mediated overexpression ................................................................ 150 5.2.2 Viral-mediated deletion ........................................................................... 155 5.2.3 Tamoxifen-inducible Cre ......................................................................... 168 5.4 Discussion ............................................................................................................. 181 Chapter 6 – Potential Translational Application of GSK3B Inhibitors .................. 186 6.1 Introduction ............................................................................................................ 186 6.2 Materials and Methods .......................................................................................... 190 6.3 Results .................................................................................................................. 195 6.4 Discussion ............................................................................................................. 213 Chapter 7 – Concluding Discussion and Future Directions .................................. 220 References ................................................................................................................. 232 v Appendix .................................................................................................................... 258 Vita .............................................................................................................................. 263 vi Clarification of Contributions Without the technical and scientific contributions of those listed below, the work reported herein would not have been possible. All other work included within this dissertation, aside from cited, is exclusively my own. Chapter 3 CIE animals were run at MUSC in the laboratory of Dr. Howard Becker under care of Marcelo Lopez. Maren Smith, Guy Harris, and myself harvested tissue. Microarray and gene list overlap analyses were performed by Maren Smith. q-RT-PCR and analyses were run by Maren Smith, Guy Harris, and myself. Correlations with ethanol drinking behavior were performed by Guy Harris. Dr. Jennifer Wolstenholme ran Ingenuity Pathway Analyses and
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