Copyright by Roberto Ulises Cofresi 2018 The Dissertation Committee for Roberto Ulises Cofresi Certifies that this is the approved version of the following Dissertation: Attenuating enduring alcohol cue reactivity via extinction during memory reconsolidation Committee: Rueben Gonzales, Supervisor Hongjoo Lee Marie Monfils Nadia Chaudhri Kim Fromme Attenuating enduring alcohol cue reactivity via extinction during memory reconsolidation by Roberto Ulises Cofresi Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin August 2018 Dedication I dedicate this dissertation to every person who has been or will be harmed by alcohol abuse and/or alcoholism. I truly hope the preclinical work presented here can inform clinical research and/or practice in a meaningful way. Acknowledgements First, I would like to thank the members of my dissertation committee for helping me accomplish the first step toward realizing my dream of someday working to answer behavioral neuroscience questions relevant to alcohol use disorder etiology and/or treatment using both human subjects and non-human animal models. Before anyone else, I need to thank Dr. Rueben Gonzales for many things, but above all else, for his faith and patience. He has been my steadfast supporter since I joined his laboratory in summer 2010. Without Dr. Gonzales, I may have not pursued a PhD at all. He helped me cope with a crisis of confidence in my last year of undergraduate that would have otherwise resulted in me abandoning my dream. He has always pushed me to grow as a trainee and been patient with my idiosyncrasies, sometimes-sluggish development, and occasional resistance to change. Moreover, he has fostered my research interests even when they took me away from the shared interest in neurochemistry that originally brought us together. I also need to thank Dr. Hongjoo Joanne Lee. She also pushed me to grow as a trainee and helped me think more critically about my ideas and experiments. Dr. Lee also helped me learn how to cope with unsuccessful fellowship and grant applications. Finally, she helped me chart a clearer course for myself in life and science. Without Dr. Lee, I may have quit my PhD. I also want to thank Dr. Marie Monfils for exposing me to interesting ideas in behavioral neuroscience, teaching me how to see and share scientific stories instead of simply reporting experimental results, and helping me build confidence in my ideas and writing. I feel lucky to have worked with a “rockstar” whose work has invigorated research on exposure-based therapies for behavioral disorders involving maladaptive associative memory. Next, I want to thank Dr. Nadia Chaudhri for advising and mentoring me from v afar. As one of the few alcohol researchers working on non-human animal models of enduring alcohol cue reactivity and its neurobiology, her feedback on my ideas and work across the last 4 years were critical to my developing interest in alcohol cue reactivity. Finally, I want to thank Dr. Kim Fromme for believing in me and my ability to make the jump from “mice to men” during my last year of graduate school. She helped me think about my ideas from a different perspective and pointed me to scientific literatures relevant to my work that I would have otherwise never discovered. I especially want to thank Dr. Fromme for helping me secure a post-doctoral fellowship position where I will learn how to study alcohol cue reactivity in human subjects. Without Dr. Fromme, I may not have taken the next step toward realizing my dream. Second, I want to thank Dr. Regina Mangieri, who was my first mentor at the University of Texas at Austin and provided my initial training in the laboratory of Dr. Gonzales. She fostered a budding interest in behavioral neuroscience research early in my undergraduate years and has continued to serve as a mentor and friend since then. Third, I would like to thank my wife, Sandie Keertstock, who kept me from burning out in the past year by forcing me to make time for family and friends, food, fun, rest, and relaxation. Fourth, I would like to thank my best friend, Taylor Allen for teaching me to accept help when I need it, for reminding me to stay open to new experiences, and who has helped me grow as a person across my undergraduate and graduate years. Fifth, I would like to thank Lauren MacKnight, Colette Clendaniels, Geoff Dilly, Nicholas Karasik, Suzanne Lewis, Anna Warden, Alisa Baron, Chantal Ramirez, and Lina Gonzalez as well as Drs. Elizabeth Smith, Rheall Roquet, Laura Ferguson, Ashley Vena, and Shannon Zandy, for stimulating existential, intellectual, and scientific conversations vi as well as helping me deal with disappointments and frustrations inside and outside academia. Sixth, I also want to thank Dr. Juan Dominguez for his life advice as well as advocacy on behalf of my admission to the Institute for Neuroscience graduate program. I also thank Dr. Laura Colgin for her advocacy. I also want to thank the former and current directors of the Waggoner Center for Alcohol & Addiction Research (WCAAR), Drs. Adron Harris and Robert Messing, for building our research community. Thanks also to Dr. Michaela Marinelli for her interest in and help with my public education projects. I also need to thank staff in the Waggoner Center for Alcohol & Addiction Research, the College of Pharmacy Division of Pharmacology & Toxicology, the College of Liberal Arts Department of Psychology, and the Institute for Neuroscience; especially, Mirna Benhamou, Gloria Fang, and Krystal Phu. Finally, I need to thank Drs. Richard Timmons and Ryan Stork from the University of Texas at Arlington who helped me win a research fellowship from the UT System Louise-Stokes Alliance for Minority Participation (LSAMP) without which I would never have approached the laboratory of Dr. Rueben Gonzales during the summer 2010. Seventh, I want to thank Drs. Greg Hixon, Nitish Mittal, Ryan Will, and James Reno for helping me, in different ways, to build my proficiency in applied statistical analysis. I also want to thank Drs. James Doherty and John Valenta for teaching me gas chromatographic analysis and various blood ethanol sampling methods. Thanks also to Ms. Suzanne M. Lewis, Ms. Kathleen M. Tuite, Ms. Innsun Park, and Mr. Dylan J. Grote for helping me score videofootage. Suzanne M. Lewis and Kathleen Tuite are also thanked for helping me conduct the pre-conditioning and conditioning phases of experiments. Dylan Grote is also thanked for his help with c-Fos immunohistochemistry. Thanks to Mr. Jarod Chaney, Ms. Lauren Schneider, and Mr. Eric Le, for helping with microscopy and Fos+ vii cell counts. Thanks to Dr. Greg Loney for suggesting the idea to automate sipper site/faceplate contact measurement at the Research Society on Alcoholism Annual Scientific Meeting in 2016. Thanks to Mr. Jonathan Rosenzweig for his help designing, prototyping, and fabricating the frame used to automate sipper site/faceplate contact measurement in conjunction with the Longhorn Maker Studio, the Aerospace Research Machine Shop, the Mechanical Engineering Machine Shop, and Mechanical Engineering Wood Shop. I want to thank Elena Lightfeather, Karen King, Nachi Shukla, and the Animal Resources Center (ARC) husbandry staff for working around my experiment schedules. I also want to thank the Custodial Services team that works the ARC for saying hello me every morning, asking me about my progress in school, and reminding me to relax sometimes. Eight, I am also exceptionally grateful to my family and friends, especially my mother Marybel Bonilla, stepfather Manuel Pesante, and maternal uncle Wilfredo Bonilla for pushing me to challenge myself in school and pursue higher education. Thank you also to my father Bernardo Cofresi for calling me every week from Puerto Rico and planning his visits to Texas around my experiment schedule. Ninth, I want to thank the National Institute of Health (NIH) and the National Institute for Alcohol Abuse and Alcoholism (NIAAA). Specifically, I want to thank the Alcohol Training Grant (ATG) (NIAAA T32AA007471) including the trainee selection committee as well as present and past administrators (especially Anita Mote). The ATG fellowship enabled me to fully immerse myself in the training opportunities at the University of Texas at Austin. I also thank the NIAAA for my supervisor’s funding (NIAAA R37AA11852), which allowed me to conduct all of the experiments described in this work. The National Science Foundation (NSF) also played an important role early in my career by funding the University of Texas System Louise-Stokes Alliance for Minority viii Participation (LSAMP), which provided the undergraduate research experience opportunity to me that landed me in my supervisor’s lab. Funding sources were not involved in study design, collection, analysis, interpretation, manuscript preparation, of the decision to submit any of the work for publication in scientific journal. ix Abstract Attenuating enduring alcohol cue reactivity via extinction during memory reconsolidation Roberto Ulises Cofresi, PhD The University of Texas at Austin, 2018 Supervisor: Rueben Gonzales One of the ways the brain can adapt to repeated alcohol intoxication is to learn about predictive environmental cues such as the sight, smell, and taste of an alcoholic beverage. Over a person’s drinking history, these cues can become associated with alcohol’s post-ingestive pharmacology and acquire the ability to elicit affective, behavioral, and physiological reactions that anticipate alcohol availability, access, and/or intoxication. This reactivity to alcohol-associated cues may facilitate problematic alcohol use and promote the progressive loss of control over alcohol use that typifies alcohol use disorder (AUD). Reactivity to alcohol cues before treatment has been linked to the course and severity of AUD.