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University of California UNIVERSITY OF CALIFORNIA Santa Barbara Age differences in the manifestation & neurobiology of negative affect during alcohol withdrawal in a mouse model of binge drinking A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Psychological & Brain Sciences by Kaziya Mai Lee Committee in charge: Professor Karen Szumlinski, Chair Professor Tod Kippin Professor Aaron Ettenberg Professor Dzwokai Zach Ma September 2017 The dissertation of Kaziya Mai Lee is approved. _____________________________________________ Aaron Ettenberg _____________________________________________ Tod Kippin _____________________________________________ Dzwokai Zach Ma _____________________________________________ Karen Szumlinski, Committee Chair July 2017 Age differences in the manifestation & neurobiology of negative affect during alcohol withdrawal in a mouse model of binge drinking Copyright © 2017 by Kaziya Mai Lee iii Acknowledgements I would like to express my deepest gratitude to my advisor, Dr. Karen Szumlinski, without whom this work would not have been possible. Through your mentorship and encouragement, the past 5 years have flown by faster than I would have thought possible. Your endless enthusiasm and commitment to research, teaching, and family is truly inspiring. I would also like to thank the other members of my dissertation committee, Drs. Tod Kippin and Aaron Ettenberg. Your constructive feedback and guidance over the years pushed me to become a better scientist, writer, critical thinker, and public speaker. I extend special thanks to Dr. Zach Ma for filling in on my committee last minute and enabling me to finish on schedule. This work was accomplished, in large part, thanks to the efforts of my exceptionally distinguished research assistants: Michal Coelho, Kimberly Sern, Mark Bocz, Mackayla Class, Genie Guzelian, Mali Suzuki, Noah Solton, Hadley McGregor, and Ryan Waltermire. Science is a collaborative effort and I was proud and grateful to have you on my team. I know each and every one of you will go on to accomplish great things. To my fellow graduate students, lab mates, and friends: Christina Shin, Chelsea Brown, Sierra Webb, Elissa Fultz, Rianne Campbell, Kyle Ploense, and Mari Purpura. You’ve been the best lab family a person could hope for! Through all the commiserating, laughing, venting, beer drinking, and traveling the country together- I’m thankful I got to share this wild ride with you. To my family- Jane, Jack, Matt, and Sean- whose support and encouragement is unwavering, even from 3,000 miles away. Thank you for always making the most of my rare iv visits home; they were the highlights of my year. From the curated entertainment and delicious food to the lively debates and questionable jokes, there’s no place I look forward to more. I promise not to be insufferable with my newly acquired initials [for longer than a week]. Zak, your devotion and companionship through every step of this crazy journey made all the difference in the world. Thank you for being there to remind me that sometimes all you need is a walk in the sunshine to turn your day around. Finally, I would like to dedicate this dissertation to the passionate and talented teachers of Cape Elizabeth High School (c. 2006), who first showed me that teaching is indeed an art form. Their compassion and genuine interest in their students’ well-being extended far above and beyond the classroom and made a profound difference in my life. I would not be where I am today without them. Attaining my Ph.D. has been a dream almost a decade in the making. The journey has been long, humbling, exhilarating, and transformative and I am forever indebted to all those who helped make it possible. v Vita of Kaziya Mai Lee July 2017 EDUCATION 2010 B.A. - Middlebury College, Department of Neuroscience & Department of Psychology 2014 M.A. - University of California, Santa Barbara, Department of Psychology 2017 Ph.D. - University of California, Santa Barbara, Department of Psychological & Brain Sciences (anticipated) AWARDS & HONORS § UCSB Graduate Opportunity Research Fellowship 2016 § Fiona and Michael Goodchild Graduate Mentoring Award 2016 § Contribution to Excellence in Teaching Award 2016 § New York Academy of Sciences Travel Award 2016 § Research Society on Alcoholism Travel Award 2014, 2015, 2016, 2017 § Middlebury College Senior Research fellowship 2009-2010 § Elizabeth Miller Palen Award 2009 § MMCRI student research scholarship 2009 § Middlebury College academic achievement grant 2008 & 2009 § Federal Science and Mathematics Access to Retain Talent Grant 2008 & 2009 § Federal academic competitiveness grant 2006 & 2007 § QuestBridge: Quest for Excellence Award 2006 RESEARCH POSITIONS 2008-2009 Research Assistant, Dr. Kim Cronise, Department of Neuroscience, Middlebury College 2009 Research Intern, Dr. Richard Riker, Intensive Care Medicine, Maine Medical Center Research Institute 2009-2010 Lab Manager, Dr. Kim Cronise, Department of Neuroscience, Middlebury College August 2012-Present Doctoral Candidate, Advisor: Dr. Karen K. Szumlinski, Department of Psychological and Brain Sciences, UCSB PROFESSIONAL ORGANIZATIONS Society for Neuroscience Research Society on Alcoholism vi PUBLICATIONS 1. Lee, K. M., Coelho, M. A., Solton, N. R., & Szumlinski, K. K. (2017). Negative affect and excessive alcohol intake incubate during protracted withdrawal from binge-drinking in adolescent, but not adult, mice. Frontiers in Psychology, 8:1128. doi: 10.3389/fpsyg.2017.01128 2. Lee, K. M., Coelho, M. A., Sern, K. R., Bocz, M. D., & Szumlinski, K. K. (2017). Anxiolytic effects of buspirone and MTEP in the Porsolt Forced Swim Test. Chronic Stress, 1, 1-9. doi: 10.1177/2470547017712985 3. Lee, K. M., Coelho, M. A., McGregor, H. A., Solton, N. R., Cohen, M., & Szumlinski, K. K. (2016). Adolescent Mice Are Resilient to Alcohol Withdrawal-Induced Anxiety and Changes in Indices of Glutamate Function within the Nucleus Accumbens. Frontiers in Cellular Neuroscience, 10, 265. doi:10.3389/fncel.2016.00265 4. Lee, K. M., Coehlo, M. A., McGregor, H. A., Waltermire, R. S., & Szumlinski, K. K. (2015). Binge alcohol drinking elicits persistent negative affect in mice. Behavioural Brain Research, 291, 385-398. doi: 10.1016/j.bbr.2015.05.055 5. Fraser GL, Riker RR, Lee K. (2009). A retrospective analysis of anti-depressant therapy for adult ICU patients. Crit Care Med, 37 (12), 478. 6. Fraser GL, Riker RR, Lee K. (2009) Prospective monitoring of depressive symptoms during ICU care: A pilot study. Crit Care Med, 37 (12), 490 MANUSCRIPTS UNDER REVIEW & IN PREPARATION 1. Lee, K. M., Coelho, M. A., Class, M. A., & Szumlinski, K. K. (2017). mGlu5-dependent modulation of anxiety during withdrawal from binge drinking in adult and adolescent male mice. Drug and Alcohol Dependence, under review 2. Lee, K. M., Coelho, M. A., Sern, K. R., & Szumlinski, K. K. (2017). Homer2 within the central nucleus of the amygdala gates withdrawal-induced anxiety in a mouse model of binge-drinking. Neuropharmacology, under review 3. Lee, K. M., Coelho, M. A., Class, M. A., Sern, K. R., Bocz, M. D., & Szumlinski, K. K. (2017). mGlu5 blockade within the nucleus accumbens shell reduces alcohol withdrawal-induced anxiety in adult and adolescent mice. In preparation vii Abstract Age differences in the manifestation & neurobiology of negative affect during alcohol withdrawal in a mouse model of binge drinking By Kaziya Mai Lee The research presented in this dissertation characterizes the manifestation and neurobiological underpinnings of negative affect during alcohol withdrawal in adult and adolescent mice using an animal model of voluntary binge drinking. A history of binge drinking elicits changes in glutamate-related protein expression within regions of the extended amygdala relevant to emotional regulation. Studying withdrawal-induced changes in protein expression may provide insight into the mechanisms mediating age-dependent differences in the negative affective consequences of alcohol abuse. The results of this work demonstrate that, similar to the human population, adult and adolescent mice differ both in their pattern of alcohol consumption and also in the consequences of that consumption. Although adolescent animals typically consume larger quantities of alcohol, adolescents are less sensitive than adults to negative affect during early withdrawal. However, adolescents binge drinkers show an emergence of negative affect later in adulthood, as well as elevated alcohol consumption. Moreover, these studies identify specific changes in protein expression within two brain regions critically involved in both emotion and addiction neurobiology- the central nucleus of the amygdala (CEA) and the nucleus accumbens shell (AcbSh). Withdrawal from binge drinking is associated with increased neuronal activity within the AcbSh, concomitant with increased glutamate-related protein expression in adult animals. Conversely, decreased expression of protein indices of Homer2-dependent mGluR signaling viii was observed within the CEA of both adult and adolescent animals. Reversing these changes using neuropharmacological or virus-mediated transgene delivery approaches reduced behavioral signs of withdrawal-induced anxiety. Together, these studies identify neurobiological substrates and pathophysiology of relevance to the negative reinforcing properties of alcohol and characterize ontogenetic differences in the behavioral and neurobiological consequences of alcohol abuse. ix Table of Contents Curriculum
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