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UNIVERSITY of CALIFORNIA, IRVINE Epigenetic Control of Medial Habenula Function in Cocaine-Associated Behaviors DISSERTATION

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UNIVERSITY of CALIFORNIA, IRVINE Epigenetic Control of Medial Habenula Function in Cocaine-Associated Behaviors DISSERTATION UNIVERSITY OF CALIFORNIA, IRVINE Epigenetic control of medial habenula function in cocaine-associated behaviors DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Alberto J. López Dissertation Committee: Professor Marcelo A. Wood, Chair Assistant Professor Christie D. Fowler Assistant Professor Stephen V. Mahler 2018 © 2018 Alberto J. López Portion of Chapters 1 & 3 © 2018 John Wiley & Sons, Inc. Portion of Chapter 2 © 2016 The Journal of Neuroscience Dedicatoria A mi Abuelita Ethel quien me mostró lo que es ser fuerte, valiente, e inteligente To my wife Christina López of whom I am completely undeserving. Your love and support are the only reasons I’ve made it this far and I’m so incredibly lucky to have a true equal with whom to share this adventure. One sky, one destiny. To my family, Lorna, Jaime, Jaime Salvador, Cecilia, Elena, and the Burgarts who have all helped provide me with opportunities they never had. To the friends I’ve made along the way (including Drs. Andre White, Janine Kwapis, and Thekla Hemstedt, & Matt Saucedo, Rianne Campbell, Amni Al-Kachak, Matt Kwapis, Sarah Cross, and the Maddi) who have always provided incredible, and often thankless, support. To my various sources of caffeine throughout the Southland that have stimulated my life and work. “Simple, maybe, but not easy. There’s nothing easy about two men sharing one life...You see, sacrifice - that’s the price of a good trick.” Alfred Borden, The Prestige 1 ii Contents List of Figures ................................................................................................................................ iv Acknowledgments........................................................................................................................... v Curriculum Vitae ........................................................................................................................... vi Abstract of the Dissertation .......................................................................................................... xii Introduction ..................................................................................................................................... 1 Substance Use Disorders, Drug-Induced Adaptations, & Cocaine-Associated Memories ....................... 1 A Brief History of Epigenetics.................................................................................................................. 7 Epigenetics in Learning & Memory........................................................................................................ 12 Epigenetic Regulation of Reward Circuitry and Response to Drugs of Abuse ...................................... 17 Structure and Function of the Medial Habenula ..................................................................................... 22 Circuitry and Organization.................................................................................................................. 22 Role in Behavior ................................................................................................................................. 25 Chapter 1: Functional Adaptations of the Medial Habenula During Reinstatement of Conditioned Place Preference ............................................................................................................................ 35 Chapter 2: Controlling Neuronal Function Through Chemogenetics ........................................... 43 Chapter 3: Medial Habenula Cholinergic Neurons Regulate Cocaine-primed Reinstatement ..... 64 Chapter 4: Epigenetic Control of Habenula-mediated Cocaine-associated Behaviors ................. 77 Chapter 5: Conclusions and Moving Forward .............................................................................. 96 References ................................................................................................................................... 103 iii List of Figures Figure 0.1 Ramon y Cajal drawing of the epithalamus 23 Figure 1.1 The MHb responds to cocaine re-exposure. 38 Figure 1.2 The MHb is engaged by cocaine-primed reinstatement of CPP. 40-41 Figure 1.3 Cocaine does not directly alter vMHb activity. 42 Figure 2.1 Bidirectional modulation of dorsal hippocampus via hSyn-DREADDs affects long-term memory processes. 52 Figure 2.2 Characterization of baseline synaptic transmission in hippocampal slices expressing hSyn-driven excitatory and inhibitory DREADD receptors. 55 Figure 2.3 Long-term plasticity changes associated with hSyn-driven DREADD receptor expression in adult hippocampal slices. 56 Figure 2.4 Promotor-specific effects of CaMKIIα DREADD receptors on synaptic transmission and long-term plasticity. 57 Figure 2.5 Modulation of dorsal hippocampus via CaMKIIα-DREADDs leads to bidirectional changes in long-term memory processes. 60 Figure 3.1 Combinatorial approach using Cre-dependent DREADD in Cre-drive line. 68 ChAT Figure 3.2 Chemogenetic activation of MHb artificially induces reinstatement of CPP. 70 Figure 3.3 CNO-priming does not induce reinstatement of CPP in DREADD-free animals. 72 Figure 4.1 Use of TdTomato +/-::ChAT-Cre Cre/+ reporter mice to isolate MHb neurons. 85 Figure 4.2 HDAC3 occupancy is altered in the MHb in response to cocaine-primed reinstatement. 86 W.T. Y298H Figure 4.3 Expression of DIO-HDAC3 and -HDAC3 is limited to Cre- expressing cell populations. 87 Figure 4.4 Loss of HDAC3 deacetylase activity generates an extinction-resistant CPP. 88 Figure 4.5 HDAC3 W.T. in the MHb does not affect cocaine-associated behaviors. 89 Figure 4.6 Expression of DIO-Nurr2c in the vMHb alters cocaine-primed reinstatement behavior. 90 iv Acknowledgments I would like to thank my mentors, Drs. Marcelo Wood, Dina Matheos, and Thomas Kash, who gave me a chance and helped mold me into the scientist I am today. I would like to thank my committee members, Drs. Christie Fowler and Steve Mahler for consistently challenging me to grow intellectually. I would like to acknowledge various collaborators for their contributions to my work and would like to thank: Dr. Eniko Kramar for providing electrophysiological recordings of the hippocampus, Dr. Vanessa Scarfone for technical assistance conducting FACS experiments, Yousheng Jia and Dr. Gary Lynch for providing whole-cell recordings of the MHb and intellectual input on vMHb function, and various members of the Wood lab for assistance on conducting experiments including Drs. Andre White, Janine Kwapis, Annie Vogel-Ciernia, and Yasaman Alaghband & Keith Sakata, Monica Espinoza, Amni Al-Kachak, Philip Hwang, Rianne Campbell, and Om Chitnis. Permission to use copyrighted material has been granted by the Society for Neuroscience Central Office and by John Wiley and Sons. v Curriculum Vitae Alberto J. López [email protected] Current Position: Doctoral Candidate University of California, Irvine Department of Neurobiology and Behavior Center for the Neurobiology of Learning & Memory Wood Lab Education 2013-Present University of California, Irvine , Irvine, CA Biological Sciences, Ph.D. Candidate Wood Lab Cumulative G.P.A.: 3.99 2007-2011 Duke University , Durham, NC Neuroscience, B.S. Minors: Chemistry, Classical Studies (Concentration in Classical Civilizations) Research and Work Experience 2013-Present Doctoral Candidate , Dr. Marcelo Wood Laboratory, University of California, Irvine 2011-2013 Laboratory Technician and Laboratory Animal Coordinator , Dr. Thomas Kash Laboratory, UNC Chapel Hill 2008-2011 Undergraduate Research Assistant, Dr. Henry Yin Laboratory, Duke University 2007-2011 Student Athletic Trainer and Head Student Trainer, Duke University Football Funding 2017-Present NIH Blueprint Diversity Specialized Individual Predoctoral to Postdoctoral Advancement in Neuroscience (D-SPAN) Award (F99/K00) National Institute of Neurological Disorders and Stroke: F99NS105217 “Role of a medial habenula circuit and Nr4a2 in regulating cocaine action during reinstatement” Submitted: 4/2017; Funded: 9/2017 Impact Score: 18 PI: López 2017 Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (F31-Diversity) National Institute on Drug Abuse: F31DA041838 “Role of a medial habenula circuit and Nr4a2 in cocaine-induced reinstatement” Submitted: 4/2016; Funded: 2/2017 Impact Score: 19; Percentile: 4 PI: López 2016-2017 Diversity Supplement NIMH R01MH101491: Role of neuron-specific nucleosome remodeling in intellectual disability National Institute on Mental Health PI: Wood vi 2014-2016 Initiative for Maximizing Student Development (MBRS-IMSD) Program Fellowship Training Grant: GM055246 Ayala School of Biological Sciences, University of California, Irvine 2014-2015 Graduate Assistance in Areas of National Need (GAANN) Fellowship Ayala School of Biological Sciences, University of California, Irvine Honors and Awards 2018 Roger W. Russell Scholar’s Award – Recipient: $1000 Center for the Neurobiology of Learning & Memory, University of California, Irvine 2017 NIDA Diversity Scholar Travel Award – Recipient: $1000 National Institute on Drug Abuse, NIH 2017 Howard A. Schneiderman Award – Recipient : $5000 Ayala School of Biological Sciences, University of California, Irvine 2017 Ford Foundation Dissertation Fellowship – Honorable Mention Ford Foundation 2016 CSHL Cellular Biology of Addiction Course – Attendee CSHL Travel Award: $1500 Cold Spring Harbor Laboratory 2016 Fine Science Tools Graduate Travel Award
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