AN INVESTIGATION OF THE NEURAL CIRCUITRY OF CUED ALCOHOL BEHAVIORS IN P AND WISTAR RATS by Aqilah Maryam McCane A Dissertation Submitted to the Faculty of Purdue University In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy Department of Psychological Sciences Indianapolis, Indiana December 2017 ii THE PURDUE UNIVERSITY GRADUATE SCHOOL STATEMENT OF COMMITTEE APPROVAL Dr. Christopher Lapish, Chair Department of Psychology Dr. Cristine Czachowski Department of Psychology Dr. Marian Logrip Department of Psychology Dr. Susan Sangha Department of Psychology Approved by: Dr. Nicholas Grahame Head of the Graduate Program iii This work is dedicated, with love, To the two four-legged adventurers, Vega and Loki who now and forever are playing in the eternal green fields To my husband, Michael, whose tireless love helped me to endure the years of graduate school To my sisters, Asiya and Fatimah, whose sleepovers and encouraging texts recharged both my body and heart To my parents, Laquila and Yahya who have encouraged and supported me since birth to become the best person that I could To my mother-in-law, Karen, who welcomed me into her family and home and has always treated me with love and kindness Lastly, to Hannibal who gave me a name which supersedes all others, “Mother” and has brought untold joy into my life iv ACKNOWLEDGMENTS I am grateful to my two mentors, Cris and Chris who have supported and mentored me these last six years. Thank you for putting up with my shenanigans and overseeing my transition from Aqilah McCane to Dr. McCane. I love you both. I would like to thank my cohort, Sarine, Chelsea and Wes, whose input and advice greatly contributed to this work. Thank you to Maureen Timm, whose assistance, training and stringent attention to detail made me a better scientist. Thank you to Brian O’Donnell, who initiated my neuroscience experience and whose mentorship and guidance has significantly influenced my scientific trajectory. No thank you to Dennis J. Devine, who subtracted points from my final project because I gave 100% and not 110%. No thank you to Jessica Beatrice Smith-Kelly, who ate my eggrolls and pudding and was an overall jerk. v TABLE OF CONTENTS LIST OF TABLES ........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix ABSTRACT ........................................................................................................................ x CHAPTER 1. INTRODUCTION .................................................................................... 1 1.1 Clinical significance .................................................................................................. 1 1.2 Genetic vulnerability factors and ethanol seeking phenotypes ................................. 2 1.3 Preclinical models of alcoholism .............................................................................. 3 1.4 Neural substrates of reward seeking ........................................................................ 10 1.5 Basolateral amygdala and reward seeking .............................................................. 11 1.6 Hippocampus and reward seeking ........................................................................... 15 1.7 Nucleus accumbens and reward seeking ................................................................. 17 1.8 Prefrontal cortex and reward seeking ...................................................................... 20 1.9 Cortico-striatal-limbic interactions and reward seeking ......................................... 23 1.10 Neural oscillations .............................................................................................. 24 1.11 Neural synchrony ................................................................................................ 26 1.12 Neural oscillations and alcohol dependence ....................................................... 30 1.13 Generation of theta oscillations .......................................................................... 32 1.14 Theta oscillations and reward seeking ................................................................ 36 1.15 Summary ............................................................................................................. 39 1.16 Overall Aims ...................................................................................................... 40 CHAPTER 2. MATERIALS AND METHODS ............................................................ 42 2.1 Subjects ................................................................................................................... 42 2.2 Behavior .................................................................................................................. 42 2.2.1 Ethanol acquisition ........................................................................................ 42 2.2.2 Lever press training ....................................................................................... 43 2.2.3 Conditioning .................................................................................................. 43 2.2.4 Extinction ....................................................................................................... 44 2.3 Electrophysiology .................................................................................................... 45 2.3.1 Electrophysiology probes .............................................................................. 45 vi 2.3.2 Surgery ........................................................................................................... 46 2.3.3 Electrophysiological recordings .................................................................... 46 2.4 Histology ................................................................................................................. 47 2.5 Data analysis ........................................................................................................... 47 CHAPTER 3. RESULTS ............................................................................................... 50 3.1 Aim 1 analysis ......................................................................................................... 50 3.2 Behavioral analyses ................................................................................................. 50 3.2.1 All animals increase free choice ethanol intake in the IAP ........................... 50 3.2.2 A subset of rats learn to discriminate between the two stimuli ..................... 51 3.2.3 Strain differences in behaviors are absent during electrophysiological recordings ...................................................................................................... 51 3.2.4 Responding decreases in extinction during electrophysiological recordings 52 3.3 Synchrony analyses ................................................................................................. 52 3.3.1 Baseline synchrony is modulated by strain and brain region ........................ 52 3.3.2 Synchrony changes over behavior ................................................................. 53 3.3.3 Synchrony changes by discriminative stimulus and responding ................... 54 3.3.4 Tone epoch ..................................................................................................... 54 3.3.5 Lever pressing epoch ..................................................................................... 55 3.3.6 Drink epoch ................................................................................................... 56 3.3.7 Synchrony changes by brain region ............................................................... 57 3.3.8 Synchrony during extinction is modulated by brain region, response and epoch .............................................................................................................. 57 3.3.9 Synchrony differs by task .............................................................................. 58 3.4 Directionality analyses ............................................................................................ 59 3.4.1 Baseline directionality ................................................................................... 59 3.4.2 DS+ Tone directionality ................................................................................ 60 3.4.3 DS+ lever pressing directionality .................................................................. 60 3.4.4 DS+ Drink directionality ............................................................................... 60 3.4.5 Extinction no-response trials directionality ................................................... 60 3.4.6 Extinction response trials ............................................................................... 61 CHAPTER 4. DISCUSSION ......................................................................................... 62 vii 4.1 Strain differences in behavior and physiology ........................................................ 62 4.2 Impaired stimuli discrimination .............................................................................. 64 4.3 Change in basal neural synchrony ........................................................................... 65 4.4 Sources of synchrony and directionality ................................................................. 67 4.5 BLA-HC synchrony ...............................................................................................