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SOHINI DUTTA, Ph.D., May 2021 BIOMEDICAL SCIENCES DISSOCIABLE ROLES OF THE NUCLEUS ACCUMBENS CORE AND SHELL SUBREGIONS IN THE EXPRESSION AND EXTINCTION OF CONDITIONED FEAR DISSERATION ADVISOR: Dr. AARON M. JASNOW The nucleus accumbens (NAc), consisting of core (NAcC) and shell (NAcS) sub-regions, has primarily been studied as a locus mediating the effects of drug reward and addiction. However, there is ample evidence that this region is also involved in regulating aversive responses, but the exact role of the NAc and its subregions in regulating associative fear processing remains unclear. Here, we investigated the specific contribution of the NAcC and NAcS in regulating both fear expression and fear extinction. Using Activity-Regulated Cytoskeleton-Associated protein (ARC) expression as an indicator of neuronal activity, we first show that the NAcC is specifically active only in response to an associative fear cue during an expression test. In contrast, the NAcS is specifically active during fear extinction. We next inactivated each subregion using lidocaine and demonstrated that the NAcC is necessary for fear expression, but not for extinction learning or consolidation/retention of extinction memory. In contrast, we demonstrate that the NAcS is necessary for the consolidation of extinction memory, but not fear expression or extinction learning. Further, inactivation of mGluR1 or ERK signaling specifically in the NAcS disrupted extinction memory but had no effect on fear expression or extinction learning itself. Our data provide the first evidence for the importance of the ERK/MAPK pathway as an underlying neural mechanism facilitating extinction consolidation within the NAcS. These findings suggest that the NAc subregions play dissociable roles in regulating fear recall and the consolidation of fear extinction memory, and potentially implicate them as critical regions within the canonical fear circuit. DISSOCIABLE ROLES OF THE NUCLEUS ACCUMBENS CORE AND SHELL SUBREGIONS IN THE EXPRESSION AND EXTINCTION OF CONDITIONED FEAR A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Sohini Dutta May 2021 © Copyright All rights reserved Except for previously published materials Dissertation written by Sohini Dutta B.Sc., University of Delhi, India, 2012 M.Sc., Bangalore University, India, 2014 Ph.D., Kent State University, Ohio, 2021 Approved by Aaron M. Jasnow, Ph.D. , Chair, Doctoral Dissertation Committee Colleen M. Novak, Ph.D. , Members, Doctoral Dissertation Committee Gail C. Fraizer, Ph.D. John Johnson, Ph.D. John Gunstad, Ph.D. Accepted by Ernest J. Freeman, Ph.D. , Director, School of Biomedical Sciences Mandy Munro-Stasiuk, Ph.D. , Interim Dean, College of Arts and Sciences TABLE OF CONTENTS TABLE OF CONTENTS………………………………………………………………………….v LIST OF FIGURES……………………………………………………………………………...vii LIST OF TABLES………………………………………………………………………………..ix LIST OF ABBREVIATIONS……………………………………………………………………..x ACKNOWLEDGEMENTS……………………………………………………………………...xii CHAPTER 1: GENERAL INTRODUCTION……….......………………………………............1 1.1 ANXIETY DISORDERS AND TRAUMA-RELATED DISORDERS………………………2 1.2 GENERAL INTRODUCTION OF NUCLEUS ACCUMBENS………................…………12 1.3 GLUTAMATERGIC TRANSMISSION IN FEAR EXPRESSION AND FEAR EXTINCTION.........................................................................................................................16 1.4 ERK/MAPK PATHWAY………………............................…………………………………19 1.5 SPECIFIC AIMS…………………………….................……………………………………23 1.6 REFERENCES……………………................………………………………………………24 CHAPTER 2: THE NUCLEUS ACCUMBENS CORE IS NECESSARY FOR FEAR EXPRESSION WHEREAS THE SHELL REGULATES FEAR EXTINCTION CONSOLIDATION………………………………...................................................……………36 2.1 INTRODUCTION……………………………………...........………………………………36 2.2 METHODS.……………………………………………..........………………………….......41 2.3 RESULTS................................................................................................................................48 2.4 DISCUSSION..........................................................................................................................63 2.5 REFERENCES........................................................................................................................66 v CHAPTER 3: MGLUR1 ACTIVATION AND THE ERK/MAPK SIGNALING PATHWAY WITHIN THE NUCLEUS ACCUMBENS SHELL IS NECESSARY FOR FEAR EXTINCTION CONSOLIDATION.............................................................................................72 3.1 INTRODUCTION...................................................................................................................72 3.2 METHODS..............................................................................................................................75 3.3 RESULTS................................................................................................................................80 3.4 DISCUSSION..........................................................................................................................93 3.5 REFERENCES........................................................................................................................95 CHAPTER 4: GENERAL INTRODUCTION.............................................................................99 4.1 LIMITATIONS AND FUTURE DIRECTIONS...................................................................108 4.2 REFERENCES......................................................................................................................110 vi LIST OF FIGURES Figure 1 Pavlovian fear conditioning and extinction of conditioned fear in rodents.......................6 Figure 2 Schematic illustrating the signaling pathway from the group 1 metabotropic glutamatergic receptors (mGluR1) to the MAPK/ERK cascade in the neurons............................22 Figure 3 A simplified schematic of major efferents to the Nucleus Accumbens Core (NAcC) and shell (NAcS) from the Basolateral Amygdala (BLA), Infralimbic Cortex (IL), Prelimbic Cortex (PL) and the Ventral Tegmental Area (VTA)................................................................................52 Figure 4 Schematic of ICC analysis experiment............................................................................62 Figure 5 The nucleus accumbens core is selectively active during fear expression whereas the shell is selectively active following fear extinction.......................................................................64 Figure 6 Confocal images of Calbindin and ARC expression in the NAc core and shell.............66 Figure 7 Inactivation of the NAc core disrupts fear expression but not extinction learning or the consolidation of extinction.............................................................................................................69 Figure 8 Inactivation of the NAc shell disrupts the consolidation of fear extinction but has no effect on fear expression or extinction learning.............................................................................72 Figure 9 Group I metabotropic glutamate receptors within the NAc shell mediate the consolidation of fear extinction.....................................................................................................98 Figure 10 Group I metabotropic glutamate receptors within the NAc core do not mediate fear expression or extinction learning.................................................................................................101 Figure 11 Pre-extinction infusions of 1ug/side U0216, within the NAc shell, disrupts fear extinction consolidation whereas 0.5ug/side U0216 has no effect on fear extinction.................105 vii Figure 12 Post-extinction infusions of 1ug/side U0216, within the NAc shell disrupts fear extinction consolidation...............................................................................................................107 viii LIST OF TABLES Table 1 Behavioral Statistical Summary of experiments 2.1,2.2, and 2.3.....................................74 Table 2 Behavioral Statistical Summary of experiments 3.1,3.2, and 3.3...................................109 ix LIST OF ABBREVIATIONS AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANOVA Analysis of variance ARC Activity-regulated cytoskeleton-associated protein BA Basal amygdala BDNF Brain-derived neurotrophic factor BLA Basolateral amygdala CB-1 Cannabinoid receptor-1 CeA Central amygdala CREB cAMP-response element binding protein CS Conditional stimulus CT Computerized tomography D1 Dopamine receptor 1 D2 Dopamine receptor 2 DA Dopamine DSM Diagnostic and Statistical Manual ERK Extracellular signal-regulated kinase fMRI Functional magnetic resonance imaging GABA Gamma aminobutyric acid GDP Guanosine diphosphate GTP Guanosine triphosphate IEG Immediate early gene x IL Infralimbic cortex ITI Inter-tone interval LA Lateral amygdala LTD Long-term depression LTP Long-term potentiation MAPK Mitogen-activated protein kinase MEK MAPK/ERK kinase mGLUR Metabotropic glutamatergic receptor mPFC Medial prefrontal cortex MSN Medium spiny neurons NAc Nucleus accumbens NAcC Nucleus accumbens core NAcS Nucleus accumbens shell NMDA N-methyl-D-aspartate OCD Obsessive compulsive disorder PB Phosphate buffer PBS Phosphate-buffered saline PL Prelimbic cortex PLC Phospholipase C PTSD Post-traumatic stress disorder US Unconditional stimulus vmPFC Ventromedial prefrontal cortex xi ACKNOWLEDGEMENTS
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