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Cellular Mechanism of Obsessive-Compulsive Disorder by Louis Yunshou Tee Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Guoping Feng, Co-Supervisor ___________________________ Dona Chikaraishi, Co-Supervisor ___________________________ Fan Wang ___________________________ Anne West Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2015 ABSTRACT Cellular Mechanism of Obsessive-Compulsive Disorder by Louis Yunshou Tee Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Guoping Feng, Co-Supervisor ___________________________ Dona Chikaraishi, Co-Supervisor ___________________________ Fan Wang ___________________________ Anne West An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2015 Copyright by Louis Yunshou Tee 2015 Abstract Obsessive-compulsive disorder (OCD) is a devastating illness that afflicts around 2% of the world’s population with recurrent distressing thoughts (obsessions) and repetitive ritualistic behaviors (compulsions). While dysfunction at excitatory glutaminergic excitatory synapses leading to hyperactivity of the orbitofrontal cortex and head of the caudate – brain regions involved in reinforcement learning – are implicated in the pathology of OCD, clinical studies in patients are unable to dissect the molecular mechanisms underlying this cortico-striatal circuitry defect. Since OCD is highly heritable, recent studies using mutant mouse models have shed light on the cellular pathology mediating OCD symptoms. These studies point toward a crucial role for ∆FosB, a persistent transcription factor that accumulates with chronic neuronal activity and is involved in various diseases of the striatum. Furthermore, elevated ∆FosB levels results in the transcriptional upregulation of Grin2b , which codes GluN2B, an N-methyl-D-aspartate glutamate receptor (NMDAR) subunit required for the formation and maintenance of silent synapses. Taken together, the current evidence indicates that ∆FosB-mediated expression of aberrant silent synapses in caudate medium spiny neurons (MSNs), in particular D1 dopamine-receptor expressing MSNs (D1 MSNs), mediates the defective cortico-striatal synaptic transmission that underlies compulsive behavior in OCD. iv Dedication To my family and friends for their invaluable encouragement and support v Contents Abstract ......................................................................................................................................... iv List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................ x Acknowledgements .................................................................................................................... xii Chapter 1: Introduction ................................................................................................................ 1 1.1 Clinical studies in OCD patients .................................................................................... 2 1.1.1 Genetic epidemiology ................................................................................................. 2 1.1.2 Cortico-striatal-thalamo-cortical circuit defect........................................................ 6 1.2 Mutant mouse models of OCD ..................................................................................... 11 1.2.1 Hoxb8-null mouse model ......................................................................................... 13 1.2.2 Slitrk5-null mouse model ......................................................................................... 14 1.2.3 Sapap3-null mouse model ........................................................................................ 15 1.3 Role of ∆FosB in neuropsychiatric disorders .............................................................. 18 1.3.1 ∆FosB in the nucleus accumbens ............................................................................. 19 1.3.2 ∆FosB in the dorsolateral striatum .......................................................................... 21 1.3.3 ∆FosB in the dorsomedial striatum ......................................................................... 23 1.4 ∆FosB and synaptic plasticity ....................................................................................... 25 1.4.1 Hebbian plasticity ...................................................................................................... 25 1.4.2 Silent synapses ........................................................................................................... 27 1.4.3 Homeostatic scaling .................................................................................................. 28 vi Chapter 2: Methods .................................................................................................................... 30 2.1 Animals ............................................................................................................................ 30 2.2 Nuclear extraction .......................................................................................................... 30 2.3 Post-synaptic density (PSD) extraction ....................................................................... 31 2.4 Western blotting ............................................................................................................. 32 2.5 Immunohistochemistry.................................................................................................. 33 2.6 Primary cortico-striatal cultures ................................................................................... 34 2.7 Immunocytochemistry ................................................................................................... 35 2.8 Real-time quantitative PCR ........................................................................................... 36 2.9 Virus production ............................................................................................................ 38 2.10 Stereotaxic injection ...................................................................................................... 41 2.11 Behavioral assays .......................................................................................................... 41 2.12 Drug treatment ............................................................................................................. 42 2.13 Electrophysiology ......................................................................................................... 43 2.14 Statistics ......................................................................................................................... 45 Chapter 3: Results ....................................................................................................................... 46 3.1 Preface .............................................................................................................................. 48 3.2 ∆FosB elevation in D1 MSNs of Sapap3 -/- mice ......................................................... 52 3.3 Compulsive grooming activates more D1 MSNs ....................................................... 56 3.4 FosB knock-down rescues compulsive grooming ..................................................... 58 3.5 Overexpression of ∆FosB increases grooming behavior ........................................... 60 3.6 FosB knock-down in D1 MSNs rescues compulsive grooming ............................... 63 vii 3.7 ∆FosB upregulates GluN2B expression ....................................................................... 65 3.8 GluN2B inhibition rescues physiology and behavior ............................................... 68 3.9 Discussion ........................................................................................................................ 71 Chapter 4: Discussion ................................................................................................................. 72 4.1 Mechanism of ΔFosB elevation..................................................................................... 73 4.2 Mechanism of striatal hyperactivity ............................................................................ 74 4.3 Mechanism of generalized anxiety .............................................................................. 77 Chapter 5: Appendix .................................................................................................................. 79 5.1 Mapping of the anxiety circuitry in Sapap3-null mice .............................................. 79 5.1.1 Brain regions acutely activated by anxiety ............................................................ 79 5.1.2 Types of neurons acutely activated during anxiety ............................................. 80 5.2 Novel strategy for labeling cells before and after Cre recombination .................... 83 5.3 Novel strategy for labeling cells that express shRNA ............................................... 85 5.4 Preliminary homeostatic plasticity experiments .......................................................
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