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Psychostimulant-Regulated Plasticity in Interneurons of the Nucleus Accumbens

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Psychostimulant-Regulated Plasticity in Interneurons of the Nucleus Accumbens Psychostimulant-Regulated Plasticity in Interneurons of the Nucleus Accumbens by David A. Gallegos Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Anne E. West, Supervisor ___________________________ Jorg Grandl ___________________________ Debra Silver ___________________________ Gregory Crawford ___________________________ Hiro Matsunami Psychostimulant-Regulated Epigenetic Plasticity in Interneurons of the Nucleus Accumbens 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 2019 ABSTRACT Psychostimulant-Regulated Epigenetic Plasticity in Interneurons of the Nucleus Accumbens by David A. Gallegos Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Anne E. West, Supervisor ___________________________ Jorg Grandl ___________________________ Debra Silver ___________________________ Gregory Crawford ___________________________ Hiro Matsunami 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 2019 Copyright by David Andres Gallegos 2019 Abstract Exposure to psychostimulant drugs of abuse exerts lasting influences on brain function via the regulation of immediate and persistent gene transcription. These changes in gene transcription drive the development of addictive-like behavior by inducing cellular and synaptic plasticities in neurons within brain reward circuits including the nucleus accumbens (NAc). The long-lasting nature of addictive-like behaviors suggests they may be mediated by equally persistent mechanisms of transcriptional regulation such as epigenetic modifications to chromatin. However, an important limitation to testing this model using traditional methods for studying chromatin is the fact that brain regions like the NAc are comprised of a variety of interacting cell types that differentially shape the region’s impact on the circuit, that are not resolved by biochemical methods. In this dissertation I will overcome this barrier by using varied, targeted methods to study cell-type specific changes in chromatin induced in the NAc by acute amphetamine exposure. We have data showing that silencing of PV+ interneurons significantly diminishes the locomotor sensitization to chronic psychostimulant exposure, revealing for the first time a function for these interneurons in addictive-like behaviors. PV+ interneurons of the NAc show amphetamine-induced transcription of genes like Fos and with repeated drug exposure display transcriptional desensitization of Fos, a process iv that is thought to be epigenetically mediated. This and other cellular adaptations occurring in PV+ interneurons persist through extensive withdrawal periods, suggesting a specific and lasting means by which these regulatory shifts underlying the behavioral response are imprinted on this cell type. Taking these data together, I work here to assess changes to chromatin structure and gene expression in PV+ interneurons of the NAc and survey their potential contributions to the addictive-like behavioral changes and cellular adaptations seen following psychostimulant use. To test this, I make use of a novel isolation method to specifically purify the nuclei of PV+ interneurons from the NAc and assay the chromatin and gene expression changes that persist following psychostimulant exposure and correlate with addictive-like behaviors. In this thesis I work to identify the programs of acute amphetamine-regulated gene expression and chromatin remodeling genome-wide in PV+ interneurons of the NAc. I subsequently use a variety of targeted bioinformatic analyses to survey the relationships between changes to the chromatin landscape genome-wide and lasting alterations in transcriptional regulation and cellular function. These studies will greatly propel our understanding of AMPH-induced transcription in PV+ interneurons and epigenetic regulation of gene expression can contribute to lasting changes in circuit function and behavioral output in the NAc. v Contents Abstract ......................................................................................................................................... iv List of Tables .................................................................................................................................. x List of Figures ............................................................................................................................... xi Acknowledgements ...................................................................................................................xiv 1. Introduction ............................................................................................................................... 1 1.1 Regulation of Gene Transcription by Neuronal Activity............................................ 1 1.2 Activity-dependent Regulation of Chromatin and the Epigenome .......................... 5 1.3 Addictive Behaviors and the Nucleus Accumbens Circuitry .................................. 17 1.4 The Cell-Types of the Nucleus Accumbens and their Functions ............................ 23 1.4.1 Spiny Projection Neurons......................................................................................... 24 1.4.2 Parvalbumin-Positive, Fast-Spiking Interneurons ................................................ 28 1.4.3 Somatostatin-positive Interneurons, Cholinergic Interneurons, and Emerging Interneuron Types .............................................................................................................. 31 1.5 Epigenetic and Transcription Regulation in the Nucleus Accumbens and Addictive Behaviors ............................................................................................................. 33 2. Parvalbumin Interneurons of the Mouse Nucleus Accumbens are Required for Amphetamine-Induced Locomotor Sensitization and Conditioned Place Preference ..... 37 2.1 Introduction ..................................................................................................................... 38 2.2 Materials and Methods .................................................................................................. 40 2.2.1 Mice ............................................................................................................................. 40 2.2.2 Antibodies .................................................................................................................. 41 2.2.3 Stereotaxic Surgery .................................................................................................... 41 vi 2.2.4 Electrophysiological TeLC Validation .................................................................... 41 2.2.5 Open Field Locomotor Activity and Locomotor Sensitization ........................... 43 2.2.6 Microdialysis .............................................................................................................. 43 2.2.7 Stereotaxic Surgery .................................................................................................... 44 2.2.8 In Situ Hybridization ................................................................................................ 45 2.2.9 Conditioned Place Preference .................................................................................. 46 2.2.10 Sucrose Preference ................................................................................................... 47 2.2.11 Statistics .................................................................................................................... 47 2.3 Results .............................................................................................................................. 48 2.3.1 Selective Disruption of Synaptic Transmission from PV+ GABAergic Interneurons of the NAc Impairs Behavioral Sensitization to Repeated AMPH Exposure .............................................................................................................................. 48 2.3.2 AMPH-Induced DA Release into the NAc is not Blocked by Silencing PV+ GABAergic Interneurons of the NAc .............................................................................. 57 2.3.3 Inhibition of PV+ Neurons of the NAc Leads to Hyperactivation of both D1- and D2R+ SPNs ................................................................................................................... 59 2.3.4 AMPH-Induced CPP is Impaired by Silencing PV-Positive GABAergic Interneurons of the NAc .................................................................................................... 64 2.4 Discussion ........................................................................................................................ 66 2.41 PV+ Interneuron Regulation of SPNs in Locomotor Sensitization and CPP ..... 67 2.42 AMPH-Induced Plasticity of PV+ Interneurons? ................................................... 70 3. Psychostimulant-Regulated Epigenetic and Transcriptional Plasticities in Nucleus Accumbens Interneurons ........................................................................................................... 71 3.1 Introduction ..................................................................................................................... 71 vii 3.2 Materials
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