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Neural Network Adaptation in the Retina: Dopaminergic Signaling Mechanisms

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Neural Network Adaptation in the Retina: Dopaminergic Signaling Mechanisms Neural Network Adaptation in the Retina: Dopaminergic Signaling Mechanisms By Heng Dai Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences May, 2018 Nashville, Tennessee Approved: Carl H. Johnson, Ph.D., Chair Douglas G. McMahon, Ph.D., Advisor Terry L. Page, Ph.D. David J. Calkins, Ph.D. i Copyright © 2018 by Heng Dai All Rights Reserved ii DEDICATION For my family: Mom, Dad, Grandma Zhanwen, Grandpa Nianci, Grandma Juzhen, Grandpa Jiangzhong, Uncle Renzhong, Uncle Yiping and Aunt Yi I could not have done it without you Love you like I always do iii ACKNOWLEDGEMENTS First and foremost, I need to acknowledge my funding sources that allowed me to carry out my dissertation research: This work was financially supported from 2011 to present by the National Institutes of Health Grants R01 EY015815 and R01 GM117650 awarded to Douglas McMahon; P50 MH096972 and R01 MH105094 awarded to Randy Blakely; P30 EY008126 and T32 EY007135-16 awarded to Vanderbilt Vision Research; F32 EY022850 awarded to Chad Jackson; and F31 MH107132 awarded to Gwynne Davis. Secondly, I would like to thank the wide variety of people who have been both supportive and influential throughout my time in graduate school, in no particular order: The McMahon Lab Post-docs: Chad Jackson, Michael Risner, Manuel A. Giannoni-Guzmán, Justin Siemann, Leigh Jackson, and Holly Resuehr Graduate students: David Sprinzen, Michael Tackenberg, Jeff Jones, and Noah Green Research and administrative staff: Lili Xi, Laurel Young, and Patricia McCleskey Dissertation Committee Douglas McMahon, Carl Johnson, Terry Page, David Calkins, and Donna Webb Collaborators Randy Blakely and Gwynne Davis Others Katherine Friedman, Division of Animal Care, and Neurochemistry Core Third, I would like to reiterate my thanks to Doug McMahon, my dissertation advisor. I would not have survived the ups and downs of my graduate studies without his patience, understanding, and support. He has always encouraged me to follow my curiosity and enthusiasm either in science or career opportunities. He was everything I could have asked for from a mentor and more. Finally, I want to thank all of my family and friends of whom there are far too many to mention by name. Thank you all for your love, friendship, and support. I wish you all success and happiness in all of the future endeavors you undertake. Heng Dai March 22nd, 2018 iv TABLE OF CONTENTS DEDICATION ............................................................................................................................................. iii ACKNOWLEDGEMENTS ......................................................................................................................... iv LIST OF FIGURES .................................................................................................................................... vii Chapter I Introduction ...................................................................................................................................................1 1.1 Project Overview .....................................................................................................................................1 1.2 Cellular organization and neuronal wiring of the vertebrate retina .........................................................3 1.2.1 Photoreceptors ..................................................................................................................................5 1.2.2 Bipolar cells ......................................................................................................................................8 1.2.3 Ganglion cells .................................................................................................................................10 1.2.4 Horizontal cells ...............................................................................................................................12 1.2.5 Amacrine cells .................................................................................................................................15 1.2.6 Dopaminergic amacrine neurons ...................................................................................................15 1.3 Retinal pathways input to dopaminergic amacrine cells ........................................................................17 1.4 Dopamine reconfigures retinal circuits for high-resolution, light-adapted vision .................................21 1.5 Useful tools to assess the role of retinal dopamine in vision .................................................................23 Chapter II Attention-Deficit/Hyperactivity Disorder-Associated Dopamine Transporter Variant Val559 Alters Retinal Function in vivo ...............................................................................................................................26 2.1 Summary ................................................................................................................................................26 2.2 Introduction ............................................................................................................................................27 2.3 Materials and Methods ...........................................................................................................................29 2.3.1 Animal usage and care. ...................................................................................................................29 2.3.2 Electroretinogram (ERG). ..............................................................................................................29 2.3.3 HPLC determination of DA and its metabolites. ............................................................................30 2.3.4 Statistical analysis. .........................................................................................................................31 2.4 Results ....................................................................................................................................................31 2.4.1 DAT Val559 homozygous male mice have increased light-adapted retinal responses ..................31 2.4.2 Retinal responses to amphetamine are blunted in male DAT Val559 HOM mice ..........................34 2.4.3 Overall retinal DA content is not influenced by DAT Val559 ........................................................35 2.4.4 The effect of DAT Val559 on photopic ERG amplitude is sex-dependent ......................................36 2.5 Discussion ..............................................................................................................................................38 2.5.1 Val559 DAT increases light-adapted retinal responses .................................................................38 2.5.2 Val559 DAT blunts retinal responses to AMPH .............................................................................39 2.5.3 Sex dependency ...............................................................................................................................39 2.5.4 ERG as a potential biomarker for ADHD .......................................................................................40 Chapter III Circadian Perinatal Photoperiod Has Enduring Effects on Retinal Dopamine and Visual Function ..........41 3.1 Summary ................................................................................................................................................41 3.2 Introduction ............................................................................................................................................42 3.3 Materials and Methods ...........................................................................................................................42 3.3.1 Animal usage and care. ...................................................................................................................42 3.3.2 Electroretinogram (ERG). ..............................................................................................................43 3.3.3 Visual Psychophysical testing. ........................................................................................................44 v 3.3.4 HPLC determination of biogenic amine concentration. .................................................................45 3.3.5 Immunohistochemistry. ...................................................................................................................46 3.3.6 Retinal RNA extraction and quantitative RT-PCR ..........................................................................46 3.3.7 Statistical analysis. .........................................................................................................................47 3.4 Results ....................................................................................................................................................47 3.4.1 Developmental photoperiod imprints retinal function ....................................................................47 3.4.2 Dopamine content is influenced by photoperiod ............................................................................50 3.4.3 Restoration of dopamine signaling rescues retinal function ..........................................................52 3.4.4 Photoperiod influences dopamine synthetic gene expression .........................................................52
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