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The External Globus Pallidus: Bidirectional Control Over Anxiety- Related Behavior Mediated by CRFR1

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The External Globus Pallidus: Bidirectional Control Over Anxiety- Related Behavior Mediated by CRFR1 The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2017 The External Globus Pallidus: Bidirectional Control Over Anxiety- Related Behavior Mediated by CRFR1 Albert J. Hunt Jr Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Hunt, Albert J. Jr, "The External Globus Pallidus: Bidirectional Control Over Anxiety-Related Behavior Mediated by CRFR1" (2017). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 732. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/732 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. THE EXTERNAL GLOBUS PALLIDUS: BIDIRECTIONAL CONTROL OVER ANXIETY-RELATED BEHAVIOR MEDIATED BY CRFR1 by Albert Lee Joseph Hunt, Jr., B.S. APPROVED: ______________________________ Shane Cunha, Ph.D. Advisory Professor ______________________________ Ruth Heidelberger, MD, Ph.D. ______________________________ Neal Waxham, Ph.D. ______________________________ Vasanthi Jayaraman, Ph.D. ______________________________ Qingchun Tong, Ph.D. APPROVED: ____________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences THE EXTERNAL GLOBUS PALLIDUS: BIDIRECTIONAL CONTROL OVER ANXIETY-RELATED BEHAVIOR MEDIATED BY CRFR1 A DISSERTATION Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Albert Lee Joseph Hunt, Jr., B.S. Houston, Texas May, 2017 Dedication I would like to dedicate this dissertation to my mother, Moira E. Mañon, and my grandmother (Mimi), Patricia E. Lajeunesse. These two women have supported me through every event in my life. Together, they raised me and taught me that I have the ability to do anything. It is because of them, and the wish to make them proud, that I decided to continue my studies and obtain my PhD. Without them, I would never have reached this goal. I have had many struggles in the past where I have fallen, and they have always been there to pick me up. Their love and support keeps me going when times are rough, and their laughter makes me smile when times are great. I respect and love these women with all of my heart, and I am so glad that I have the opportunity to dedicate this body of work to them. They truly deserve it. iii Acknowledgements There are so many people I wish to acknowledge that I do not know where to begin. First, I would like to acknowledge the neuroscience program and all of the students involved. Through classes and candidacy, and now my defense, I have always had their support. It is a program that creates a family environment in nature and truly made my time in graduate school enjoyable. I would like to acknowledge the terrific staff at GSBS who support the students as if they were their own children. Without the staff, my time at GSBS would have definitely not have been as enjoyable. I would like to thank my committee members: Shane Cunha, PhD; Ruth Heidelberger, MD, PhD; Neal Waxham, Vasanthi Jayaraman, PhD; Qingchun Tong, PhD; and former member Nicholas Justice, PhD, for letting me meet them in their offices to discuss my science, complain about my problems, or just listen to me ramble about experiments. Without them, none of this would be possible. I want to specifically acknowledge Brenda Gaughan, Director of Academic Affairs, for helping me get through one of the hardest times of my personal life. I want to acknowledge my brothers, Matthew Hunt and Christopher Hunt, for just being great. Also, I want to acknowledge my sister-in-law, Jessica Hunt, who is the sister I always wanted. I want to acknowledge my friends, most of which I have been friends with for 15 to 20 years. Brandon Watkins, Roy Ybarra, Kolby Malone, Ryan James Yezak, David Thompson, and Alex Kovacs are the best guy friends you could ask for. I want iv to acknowledge my girls: Ashley Stella, Mary (Katie) Rountree, Kendra Smith-Phillips, Sonya Garza, and Andrea Gallagher for being the most supportive and loving group of people. Both the guys and the girls are truly my second, chosen family. Especially, I want to acknowledge the GSBS entering class of 2013. We made it through two weeks of “boot camp” which was not the most fun of times. However, all of the time spent together lead to strong and lasting friendships that I will cherish for the rest of my life. Lastly, I want to acknowledge my wonderful husband Diego Anibal Morales- Scheihing. His unconditional love and support keep me going and make everyday full of laughter. v Abstract THE EXTERNAL GLOBUS PALLIDUS: BIDIRECTIONAL CONTROL OVER ANXIETY-RELATED BEHAVIOR MEDIATED BY CRFR1 Albert Lee Joseph Hunt, Jr., B.S. Advisory Professor: Shane Cunha, Ph.D. Corticotropin-releasing factor receptor 1 (CRFR1), the principle receptor responsible for the anxiogenic activity of the stress peptide CRF, is abundantly expressed in the external globus pallidus (GPe) raising the question whether activity in the GPe is altered in response to stress. I show that CRFR1 expressing neurons are of the “prototypic” subtype of GPe neurons. I provide evidence of novel circuits from CRF neurons in stress-responsive nuclei, including the paraventricular nucleus of the hypothalamus (PVN) and the central nucleus of the amygdala (CeA), that provide excitatory input to the GPe. Additionally, I show that activation of CRFR1 neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) increases anxiety-related behavior and movement. I show that anxiety-related behavior and movement are decreased in response to activation of Npas1+ neurons, a class of neuron in the GPe that are primarily of the “arkypallidal” subtype. My evidence indicates that CRF neurons may project to the GPe to modulate anxiety- related behavior and movement through differential synaptic input to distinct GPe neuronal subtypes. CRF to GPe circuits provide possible therapeutic avenues to treat anxiety disorders comorbid with basal ganglia neurodegenerative diseases that cause aberrant activity in the GPe such as Parkinson’s disease. vi Table of Contents DEDICATION ............................................................................................................ III ACKNOWLEDGEMENTS ......................................................................................... IV ABSTRACT ............................................................................................................... VI TABLE OF CONTENTS ........................................................................................... VII FIGURES .................................................................................................................... X ABBREVIATIONS .................................................................................................... XII INTRODUCTION ........................................................................................................ 1 THE STRESS RESPONSE, HPA-AXIS, AND CORTICOTROPIN-RELEASING FACTOR ............ 2 THE BASAL GANGLIA AND THE EXTERNAL GLOBUS PALLIDUS ..................................... 20 COMPUTATIONAL AND THEORETICAL NEUROSCIENCE ASPECTS OF THE EXTERNAL GLOBUS PALLIDUS ................................................................................................................ 30 OPENING REMARKS ................................................................................................. 33 EXPERIMENTAL PROCEDURES ........................................................................... 35 ANIMAL CARE AND GENETIC CROSSES ....................................................................... 36 TISSUE PREPARATION, IMMUNOHISTOCHEMISTRY, AND CELL QUANTIFICATION .............. 37 STEREOTAXIC INJECTIONS OF ADENO-ASSOCIATED VIRUS ........................................... 38 SLICE PREPARATION ................................................................................................ 39 ELECTROPHYSIOLOGICAL RECORDINGS ..................................................................... 40 DATA ACQUISITION AND ANALYSIS ............................................................................. 40 CALCULATION OF PSEUDOTYPED RABIES VIRUS “CONNECTIVITY RATIO” ..................... 41 BEHAVIORAL TESTING .............................................................................................. 41 vii OFA. .................................................................................................................. 41 LDT. ................................................................................................................... 42 Marble Burying. ................................................................................................
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