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University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2015-06-22 The Role of Medial Habenula-Interpeduncular Nucleus Pathway in Anxiety: A Dissertation Xueyan Pang University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Behavioral Neurobiology Commons, and the Molecular and Cellular Neuroscience Commons Repository Citation Pang X. (2015). The Role of Medial Habenula-Interpeduncular Nucleus Pathway in Anxiety: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M2VP49. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/811 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. THE ROLE OF MEDIAL HABENULA-INTERPEDUNCULAR NUCLEUS PATHWAY IN ANXIETY A Dissertation Presented By XUEYAN PANG Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY June 22, 2015 PROGRAM IN NEUROSCIENCE THE ROLE OF MEDIAL HABENULA-INTERPEDUNCULAR NUCLEUS PATHWAY IN ANXIETY A Dissertation Presented By XUEYAN PANG The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation Andrew R. Tapper, Ph.D., Thesis Advisor Paul D. Gardner, Ph.D., Thesis Advisor Joel Richter, Ph.D., Member of Committee Haley E. Melikian, Ph.D., Member of Committee Fen-Biao Gao, Ph.D., Member of Committee Darlene H. Brunzell, Ph.D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee David R. Weaver, Ph.D., Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the school. Anthony Carruthers, Ph.D., Dean of the Graduate School of Biomedical Sciences Program in Neuroscience June 22, 2015 iii This dissertation is dedicated to my beloved husband-Yong, my lovely children- Sophia and Eric and my parents. I give my deepest expression of love and appreciation for the encouragement that you gave and the sacrifices you made during this graduate program. Thank you for the support and company during late nights of typing. iv ACKNOWLEDGEMENTS First of all, I want to thank my graduate advisors, Dr. Andrew R. Tapper and Dr. Paul D. Gardner. I first worked with Andrew as a research associate for one year from 2009. That time I just came from China and had some problem to communicate with people because of the language barrier. But I could feel Andrew‟s enthusiasm and determination toward learning, teaching and researching. Instead of letting me focus on the routine lab maintenance, he encouraged me to take part in an interesting research project. Andrew has an ability to explain a topic in depth and yet simplify it with an interdisciplinary point of view. And we talked about the project progress every week. From that on, I started to enjoy the boring research and decided to become a graduate student and study for the PhD degree. In 2010, I enrolled in UMass Medical School and joined the Program in Neuroscience. After several rotations in the first year, I decided to join in Dr. Tapper‟s lab and Dr. Gardner‟s lab (Tardner lab), as I really like the training and guidance I can get from the mentors. It is very nice that Andrew and Paul both have “open door policy” in their office and we have “two on one” meeting almost every week. Therefore, in the past five years, whenever there is any problem about my project, I can talk with them and they always encourage me and try to figure it out together. With their help, I went through the ups and downs for the projects, which make me grow up to be a more independent researcher. And finally now I am close to get my PhD degree. v Not only for the research project, I also got many help for my life. As an international student who lives in a totally different culture, it is very stressful. But like the lab parents, whenever there is frustration and happiness in life, decision to make for the career planning, they are always there to listen, to support and to give advice. Thanks, Andrew and Paul. I am also sincerely grateful to my thesis committee members –Dr. David Weaver, Dr. Fen-Biao Gao, Dr. Joel Richter, Dr. Haley Melikian, and Dr. Darlene Brunzell. Thank you for all the insightful comments for my research presented in the thesis here. Special thanks to Dr. David Weaver, who is the chair of the Program in Neuroscience and also the chair of my QE, TRAC and dissertation exam. Thank you for always taking the time to listen, to support, and to encourage. I would like to thank everyone in the Tardner lab: Rubing Zhao-Shea, Liwang Liu, Jennifer Ngolab, Melissa Guilford, Steven Degroot, Alison Casserly, Susanna Casacuberta, Ciearra Smith, Anthony Sacino; as well as the former Tadner lab members: Linzy Hendrickson, Lindsey Soll, Ma Reina Improgo, Eric Hogan, Michael Scofield. Thank you so much for all the generous help and support, and also thank you so much for providing fun and happy atmosphere for the past five years. Special thanks to Rubing, who has been a sister, a friend and a teacher in this chapter of my life. Thank you so all the help in academics as well as in everyday life. Finally, I would like to thank my family and friends in China who are always there providing non-stop support and encouragement. Thank you. vi ABSTRACT Recently, the medial habenula-interpeduncular (MHb-IPN) axis has been hypothesized to modulate anxiety although neuronal populations and molecular mechanisms regulating affective behaviors in this circuit are unknown. Here we show that MHb cholinergic neuron activity directly regulates anxiety-like behavior. Optogenetic silencing of MHb cholinergic IPN inputs reduced anxiety-like behavior in mice. MHb cholinergic neurons are unique in that they robustly express neuronal nicotinic acetylcholine receptors (nAChRs), although their role as autoreceptors in these neurons has not been described. nAChRs are ligand- gated cation channels that are activated by the excitatory neurotransmitter, acetylcholine (ACh), as well as nicotine, the addictive component of tobacco smoke. We expressed novel nAChR subunits that render nAChRs hypersensitive to ACh, ACh detectors, selectively in MHb cholinergic neurons of adult mice. Mice expressing these ACh detectors exhibited increased baseline anxiety-like behavior that was alleviated by blocking the mutant receptors. Under stressful conditions, such as during nicotine withdrawal, nAChRs were functionally upregulated in MHb cholinergic neurons mediating an increase in anxiety-like behavior. Together, these data indicate that MHb cholinergic neurons regulate anxiety via signaling through nicotinic autoreceptors and point toward nAChRs in MHb as molecular targets for novel anxiolytic therapeutics. vii Table of Contents Title Page…………………………………………...………….…………………………i Signature page…...................................................................................................ii Acknowledgements………..……………………………………………………………iv Abstract……………………….………………………………………….………………vi Table of Contents………………………………………………………………………vii List of Tables……………………….…………………………………….………….......x List of Figures…………………….……………………………………….……………..x List of Abbreviations……………………...……………………………...……………xiii Copy Right Page………………………………………………………………………xvi Chapter I: Introduction…………………………………………………….…………....1 I.A. Anxiety disorder and current therapeutics……..………….……………2 I.B. The brain circuitry of anxiety disorders…..…………….….…..………..3 I.C. The anatomy of medial habenula and interpeduncular nucleus pathway.....................................................................................................10 I.D. The role of MHb in the anxiety, fear and depression.........................19 I.E. nAChR: structure, function and the role in anxiety................………22 I.F. Nicotine, nAChR and anxiety…………………....... ..............................40 Chapter II: MHb cholinergic neurons are involved in anxiety……………….….…44 II.A. Introduction…….…………………………………………………….…45 II.B. Materials and methods………..…………………………………...….…47 II.C. Results……………..…..…………………………………………….…53 nAChR activity in the MHb but not the IPN regulates anxiety-like behavior in mice...………………………….……………………….…53 Silencing of MHb cholinergic neurons decreases anxiety-like behaviors…………….…………………………………………….…55 Activation of MHb cholinergic neurons induces hypolocomotion…57 II.D. Discussion………………………………………………………………...58 viii Chapter III: nAChRs in the MHb cholinergic neurons are critical for anxiety……70 III.A. Introduction………………………………………………………….…71 III.B. Materials and methods……………………………………………….…72 III.C. Results……………………………………………………………………80 nAChRs are highly expressed in the MHb cholinergic neurons…..80 α4* nAChRs are necessary and sufficient for nicotine activation of MHb cholinergic neurons…………………………………………….81 “AChR detectors” are functionally expressed in MHb cholinergic neurons…………………………………………………………………82 “ACh detector” expressing mice showed increased anxiety-like behavior ……………………………………………………………….84 “ACh detector” expressing mice showed prolonged hypolocomotion by high dose of
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