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Investigating the Neural Circuits That Control Cataplexy

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Investigating the Neural Circuits That Control Cataplexy Investigating the Neural Circuits that Control Cataplexy by Zoltán Torontali A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Cell & Systems Biology University of Toronto © Copyright by Zoltán Torontali 2019 Investigating the Neural Circuits that Mediate Cataplexy Zoltan Torontali Doctor of Philosophy Department of Cell & Systems Biology University of Toronto 2019 Abstract In this thesis I explored a long-standing hypothesis that the paralysis occurring during REM sleep and cataplexy share a common neural mechanism. Cataplexy, a debilitating symptom of narcolepsy, is the abrupt onset of skeletal muscle paralysis during wakefulness. Under normal conditions, neurons of the sublaterodorsal tegmental region have been shown to be active during REM sleep and either activate GABA/glycine neurons of the ventral medulla or inhibitory interneurons in the spinal cord which in turn silences motoneurons and results in REM sleep muscle paralysis. The mechanism mediating the paralysis of cataplexy has not been fully characterized but is hypothesized to result from the abnormal activation of SLD neurons during wakefulness. First, I investigated if activation of all cells in the SLD nucleus could trigger cataplexy in wildtype (hypocretin-intact) mice and narcoleptic (hypocretin knockout) mice. Next, I investigated if glutamatergic, VGLUT2-expressing, neurons of the SLD were the cellular phenotype responsible for triggering cataplexy in wildtype and narcoleptic mice models. This final investigation required the development of a new hypocretin knockout mouse line (hypocretin-/-, VGLUT2-Cre mice). This new model is scientifically important as it provides an innovative toolkit for neuroscientists to examine the role of glutamatergic cell populations throughout the brain of mice with a narcolepsy phenotype. Several major conclusions can be drawn from my results: ii 1. Cataplexy and REM sleep share a common neural mechanism that generates muscle paralysis. Activation of the SLD nucleus triggered cataplexy in wild type mice. This is a significant finding as it is the first time that cataplexy has been triggered in wildtype mice. Similarly, narcoleptic mice experienced an increase in the number of cataplexy episodes after activation of the SLD nucleus. 2. Activation of VGLUT2-SLD neurons in VGLUT2-Cre (hypocretin intact) mouse results in overall muscle weakness during wakefulness but does not trigger cataplexy episodes. 3. The VGLUT2-expressing SLD neurons are a component of the neural circuit that triggers cataplexy. Activation of the VGLUT2-SLD neurons in hypocretin knockout mice resulted in increased number of cataplexy attacks without altering the duration of the episode. iii Acknowledgments First and foremost, I must thank my supervisor, Dr. John Peever, for his patient guidance throughout my time in his laboratory. John not only established the foundation for my scientific career, but has gone above and beyond in promoting and supporting it. I am forever grateful for the skills, knowledge and experience I have gained under his mentorship. A very special gratitude must be extended to Dr. Jimmy Fraigne. Jimmy has not only been a mentor all these years but also a best friend. One could not find a more positive person who was always able and willing to help focus my enormous energy and passion in the right direction. Our friendship and memories will be cherished for the rest of my life. Every PhD student should be as lucky as I was to have a friend and mentor like Jimmy. I would also like to thank members of the Peever Lab (in alphabetical order) that made my time enjoyable. Thank you to Patti Brooks for the encouragement and 5pm reminders! Thank you Sharshi Bulner for the comical conundrums he finds himself in as they always lightened the mood. Christian Burgess’s sense of humor, advice and drive for scientific excellence was always (and continues to be) an inspiration for me. Negar Golmohammadi and Mohamad Hamieh’s lively and cheerful personalities were always the perfect remedy for my anxiety. A special mention must go out to Paul Sanghera, who was always a phone call away and a friend that could always find a different lens to look at any situation. I hope to continue our philosophical journeys. Dry humor and encouragement was the specialty of Peter Schwarz-Lam. Your quick witted comments was always a treat! I would like to thank Han-hee Lee for the chats over coffee. Daniel Li was not only a fantastic lab-mate but also a fun room-mate. I would also like to single out Matthew Snow, who is a fantastic friend! Our shenanigans were always the most fun and I am lucky to have such a talented proof-reader! Thank you Nicole Yee for the encouragement and support. I would like to iv thank my extended family outside the lab but within the Sleep Field - you all know who you are and our memories will be cherished. I must mention my greatest cheerleaders, Mom (Katica Torontali) and Dad (John Torontali). You both encouraged me since I was young to pursue my curiosity and passion. Constant moral and emotional support was provided from both of my parents and words cannot express how grateful I am to have the best parents in the world. This thesis would not have been possible without their love and support. I love them both very much! My dearest sister, Pearl, was also there for many late night calls and has taught me the art of being a good listener. Finally, I would like to thank Jessica Pressey for her love and support throughout this journey. I would like to thank the members of my doctoral committee - Dr Kaori Takehara- Nishiuchi, Dr. John Yeomans, Dr. Junchul Kim and Dr. Ritchie Brown. Their honest appraisal and discussion of my work has led to an elevated thesis and a very enjoyable thesis defence! I would also like to thank the University of Toronto, Ontario Graduate Scholarship, Canadian Institute of Health and Research. Finally, I would like to immortalize my kindred spirit, Oscar, by acknowledging him. He is the best dog a human could have and our long walks helped my brain disconnect from the lab. v Table of Contents Acknowledgments ..................................................................................................................... iv List of Tables ............................................................................................................................. xii List of Figures ........................................................................................................................... xiii Chapter 1: Introduction ...................................................................................................... 1 1.1 Narcolepsy ............................................................................................................................. 1 1.1.1 Overview ......................................................................................................................................... 1 1.1.2 Diagnosis ......................................................................................................................................... 1 1.1.3 A brief history of the link between hypocretin and narcolepsy ......................................................... 2 1.2 Cataplexy ............................................................................................................................... 9 1.2.1 Overview ......................................................................................................................................... 9 1.2.2 Features of Cataplexy ...................................................................................................................... 9 1.2.3 Status cataplecticus ....................................................................................................................... 13 1.2.4 Treatment of Cataplexy ................................................................................................................. 13 1.3 Animal Models and Pathophysiology ................................................................................... 16 1.3.1 Canine Model of Cataplexy ............................................................................................................ 16 1.3.2 Mouse Models of Cataplexy .......................................................................................................... 17 1.4 Rapid Eye Movement Sleep ................................................................................................. 21 1.4.1 Transections: Substantiating REM sleep as a state and the duality of sleep .................................... 21 1.4.2 Neurotransmitters within the SLD pontine region regulating behavior ........................................... 24 1.5 REM sleep muscle paralysis ................................................................................................. 28 1.5.1 Defining the location of the SLD ..................................................................................................... 34 1.6 REM sleep intrusion hypothesis ........................................................................................... 35 1.6.1 The SLD nucleus and REM sleep intrusion hypothesis ..................................................................... 40 vi 1.6.2 The neurobiology of cataplexy ..................................................................................................... 40 1.7 Chemogenetics: Investigating behavior by harnessing the control of neurons
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