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The Role of Acetylcholine Signaling in the C. Elegans Egg-Laying Circuit

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The Role of Acetylcholine Signaling in the C. Elegans Egg-Laying Circuit Please do not remove this page The Role of Acetylcholine Signaling in the C. elegans Egg-Laying Circuit Kopchock III, Richard https://scholarship.miami.edu/discovery/delivery/01UOML_INST:ResearchRepository/12386237800002976?l#13386237790002976 Kopchock III, R. (2021). The Role of Acetylcholine Signaling in the C. elegans Egg-Laying Circuit [University of Miami]. https://scholarship.miami.edu/discovery/fulldisplay/alma991031606953802976/01UOML_INST:ResearchR epository Open Downloaded On 2021/09/27 00:18:59 -0400 Please do not remove this page UNIVERSITY OF MIAMI THE ROLE OF ACETYLCHOLINE SIGNALING IN THE C. ELEGANS EGG- LAYING CIRCUIT By Richard Kopchock III A DISSERTATION Submitted to the Faculty of the University of Miami in partial fulfillment of the requirements for the degree of Doctor of Philosophy Coral Gables, Florida August 2021 ©2021 Richard Kopchock III All Rights Reserved UNIVERSITY OF MIAMI A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy THE ROLE OF ACETYLCHOLINE SIGNALING IN THE C. ELEGANS EGG- LAYING CIRCUIT Richard Kopchock III Approved: ________________ _________________ Kevin M. Collins, Ph.D. Julia E. Dallman, Ph.D. Associate Professor of Biology Associate Professor of Biology ________________ _________________ Mason Klein, Ph.D. Guillermo Prado, Ph.D. Assistant Professor of Physics Dean of the Graduate School ________________ R. Grace Zhai, Ph.D. Professor of Molecular and Cellular Pharmacology KOPCHOCK, RICHARD, III (Ph.D., Biology) The Role of Acetylcholine Signaling in the C. elegans (August 2021) Egg-Laying Circuit Abstract of a dissertation at the University of Miami. Dissertation supervised by Professor Kevin M. Collins. No. of pages in text. (95) Successful execution of animal behavior requires coordinated activity and communication between multiple cell types. Studies using the relatively simple neural circuits of invertebrates have helped to uncover how conserved molecular and cellular signaling events drive such changes in animal behavior. To understand the mechanisms underlying neural circuit activity and behavior, I have been studying a small and relatively isolated neural circuit that drives egg-laying behavior in the nematode worm C. elegans. C. elegans is an ideal model organism for such studies due to its completely mapped-out nervous system (connectome), well-established molecular toolkit, and similarity of its nervous system to higher animals, including humans. Among the similarities of the C. elegans nervous system to that of higher animals is the types of neurotransmitters used to drive neural circuit activity and behavior. One such neurotransmitter, acetylcholine (ACh), is vital for animal nervous systems and is a potential therapeutic target for a wide range of human diseases. The goal of my dissertation is to determine how the neurotransmitter acetylcholine functions within the C. elegans egg-laying circuit to regulate circuit signaling events and their resultant effects on behavior. In Chapter 1, I show that the cholinergic (i.e. acetylcholine-releasing) Ventral C (VC) motor neurons are important for vulval muscle contractility and egg laying in response to serotonin. Ca2+ imaging experiments show the VCs are active during times of vulval muscle contraction and vulval opening, and optogenetic stimulation of the VCs promotes vulval muscle Ca2+ activity. Blocking VC neurotransmission inhibits egg laying in response to serotonin and increases the failure rate of egg-laying attempts, indicating that VC signaling facilitates full vulval muscle contraction and opening of the vulva for efficient egg laying. I also found the VCs are mechanically activated in response to vulval opening. Optogenetic stimulation of the vulval muscles is sufficient to drive VC Ca2+ activity, and this induction of VC Ca2+ activity requires muscle contractility, showing the presynaptic VCs and the postsynaptic vulval muscles can mutually excite each other. Together, my results demonstrate that the cholinergic VC neurons facilitate efficient execution of egg-laying behavior by coordinating postsynaptic muscle contractility in response to serotonin and mechanosensory feedback. In Chapter 2, I demonstrate that postsynaptic nicotinic ACh receptors (nAChRs) regulate vulval muscle activity and egg-laying behavior. C. elegans lay eggs in response to nAChR-agonists such as levamisole and nicotine, and loss-of-function mutations in the nAChR subunit genes unc-29, unc-38, and unc-63 confer insensitivity to those agonists. Ca2+ imaging of the vulval muscles in unc-29 and unc-63 mutants reveals a decrease in the frequency of Ca2+ transients, which indicates that these nAChR subunits are involved in initiating vulval muscle activity. Optogenetic stimulation of the presynaptic cholinergic VA and VB motor neurons leads to excitation of the vulval muscles, and this excitation is partially dependent on receptors encoded by unc-29 and unc-63, which provides evidence for an excitatory cholinergic synapse that has not been previously studied. To determine if cholinergic signaling and full vulval muscle contraction is dependent on other signaling factors, I tested nAChR subunit mutants for their ability to lay eggs in exogenous serotonin. Serotonin is a potent stimulator of egg laying in wild type animals, but it fails to stimulate egg laying in unc-29 and unc-63 nAChR loss-of-function mutants. In all, my results show that the VA and VB motor neurons provide nAChR-dependent excitatory input onto the vulval muscles, and that cholinergic signaling acts in a common pathway with serotonin to facilitate egg-laying behavior. In Chapter 3, I examine how voltage-gated Ca2+ channels (VGCCs) interact with cholinergic and serotonergic signaling to regulate vulval muscle activity and egg-laying behavior. Both the P/Q/N-type VGCC UNC-2 and L-type VGCC EGL-19 are important for normal egg-laying behavior. UNC-2 facilitates egg laying in response to exogenous serotonin, since gain-of-function unc-2 mutants respond potently to serotonin while loss- of-function unc-2 mutants instead become inhibited. Loss-of-function egl-19 mutants are completely insensitive to serotonin, indicating EGL-19 is necessary for serotonin-induced egg laying, while gain-of-function egl-19 mutants show variable responses based on the severity of the allele. Ca2+ imaging of the vulval muscle in egl-19 mutants reveals increased and decreased frequency of Ca2+ transients in gain-of-function and loss-of-function mutants, respectively. The decreased Ca2+ transient frequency of loss-of-function egl-19 mutants cannot be rescued by serotonin, suggesting that EGL-19 is a necessary downstream effector of serotonergic signaling. Finally, I show that nAChR agonists stimulate egg laying through an EGL-19 dependent pathway. Loss-of-function egl-19 mutants are insensitive to nAChR agonists, supporting a model where nAChR signaling leads to activation of EGL-19 to drive vulval muscle contraction and egg laying. Together, these results show that cholinergic signaling shares a common pathway with serotonergic signaling to influence L-type VGCC activity in the C. elegans egg-laying circuit. The connectome of the C. elegans has greatly informed neural circuit studies, but it has also revealed that connectivity alone is not sufficient to explain nervous system operation. The functional component of neural circuits is just as, if not more, important than the connectivity itself. The C. elegans egg-laying circuit presents a tractable model for the in vivo study of how neural circuits function at every biological level, from genes to cells to behavior, due to its relatively limited connectivity and amenability to molecular and cellular analysis. My dissertation draws upon both fundamental principles of neuroscience and work specific to the C. elegans egg-laying circuit to reveal how this circuit functions to drive behavior. Through this, I found novel roles for the previously understudied VC neurons, which make up 6 of the only 302 neurons in C. elegans. In addition, I provide evidence for a convergent pathway between the classical neurotransmitters acetylcholine and serotonin in driving muscle contraction. This convergent pathway ultimately acts on the L-type voltage-gated calcium channels to drive egg-laying behavior. ACKNOWLEDGEMENTS I would like to thank my advisor, Kevin Collins, for his steadfast commitment to my growth and success as both a scientist and a person. His support and guidance throughout the years has been more than I could have ever hoped for upon starting my PhD. I would also like to thank my committee members Grace Zhai, Mason Klein, and Julia Dallman for their immensely helpful perspectives and feedback on my work. I am especially grateful for Julia Dallman who has been a constant source of scientific expertise and enthusiasm toward my research. I would also like to give a shoutout to James Baker for being a cool person in general. Finally, I would like to give a special thank you to my mom and three sisters for their relentless positivity and faith in me throughout the years. This work was funded by grants from the NIH (R01-NS086932) and NSF (IOS- 1844657) to KMC. RJK 3rd was supported by a University of Miami Maytag Fellowship. We thank David M. Miller III for sharing plasmids and Mark Alkema for sharing strains. Some of the strains used in this study were provided by the C. elegans Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). iii TABLE OF CONTENTS Page LIST
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