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A Dissertation Entitled Monoamines Differentially Modulate A Dissertation entitled Monoamines Differentially Modulate Neuropeptide Release from Distinct Sites Within A Single Neuron Pair by Tobias Samuel Thomas Clark Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biology _________________________________________ Dr. Richard Komuniecki, Committee Chair _________________________________________ Dr. Bruce Bamber, Committee Member _________________________________________ Dr. Patricia Komuniecki, Committee Member _________________________________________ Dr. Robert Steven, Committee Member _________________________________________ Dr. Ajith Karunarathne, Committee Member _________________________________________ Dr. Amanda Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August, 2018 Copyright 2018, Tobias Samuel Thomas Clark This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Monoamines Differentially Modulate Neuropeptide Release from Distinct Sites Within A Single Neuron Pair By Tobias Samuel Thomas Clark Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biology The University of Toledo August 2018 Monoamines and neuropeptides modulate behavior, but monoaminergic-peptidergic cross talk remains poorly understood. In C. elegans, serotonin and the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. For example, the ASI neuropeptides required for TA inhibition, encoded by nlp-1, -14 and -18 are distinct from those required for OA inhibition, encoded by nlp-6, -7, and -9. In the present study, NLP-9, -14:: or -18::GFPs co-localized with the synaptic marker, mCHERRY::RAB-3 in the distal portion of the ASI axons, where synapses have been identified previously by electron microscopy. Neuropeptide and RAB-3 positive axonal puncta were also consistently observed extra- synaptically near ASI soma. ASI::NLP-14::GFP and ASI::NLP-9::mCHERRY co- localized to both synaptic and extra-synaptic puncta, but the GFP/mCHERRY ratios in extra-synaptic/synaptic puncta differed significantly, suggesting that TA- and OA- dependent neuropeptides may be differentially trafficked and/or localized. TA, but not iii OA, selectively increased the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively. In contrast, OA, but not TA, selectively increased the release of ASI neuropeptides encoded by nlp-9 asymmetrically, only from synaptic/perisynaptic regions of the right ASI axon. The predicted preprosequences of the three TA-dependent neuropeptide-encoding genes differed markedly from the three OA-dependent genes. However, these distinct preprosequences were not sufficient to confer monoamine-specificity, as the release of chimeric neuropeptides containing swapped pre-pro-sequences did not respond to the predicted monoamine. In contrast, the release of a truncated NLP-14::GFP containing only the first 95 amino acids and only five of a predicted 12 neuropeptides responded to TA but not OA, demonstrating that additional N-terminal sequence was required for monoamine-specificity. Collectively, our results demonstrate that TA and OA differently modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs and highlight the complexity of monoaminergic/peptidergic modulation, even animals with a relatively simple nervous system containing only 302 neurons. iv Acknowledgements First and foremost, I would like to sincerely thank my advisor and mentor, Dr. Rick Komuniecki. Rick has taught me so many lessons about science and life, which often echo daily, and have helped steer my development, as both a person and scientist. For these lessons and patience, I am eternally grateful. My dear thanks go to all my friends on this side of the Atlantic for helping me adjust to life in America and making me feel at home. In particular, I offer my heartfelt appreciations to Steven Dajnowicz, Mitchell Oakes and Dr. Wen Jing Law for their engaging discussions, assistance inside and outside the lab, lifelong lessons taught and general friendship over the years. I am also forever thankful to have RaeLynne MacBeth by my side. She has been a constant motivation and support, spending countless nights and weekends working with me. I am a better person for having her in my life. To my many family members and friends back home, especially my parents, sisters and brother, thank you for the ongoing support and love over the years. You have each helped in your own way to keep me moving along this path and know that although I am no longer close by, nothing has changed between us. Last, and certainly not least, I thank Dr. Patricia Komuniecki, Dr. Bruce Bamber, Dr. Robert Steven and Dr. Ajith Karunarathne for agreeing to be on my committee and their time. v Table of Contents Abstract .......................................................................................................................... iii Acknowledgements .......................................................................................................v Table of Contents ........................................................................................................ vi List of Figures .............................................................................................................. ix List of Abbreviations ...................................................................................................x List of Symbols .............................................................................................................xv 1. Introduction ...............................................................................................................1 1.1 Monoamines and Neuropeptides as Neurotransmitters ...............................4 1.2 The Role of TA, OA and Neuropeptides in Invertebrates ...........................9 1.3 Dense Core Vesicle Formation and Neuropeptide Packaging ...................14 1.4 Significance................................................................................................22 2. Materials and Methods .......................................................................................26 2.1 Materials ....................................................................................................26 2.2 Nematode Strains .......................................................................................27 2.3 Construction of C. elegans Transgenes .....................................................27 2.4 Behavioral Assays ......................................................................................28 vi 2.5 Confocal Microscopy .................................................................................29 2.6 Neuropeptide Fluorescence Assay .............................................................30 2.7 RNA Isolation and cDNA Synthesis..........................................................31 2.8 Quantitative PCR .......................................................................................31 2.9 Bioinformatic Analysis ..............................................................................32 2.10 Statistics .....................................................................................................32 3. Results ........................................................................................................................33 3.1 Distinct Subsets of ASI Neuropeptides Are Essential for the TA- and OA- dependent Inhibition of Aversive Responses to 1-octanol ................................................33 3.2 TA- and OA-dependent Neuropeptides Appear to Co-localize at Individual ASI Synapses.....................................................................................................................37 3.3 TA and OA Stimulate the Release of Distinct Subsets of ASI Neuropeptides....................................................................................................................42 3.4 ASI Neuropeptide Proproteins Required for Either TA- or OA-dependent Inhibition Contain Different Leader Sequences ................................................................48 4. Discussion ..................................................................................................................55 4.1 Monoaminergic/peptidergic Crosstalk is Extensive and Modulates Most Key C. elegans Behaviors ..................................................................................................57 4.2 Monoaminergic/peptidergic Interactions Are Also Important in Other Organisms ..........................................................................................................................62 4.3 Both TA- and OA-dependent ASI Neuropeptides Co-localize in the ASIs .....64 4.4 TA and OA Differentially Modulate Neuropeptide Release from the ASIs ....68 4.5 OA Asymmetrically Stimulates Neuropeptide Release from the ASIs ...........71 vii 4.6 Monoamines and Neuropeptides Interact Directly to Modulate Release ........73 4.7 The TA- and OA-dependent ASI Neuropeptides Contain Different Predicted Preprosequences .................................................................................................................77 4.8 Summary ..........................................................................................................83
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