ORCID ID

0000-0001-7578-3511

Publication Date

2020-09-30

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Neurobiology; Alkema Lab

First Thesis Advisor

Mark Alkema

Keywords

neuropeptides, neuromodulation, C. elegans, co-transmission, biogenic amines, fight or flight response, behavior, neuropeptide receptors, arousal, G-protein signaling, stress, insulin signaling, daf-16/FOXO, longevity, neural circuits, compound motor sequence, calcium

Abstract

To survive, animals must adapt to a complex and challenging world in a way that is flexible and responsive, while maintaining internal homeostasis. Neuromodulators provide a means to systemically alter behavioral or physiological state based on intrinsic or extrinsic cues, however dysregulated neuroendocrine signaling has negative consequences for fitness and survival. Here I examine neuroendocrine function and dysfunction using the escape response in Caenorhabditis elegans. The RFamide neuropeptide FLP-18 is a co-transmitter with the monoamine tyramine and functions both synergistically and antagonistically to tyramine in coordinating escape behavior. Using behavioral analysis and calcium imaging, I show that FLP-18 functions primarily through the G-protein coupled receptor (GPCR) NPR-5 to increase calcium levels in muscle, enhancing locomotion rate, bending and reversal behavior during the escape response.

Furthermore, I examine the relationship between persistent acute stress and resilience using repeated activation of the escape response as a model of neuroendocrine dysregulation. Repeated activation of the escape response shortens lifespan and renders animals more susceptible to thermal, oxidative, and nutritional stress. Tyramine release is necessary and sufficient for this effect and activity of the tyraminergic RIM neurons is differentially regulated by acute versus long-term stressors. Impaired stress resistance requires both the GPCR TYRA-3 in the intestine and intestinal neuropeptide release. Activation of the insulin receptor DAF-2 is downstream of TYRA-3 and inhibits the transcription factors DAF-16/FOXO, SKN-1/Nrf2 and HSF-1, linking monoamine signaling in acute stress to the insulin signaling pathway and impaired resilience to long-term stressors.

DOI

10.13028/ghnv-5048

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Tuesday, October 19, 2021

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