The long-term objective of this project is to understand how genes specify the development and functioning of a behavioral system. The anatomically simple neuromuscular system of the nematode Caenorhabditis elegans consists of diverse types of neurons and muscles while being sufficiently small and simple to allow a complete description of its cells, neural circuits and cell lineage, facilitating the identificatio of anatomical and developmental lesions caused by mutations. Studies of the C. elegans egg-laying system and of the neuromuscular systems that control behaviors coordinately regulated with egg laying offer opportunities for the analysis of a broad variety of fundamental biological problems of relevance to many human disorders. In this project, mutants abnormal in the behavior of egg laying or in behaviors co-regulated with egg laying will be identified and analyzed to establish mechanisms that modulate C. elegans behavior in response to both the environment and experience. Methods of genetics, molecular biology, biochemistry, cell biology, electrophysiology and behavioral biology will be used. Two major questions will be addressed. First, what are the molecular, cellular and neural-circuit mechanisms that mediate behavioral responses to changes in oxygen concentration? Both acute and chronic oxygen deprivation have profound effects on cellular physiology and animal behavior. Oxygen deprivation is responsible for the cardiac damage in heart attacks, and the restoration of normal levels of oxygen after a period of oxygen deprivation is responsible for the neurological damage in ischemic strokes. The major pathway that mediates responses to chronic oxygen deprivation was discovered from studies of the C. elegans egg-laying system, has been implicated in many human disorders and has defined major therapeutic targets for ischemic disorders and cancer. This project will identify new components of this important pathway as well as reveal how this pathway controls animal behavior. Second, what are the molecular genetic mechanisms that control nervous system signaling to modulate behavior and define behavioral states? Nerve cells communicate with other nerve cells and with muscles by releasing and responding to chemical neurotransmitters and neuromodulators. This process is fundamental to all aspects of human action, perception, language, emotion and thought, and disruptions in this process are responsible for many neurologic and neuropsychiatric disorders. This project will analyze a newly discovered gene that functions in neurochemical signaling and is implicated in controlling a specific class of neuromodulator, neuropeptides, which are involved in many aspects of human physiology, including reproduction, growth, metabolism, sleep and memory as well as in the assumption of one of two alternative behavioral states, such as hunger-satiety, sleep-wakefulness and monogamy-polygamy.

Public Health Relevance

An understanding of the fundamental mechanisms that control animal development and behavior is key to an understanding of many aspects of human health and disease. This project proposes to identify such mechanisms by analyzing the development and functioning of the egg-laying system of the experimentally tractable roundworm Caenorhabditis elegans, which shares many genetic, molecular and cellular features with more complicated animals, including humans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Sesma, Michael A
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Van Bael, Sven; Watteyne, Jan; Boonen, Kurt et al. (2018) Mass spectrometric evidence for neuropeptide-amidating enzymes in Caenorhabditis elegans . J Biol Chem 293:6052-6063
Burton, Nicholas O; Dwivedi, Vivek K; Burkhart, Kirk B et al. (2018) Neurohormonal signaling via a sulfotransferase antagonizes insulin-like signaling to regulate a Caenorhabditis elegans stress response. Nat Commun 9:5152
Burton, Nicholas O; Furuta, Tokiko; Webster, Amy K et al. (2017) Insulin-like signalling to the maternal germline controls progeny response to osmotic stress. Nat Cell Biol 19:252-257
Luo, Shuo; Horvitz, H Robert (2017) The CDK8 Complex and Proneural Proteins Together Drive Neurogenesis from a Mesodermal Lineage. Curr Biol 27:661-672
Paquin, Nicolas; Murata, Yasunobu; Froehlich, Allan et al. (2016) The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior. Curr Biol 26:862-71
Bhatla, Nikhil; Droste, Rita; Sando, Steven R et al. (2015) Distinct Neural Circuits Control Rhythm Inhibition and Spitting by the Myogenic Pharynx of C. elegans. Curr Biol 25:2075-89
Ma, Dengke K; Li, Zhijie; Lu, Alice Y et al. (2015) Acyl-CoA Dehydrogenase Drives Heat Adaptation by Sequestering Fatty Acids. Cell 161:1152-1163
Bhatla, Nikhil; Horvitz, H Robert (2015) Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory receptor orthologs and pharyngeal neurons. Neuron 85:804-18
de la Cruz, Ignacio Perez; Ma, Long; Horvitz, H Robert (2014) The Caenorhabditis elegans iodotyrosine deiodinase ortholog SUP-18 functions through a conserved channel SC-box to regulate the muscle two-pore domain potassium channel SUP-9. PLoS Genet 10:e1004175
Rawson, Randi L; Yam, Lung; Weimer, Robby M et al. (2014) Axons degenerate in the absence of mitochondria in C. elegans. Curr Biol 24:760-5

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