Despite the importance of sleep to our well-being and its impact on disease and work productivity, our cellular and molecular understanding of sleep regulation is limited. Sleep/wake regulation arises via the interaction between neurons. We are investigating the regulation of a sleep behavior during larval transitions called lethargus in the roundworm C. elegans. Lethargus shows both behavioral and molecular genetic similarities to sleep in mammals and Drosophila. Since identifying the neuronal circuit regulating sleep is the next step in the analysis of this behavior, we propose to identify sleep-regulating neurons in C. elegans.
In Aim 1 we will conduct an optogenetic screen for interneurons that modulate feeding and locomotion rate, as sleep is characterized by cessation of these behaviors.
In Aim 2 we will test whether candidate sleep-modulating interneurons identified in Aim 1 affect sleep-like sensory arousal thresholds and behavioral quiescence. We will also establish the order of action of sleep/wake active neurons. Our studies will make use of innovative optogenetic stimulation, optical imaging, and image processing technologies for perturbing neurons, quantifying feeding movements, measuring quiescence behavior, and measuring arousal thresholds. Our overall goal of identifying every interneuron modulating sleep/wake in an animal is a goal never before accomplished in any animal, yet it is feasible in C. elegans due to the simplicity of its nervous system. Our experiments will provide a knowledge base for mechanistic studies of genes affecting C. elegans sleep-like behavior as well as for physiological studies of sleep-regulating neurons.

Public Health Relevance

The use of model organisms such as C. elegans to understand the genetic basis of sleep is improving our understanding of human sleep disorders. Our research will identify neurons that regulate sleep, which is an important step for understanding sleep-related genes in C. elegans and humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS091500-02
Application #
9020274
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
He, Janet
Project Start
2015-03-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
McCloskey, Richard J; Fouad, Anthony D; Churgin, Matthew A et al. (2017) Food responsiveness regulates episodic behavioral states in Caenorhabditis elegans. J Neurophysiol 117:1911-1934
Iannacone, Michael J; Beets, Isabel; Lopes, Lindsey E et al. (2017) The RFamide receptor DMSR-1 regulates stress-induced sleep in C. elegans. Elife 6:
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Yuan, Jinzhou; Ko, Hungtang; Raizen, David M et al. (2016) Terrain following and applications: Caenorhabditis elegans swims along the floor using a bump and undulate strategy. J R Soc Interface 13:
Trojanowski, Nicholas F; Raizen, David M; Fang-Yen, Christopher (2016) Pharyngeal pumping in Caenorhabditis elegans depends on tonic and phasic signaling from the nervous system. Sci Rep 6:22940
Trojanowski, Nicholas F; Raizen, David M (2016) Call it Worm Sleep. Trends Neurosci 39:54-62
Trojanowski, Nicholas F; Nelson, Matthew D; Flavell, Steven W et al. (2015) Distinct Mechanisms Underlie Quiescence during Two Caenorhabditis elegans Sleep-Like States. J Neurosci 35:14571-84
Nelson, Matthew D; Janssen, Tom; York, Neil et al. (2015) FRPR-4 Is a G-Protein Coupled Neuropeptide Receptor That Regulates Behavioral Quiescence and Posture in Caenorhabditis elegans. PLoS One 10:e0142938

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