The timing of sleep behavior is controlled by a feedback loop involving expression of genes of the `molecular clock'. How this clock regulates sleep behavior is poorly understood. This project is focused on understanding how the timing mechanism regulates sleep behavior at a single neuron resolution. We use the lethargus stage in the roundworm C. elegans as a model for sleep. Lethargus is a quiescent state that shows both behavioral and molecular genetic similarities to mammalian sleep. We have identified a sleep-inducing neuropeptide called NLP-22, which is expressed in one pair of neurons, the RIAs. We will use a combination of genetic, optical, and behavioral tools to study the mechanism by the RIA neurons integrate timing molecular signals with sleep signals from other neurons and how they ultimately affect peripheral target organs.
In Aim 1, we focus on understanding the role of the RIA neurons in sleep regulation.
In Aim 2, we investigate the mechanism by which NLP-22 induces feeding quiescence. And in Aim 3 we use a discovery approach to identify new somnogenic signals. Our project makes use of the powerful genetic and optical tools available in C. elegans to illuminate the molecular mechanism of sleep regulation within a defined neural circuit.

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 the mechanisms by which a sleep- promoting nerve cell works and will identify additional sleep-promoting genes. Discoveries made here can be later translated to other animals with the ultimate goal of finding new molecular targets for diagnosing and treating sleep disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088432-04
Application #
9405047
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
He, Janet
Project Start
2015-02-15
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
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
Fouad, Anthony D; Pu, Shelley H; Teng, Shelly et al. (2017) Quantitative Assessment of Fat Levels in Caenorhabditis elegans Using Dark Field Microscopy. G3 (Bethesda) 7:1811-1818
Davis, Kristen C; Raizen, David M (2017) A mechanism for sickness sleep: lessons from invertebrates. J Physiol 595:5415-5424
DeBardeleben, Hilary K; Lopes, Lindsey E; Nessel, Mark P et al. (2017) Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 in Caenorhabditis elegans. Genetics 207:571-582
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:
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 (2016) Call it Worm Sleep. Trends Neurosci 39:54-62
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
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
Yuan, Jinzhou; Zhou, Jessie; Raizen, David M et al. (2015) High-throughput, motility-based sorter for microswimmers such as C. elegans. Lab Chip 15:2790-8
Yuan, Jinzhou; Raizen, David M; Bau, Haim H (2015) A hydrodynamic mechanism for attraction of undulatory microswimmers to surfaces (bordertaxis). J R Soc Interface 12:20150227

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