The long-term goal of this research is to understand the genetic regulation of sleep and sleep-like states. Sleep-wake regulation consists of clock timing and of sleep onset and offset signals. Execution of the sleep state requires sensory gating, which refers to the phenomenon of reduced responsiveness during sleep. Sensory gating is a poorly-understood yet fundamental property of sleep that distinguishes it from quiet wakefulness. This proposal aims to advance our mechanistic understanding of sensory gating using the model organism Caenorhabditis elegans. The approach is to study lethargus, a sleep-like period that occurs during the life cycle of C. elegans. In this grant period, the global hypothesis to be tested is that EGL-4/PKG and cAMP signaling act antagonistically in sensory neurons to regulate sensory input during lethargus, and that reduced sensory input in turn facilitates sleep-like behavior. This global hypothesis will be tested through four specific aims.
Specific aim 1 will test the hypothesis that the molecular mechanism that regulates sensory responsiveness during lethargus is the same molecular mechanism that regulates chemosensory adaptation. This hypothesis will be tested by assessing for an association between defects in sensory adaptation and defects in sensory gating during lethargus. Additionally, we will test whether animals adapt more readily during lethargus than outside of lethargus.
Specific aim 2 will test the hypothesis that cAMP signaling acts in sensory neurons to antagonize sensory gating during lethargus. This hypothesis will be tested by expressing the gene pde-4, which normally degrades cAMP, in sensory neurons. In addition, we will assess the gene order relationship between egl-4 and pde-4 is regulating sensory gating.
Specific aim 3 will test the hypothesis that sensory input regulates sleep-like behavior.
This third aim will be tested by examining the effects on sleep-like behavior of dampening sensory input during lethargus and of mutants and operations that reduce sensory function. The final specific aim will perform a genetic screen to identify genes required for the enhanced sleep- like behavior in egl-4 gain of function mutants. Given the phylogenetic conservation of sleep and sleep-like states and the conservation of cGMP-and cAMP-dependent signaling pathways, it is likely that these experiments will shed light on sleep regulation in other species. Improved understanding of sleep regulation will enhance the diagnosis and treatment of people with sleep-disorders.

Public Health Relevance

Sleep disorders and sleep deprivation are major unmet public health problems. This proposal aims to add to our understanding of sleep regulation, in order to enhance the diagnosis and treatment of patients with sleep disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biological Rhythms and Sleep Study Section (BRS)
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Mitler, Merrill
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University of Pennsylvania
Schools of Medicine
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Yuan, Jinzhou; Raizen, David M; Bau, Haim H (2015) Propensity of undulatory swimmers, such as worms, to go against the flow. Proc Natl Acad Sci U S A 112:3606-11
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Nagy, Stanislav; Raizen, David M; Biron, David (2014) Measurements of behavioral quiescence in Caenorhabditis elegans. Methods 68:500-7
Yuan, Jinzhou; Raizen, David M; Bau, Haim H (2014) Gait synchronization in Caenorhabditis elegans. Proc Natl Acad Sci U S A 111:6865-70

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