Function and Regulation of Sleep

Quiescent behavioral states are universal to the animal world with the most famous and mysterious of these being sleep. Despite the fact that we spend one third of our life sleeping, and despite the fact that (probably) all animals sleep, the core function of sleep remains unknown. In addition, the molecular basis underlying sleep/wake regulation is poorly understood.

We use the roundworm C. elegans as a model system to address these questions. C. elegans offers many experimental advantages including powerful genetic tools and a simple neuroanatomy.

Growth of C. elegans from an embryo to an adult is punctuated by four molts, during which the animal secretes a new cuticle and sheds its old one. Prior to each molt the worm has a quiescent behavioral state called lethargus. Lethargus has several similarities to sleep including rapid reversibility to strong stimulation, increased sensory arousal threshold, and homeostatic regulation. Remarkably, genetic regulation of lethargus quiescence is similar to genetic regulation of sleep in other animals. This suggests that sleep appeared very early in animal evolution and that studying worm sleep can inform our understanding of human sleep. 

In addition to developmentally-timed sleep (DTS), C. elegans also sleeps after exposures to environments that induce sickness or cellular stress. Such exposures include high heat, ultraviolet light, certain chemicals, and others. This stress-induced sleep (SIS) requires two peptidergic neurons called ALA and RIS. RIS and ALA are activated by epidermal growth factor signaling. 

We are currently studying genes that regulate C. elegans sleep. 

By studying the purpose and regulation of nematode sleep we hope to gain insight into why sleep had evolved, a central biological mystery.

Understanding Fatigue

Fatigue can occur during health, for example after weight lifting or long-distance running, and after sleep curtailment. But fatigue is particularly prevalent during sickness. Fatigue is a major disabling symptoms in patients with chronic diseases such as multiple sclerosis, rheumatoid arthritis, chronic infection, cancer (and cancer treatment), and others. Pathological fatigue is also observed alone and in the absence of a clearly-defined systemic disease. Mechanisms underlying such fatigue are poorly understood. To begin to understand these mechanisms, we are making use of the C. elegans system. We focus on stress-induced sleep since this behavior accompanies systemic illness. Genetic regulators of SIS identified in worms may have homologous genes that regulate fatigue in humans.