Worm study uncovers secrets of sleep
After an exhausting or stressful day, there’s often nothing better than a good night’s sleep to help restore our mental and physical well-being. “We believe that sleep is essential because it is present in all animals that have a nervous system,” notes SLEEPCONTROL project coordinator Henrik Bringmann from the Dresden University of Technology in Germany. “There is no animal we know of that has a nervous system but does not sleep.” Across species, sleep is controlled by specialised neurons that fire specifically during sleep, called sleep-active neurons. While their existence has been known for decades, little is known about how they are controlled and function at the molecular level. This is partly due to the difficulties inherent in studying the genetics of sleep.
A suitable animal model system
“Many sleep traits are non-specific,” explains Bringmann. “For example, a mutant mouse that does not sleep much could have a defect in its sleep controls system, but also in its arousal system and simply be stressed.” Another challenge is that a lack of sleep is thought to often be lethal for animal subjects. Research carried out at Bringmann’s lab has made important progress in this field. Sleep in roundworms has been shown to depend on a single sleep-active neuron, called RIS. Furthermore, roundworm mutants, where a lack of sleep has been found to be non-lethal, were also identified. “RIS is very similar to human sleep-active neurons,” notes Bringmann. “Taking this away removes sleep. At the lab, we had in our hands therefore a simplified sleep-active neuron system, inside a suitable animal model system.”
Mechanisms of sleep
The goal of the SLEEPCONTROL project, which was undertaken with the support of the European Research Council, was to use this animal model system to learn about how RIS works at the molecular level. To achieve this, a genetic analysis of sleep mutants was carried out. Neuron activity was imaged and manipulated. “We were able to identify three mechanisms that activate the sleep neuron RIS,” he says. “We showed that upon heat stress, a conserved factor called EGF activates the RIS neuron directly as well as through a second neuron. In this way, sleep is increased when the cells of the body are stressed by heat.” The project team identified anti-ageing genes that activate RIS during starvation, and thus help to promote survival. “We also showed that injury of the skin causes the release of antimicrobial peptides,” continues Bringmann. “These travel to the nervous system to activate RIS and cause sleep, which is helpful for the worm to survive injury.”
Addressing sleep disorders
SLEEPCONTROL also identified AP2, a protein required for sleep in RIS, to also control sleep in mouse models. The project’s work in worm models could therefore have relevance in understanding mammalian – and thus human – sleep mechanisms. “By activating sleep-promoting genetic pathways, it should be possible to develop therapies for human sleep disorders,” he adds. “This is a long-term aspiration. Sleep in mammals is much more complex than in worms, and also harder to study. But the worm gives us a roadmap for where to go.” Bringmann aims to continue this work into better understanding the fundamental principles and mechanisms that control sleep in worms. These results will provide hypotheses that can then be translated to and tested in mouse models. “The final step is to translate this work to humans, to help us understand human sleep and its disorders, and to develop sleep disorder treatments,” concludes Bringmann. “This will require a concerted and lengthy effort by many labs.”
Keywords
SLEEPCONTROL, sleeping, sleep, neurons, RIS, genetic, AP2, therapies