New Worlds: We ‘sleep with the zebrafish’

Circadian rhythms do more than tell us when to sleep or wake. Disruptions in the cycle are associated with depression, weight problems and jet lag.

By JUDY SIEGEL-ITZKOVICH
Woman sleeping bed insomnia 311 (photo credit: Thinkstock/Imagebank)
Woman sleeping bed insomnia 311
(photo credit: Thinkstock/Imagebank)
Zebrafish – those black-and-white- striped creatures common to fresh-water aquariums – can teach us a thing or two about sleep cycles. Circadian rhythms do more than tell us when to sleep or wake. Disruptions in the cycle are associated with depression, weight problems and jet lag. Now neurobiologist Prof. Yoav Gothilf of TA is looking to the zebrafish to learn about how the human circadian system functions.
Gothilf and his doctoral student Gad Vatine, in collaboration with Prof. Nicholas Foulkes of the Karlsruhe Institute for Technology in Germany and Dr. David Klein of the US National Institutes of Health, has discovered that a mechanism that regulates the circadian system in zebrafish also plays a role in running its human counterpart. The discovery may help to develop new treatments for human ailments such as mental illness or sleep disorders. Their research appears in PLoS Biology and FEBS Letters.
Zebrafish may be small, but their circadian system is similar to that of human beings. As test subjects, says Gothilf, they also have distinct advantages: their embryos are transparent ; their genetics can be easily manipulated; and their development is quick. Previous studies revealed that a gene called Period2 (also present in humans) is associated with its circadian system, and is activated by light. “When we knocked down the gene in our zebrafish models,” says Gothilf, “the circadian system was lost.” This highlighted the importance of the gene, but the researchers had yet to discover how light triggered gene activity.
The team subsequently identified a region called LRM (Light Responsive Model) within Period2. Within this region, there are short genetic sequences called Ebox, which mediate clock activity, and Dbox, which confer light-driven expression. Based on this information, they identified the proteins that bind the Ebox and Dbox and trigger the light-induction of the Period2 gene – a process important for synchronization of the circadian system.
To determine whether a similar mechanism exists in humans, Gothilf and his fellow researchers isolated and tested the human LRM and inserted it into zebrafish cells, where the human LRM behaved in exactly the same way, activating Period2 when exposed to light. This unveiled a fascinating connection between humans and the five-centimeter fish.
Zebrafish and humans could have much more in common, Gothilf says, leading to breakthroughs in human medicine. Unlike rats and mice but like human beings, zebrafish are diurnal. This provides an opportunity to manipulate the circadian clock, testing different therapies and medications and discovering how disruptions, whether caused by biology or lifestyle, can best be treated.
The TAU professor believes this model has further applications to brain and biomedical research.
Researchers can already manipulate the genetic makeup of zebrafish, for example, to make specific neurons and their synapses easy to see and track. “Synapses can be actually counted. This kind of accessible model can be used in research into degenerative brain disorders,” he notes, adding that several additional groups at TAU are now using zebrafish to advance their work.
CLOUDS AND GAZELLES What do a herd of gazelles and a mass of clouds have in common? A mathematical formula that describes the population dynamics of such prey animals as gazelles and their predators has been used to model the relationship between cloud systems, rain and tiny floating particles called aerosols. This model, recently published in the Proceedings of the [US] National Academy of Sciences (PNAS), may help scientists understand how human-produced aerosols affect rainfall.
Clouds are major contributors to the climate, particularly the shallow marine stratocumulus clouds that form huge decks over the subtropical oceans and cool the atmosphere by reflecting part of the incoming solar energy back to space. Drs. Ilan Koren of the Weizmann Institute’s environmental sciences and energy research department and Graham Feingold of the NOAA Earth System Research Laboratory in Colorado found that equations for modeling prey-predator cycles were a handy analogy for cloud-rain cycles. Just as predator and prey populations expand and contract at the expense of one another, so too rain depletes clouds. And just as the availability of grass affects herd size, the relative abundance of aerosols – which “feed” the clouds as droplets condense around them – affects cloud shapes. A larger supply of airborne particles gives rise to more droplets, but these droplets are smaller, and thus remain high in the cloud rather than falling as rain.
In previous research, Feingold and Koren had “zoomed in” to discover oscillations in convective cells in marine stratocumulus. Now they returned to their data, but with a “top-down” approach to see if a generalized formula could reveal something about these systems. Using just three simple equations, they developed a model showing that cloud-rain dynamics mimic three known predator-prey modes. Like gazelles and lions, the two can oscillate in tandem, the “predator” rain cycle following a step behind peak cloud formation – or the two can reach a steady state in which the clouds are replenished at the same rate (as in a light, steady drizzle). The third option is chaos.