Dozens of chemical interactions in the vertebrate brain go into maintaining a natural sleep schedule, and scientists have recently found one more player on the field: a neurochemical called neuromedin U, or Nmu. The protein, which was analyzed in zebrafish but is also found in humans, acts to stimulate wakefulness, particularly in the morning. The study appears Feb. 17, 2016 in Neuron.
"We found a gene that's involved in promoting wakefulness and suppressing sleep, and only a handful of genes have been shown to do that," says senior author David Prober, a sleep biologist at the California Institute of Technology. Prober and his colleagues uncovered the gene's function in a large-scale screening project.
Researchers have studied the underpinnings of sleep for decades, but many of the genes and proteins that scientists have found to affect the sleep/wake cycle in mammals were discovered serendipitously. These discoveries don't yet tell the whole story -- so in a bid to uncover new parts of the system, Prober and his collaborators Jason Rihel and Alex Schier turned to zebrafish, which share brain structures related to sleep with humans.
The researchers overexpressed over a thousand different human genes in zebrafish larvae, one at a time, to look at their effects on sleep/wake cycles. The zebrafish were engineered to ramp up expression of their human gene when they were incubated in warm water at 37 degrees Celsius; this enabled the research team to switch the genes on at any point and track the changes in the animals' sleep patterns.
When Prober and his colleagues turned on the gene for the human version of Nmu, the zebrafish became much more active. The researchers then overexpressed the zebrafish version of Nmu, which also resulted in hyperactivity and insomnia. "The night after we turn on expression of the gene, the animals almost don't sleep at all," says Prober.
On the other hand, when the research team mutated the zebrafish nmu gene so the fish couldn't express the protein, the larval fish were less active during the day. The adult mutant fish were also sluggish, especially at dawn, when normally they would be active and alert. "This suggests that Nmu might be particularly important in promoting the transition from nighttime sleep to daytime wakefulness," says Prober. "You could think of Nmu as nature's alarm clock that helps to get you going in the morning."
Some previous studies of Nmu found that it also affects activity levels in rodents, but the mechanism for its action was unclear. The researchers found that Nmu likely promotes wakefulness in zebrafish by activating neurons in the brainstem that express a gene called corticotropin releasing hormone (crh). Prober suggests that the study could inform research into human insomnia.
"The basis for chronic insomnia is largely unknown," he says. "It's possible that hyperactivity of the Nmu pathway might underlie some cases of this condition, but future studies in humans would have to test this idea."
Funding was provided by the NIH, the European Research Council Starting Grant, the UCL Excellence Fellowship, the High-Tech Fund of the Dana-Farber Cancer Institute, the Ellison Foundation, and the Mallinckrodt, Rita Allen, and Brain and Behavior Research Foundations.
Neuron, Chiu et al.: "A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States" http://dx.doi.org/10.1016/j.neuron.2016.01.007
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