A new molecular alarm clock in vertebrates

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 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.

This image is of a brain from a five-day-old zebrafish larva showing neurons that are activated in response to Nmu overexpression
This image is of a brain from a five-day-old zebrafish larva showing neurons that are activated in response to Nmu overexpression. Neurons expressing the gene corticotropin releasing hormone (crh) are labeled bright green, and neurons that express cfos, a marker of general neuronal activity, are labeled magenta. The image shows that crh-expressing neurons in the hindbrain are activated by Nmu overexpression. Scale bar = 100 µm.
Image Credit: Chiu et al./Neuron 2016

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.”

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