For animals without eyelids, fish are surprisingly capable of catching some serious shut-eye. When zebrafish (Danio rerio) doze off, they catch their z’s much like people do, new research shows. These striped swimmers even appear to experience the piscine equivalent of REM sleep, the stage in which humans dream—and something that, until now, has only been reported in mammals, birds, and reptiles. That doesn’t necessarily mean that fish are dreaming, or even that their version of sleep is completely identical to ours. Even so, the study, published today in the journal Nature, suggests that multistage snoozing could be common among vertebrates—the group of animals that includes mammals, birds, reptiles, amphibians, and fish—and may have arisen more than 450 million years ago. “This paper is a long time coming,” says Audrey Chen Lew, a neurobiologist at the University of California, Irvine who was not involved in the study. “It’s really nice work that...demonstrates similarities between fish and humans and other mammals that we haven’t seen before.”

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That sleep is more or less ubiquitous among complex animals such as vertebrates, which all have the neural circuitry that makes up the spinal cord, might sound like a no-brainer. But in the world of neurobiology, things aren’t so black and white. One issue is that sleep isn’t always easy to measure or identify. In some creatures, it’s an easy behavior to pick out: As they doze off, many animals will settle into a relaxed posture, stop most of their movements, and become less aware of their surroundings for an extended period of time (without entering a coma or other difficult-to-reverse state of being). Other organisms, however, don’t abide by these criteria, prompting researchers to search for a more cellular definition of sleep—something that might be universally detectable among all those who do, in fact, engage in regular slumber. Zebrafish are transparent during their first few weeks of life. Shown here is a larva, or juvenile. Image Credit: Shawn Burgess, NHGRI, Wikimedia Commons That’s actually something that scientists have more or less nailed down in mammals, birds, and reptiles, all of which exhibit similar patterns of electrical activity in the brain when hitting the hay. Fish, on the other hand, have remained mostly mysterious, due in part to the fact that many sleep research methods are tailored to humans and other land-based species. But even though they’re separated by at least 400 million years of evolution, fish and humans aren’t all that different. Throughout the piscine body are familiar hallmarks of human physiology, down to the genes written into their DNA. When it comes to fish, all the right machinery is there for human-like sleep, says study author Philippe Mourrain, a neurobiologist at Stanford University. It’s just that no one had yet found a way to check if it was doing the same thing. So a team of scientists led by Mourrain decided to invent a method of their own. In human sleep studies, sensors hooked up to a person’s body record their brain activity, heart rate, breathing, and muscle movements. Taking inspiration from this comprehensive suite of measurements, the researchers developed what was, in effect, a whole-body scan for a zebrafish—a striped, inch-long minnow that develops with a transparent body during its first few weeks of life. This see-through skin was key to the experiment’s success, as it allowed the researchers to peer directly into the fish’s organs without the need for surgeries or other invasive procedures, says study author Louis Leung, who conducts research under Mourrain’s supervision. In humans, many sleep study measurements are collected by recording electrical signals by way of electrodes on the skin. But the fish’s transparency allowed the researchers to gather the same kinds of data by simply putting fluorescent markers into cells, which then lit up in the presence of electrical signals, yielding a pictorial play by play of individual cells’ behavior over time.

When the team analyzed the brain waves of a school of juvenile zebrafish in repose, they discovered two familiar patterns of electrical activity. The first bore a striking resemblance to what’s known in humans as deep or slow-wave sleep, so named because it produces a series of synchronized, low-frequency brain waves. In people, deep sleep is marked by low brain activity, and is thought to give the body the opportunity to recuperate. It may also play a role in memory consolidation. If that’s also true in fish, Mourrain says, it makes a lot of sense. Even in animals for whom life goes along swimmingly, there’s always a need for some R&R. And fish, too, need to learn. But Mourrain was far more taken aback to see another hallmark of human sleep echoed in zebrafish: the state in which people dream. So-called rapid-eye movement (REM) sleep is actually bursting with brain activity, on par with measurements taken during waking hours. The big difference, of course, is that the rest of the body isn’t awake, and is actually mostly immobilized (except for the eyes, which, in humans, jerk back and forth). Much of this also appears to be true for zebrafish, except for their eyes, which kept quiet along with the rest of the body, Mourrain says. (Many other animals also keep their eyes still during REM sleep.) Neither deep sleep nor REM sleep was completely identical between humans and fish, points out Guliz Ozcan, a neurobiologist and zebrafish expert at University College London who was not involved in the study. For one thing, the zebrafish equivalent of slow-wave sleep was a lot, well, slower. Despite these differences, Ozcan says, the neural “signatures” of both states are clearly recognizable—implying that the human version of sleep might be far less human than once thought. With these new findings, Leung says, zebrafish can now join the growing list of vertebrates in which sleep has been pinpointed on a more molecular level. Without testing every single vertebrate in existence, it’s hard to say whether multistage sleep is universal in this group, he adds. But as a representative for fish—which comprise around half of all known vertebrate species—the zebrafish and its startling slumber hint that multistage sleep may have been present in a common ancestor of mammals, birds, reptiles, and fish, which lived at least 450 million years ago. Amphibians are likely to share the trait as well, since they’re more closely related to us than fish are, Mourrain says. The next step, he adds, will be to see if the same signatures extend even further back in evolutionary time. Top: A zebrafish larva with a fluorescent central nervous system. Cells light up as they become active. Bottom: The central nervous system and muscles of the zebrafish, illuminated with the same fluorescence. Using this system, researchers were able to record cellular signatures of sleep without invasive procedures. Image Credit: Courtesy of Louis Leung, Stanford University Such deep-rooted implications make this paper “a total breakthrough,” says Eva Naumann, a neurobiologist at Duke University who was not involved in the study. “I can’t overstate it: [Finding these patterns of brain activity] was the missing piece of the puzzle...I’ve been waiting for a study like this to come out ever since I started working in this field.” The big picture here doesn’t paint humans as primitive, though. Rather, these results should “elevate the zebrafish as a model system to study neural phenomena like sleep,” Naumann adds. The study’s results also showed that, when deprived of sleep or treated with sleeping pills, zebrafish react similarly to humans both behaviorally and physiologically, hinting that they could also be useful in screening drugs to treat irregular or disordered sleep, Ozcan says. There’s still, however, the elephant in the room: Despite being so widespread, sleep and all its stages continue to puzzle researchers trying to suss out their true purpose. But whatever it is that dozing is doing, if it really did evolve this long ago, and stuck around in so many species, “that points to something really essential,” Leung says. As for whether zebrafish dream during their version of REM, that’s still an open question. If dreaming is a product of learning and memorization, it’s certainly possible, Mourrain says. After all, most breakthroughs come from the most unexpected places, he says. Including the ones people (or any other species, perhaps) never even dreamed of.

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