Are happy fish better for science?

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Are happy fish better for science?

March 27, 2018 - 09:25

If they weren't in the windowless basement of a cavernous biomedical research building, the "Aquatic Suites" might sound like a cushy vacation destination.

But the zebrafish here at the University of Michigan (UM) still have it pretty good. In a large room full of aquaria, the striped, pinkie-size swimmers flit past fake green plants, white plastic tunnels, and multicolored marbles that may remind them of the bottoms of lakes and streams. These simple accoutrements are a luxury for creatures typically housed with little more than food and the water they swim in. And the enrichments may make the animals better at what they do: serving as important models for human disease.

For decades, lab animals such as rodents and fish have lived in barren enclosures: a small plastic box, few—if any—companions, and little else. The smaller the number of variables, the thinking went, the greater the accuracy of the experiment. But a growing number of studies suggests that this approach may have backfired. Only one in nine drugs that works in animals ever succeeds in human clinical trials, and labs often struggle to reproduce one another's results. Could the environment these creatures live in be part of the problem?

That's what a new group of advocates argues. "We're trying to control these animals so much, they're no longer useful," says Joseph Garner, a behavioral scientist who runs a program to improve the value and welfare of lab animals at Stanford University in Palo Alto, California. "If we want animals to tell us about stuff that's going to happen in people, we need to treat them more like people."

Garner and others are pushing scientists to enrich the lives of the creatures in their care by giving them toys, companions, and opportunities to exercise and explore—in short, a life more like they would have in the wild. These proponents are driven by both a concern for the welfare of lab animals and a desire to make their contributions to research more meaningful. And they're beginning to conduct experiments that show that such enrichments not only benefit animals, but science as well.

However, other researchers fear that adding extras to animal cages could muddy experiments and exacerbate the reproducibility crisis. And given the tens of millions of rodents and fish in U.S. labs alone, they blanch at the cost. "There's nothing natural about what we're doing, and adding a few tubes to a cage is not going to change that," says Jonathan Godbout, a neuroscientist at The Ohio State University (OSU) in Columbus who studies aging and stress in mice. "The more we spend on this stuff, the less research we can do."

Putting enrichment to the test

Back in the aquatic suites, veterinarian Jennifer Lofgren is peering into a zebrafish tank. There's a transparent plastic divider in the middle, with a hole to swim through. On one side is an enrichment—multicolored marbles lining the bottom—while the other side is empty. The idea is to see where fish spend more time, and thus which enrichment, if any, they prefer. "We can't just throw random objects like treasure chests in there because we think it looks cool," Lofgren says. "We want to put some science behind it."

That's the goal of the university's Refinement & Enrichment Advances Laboratory (REAL), an unusual program Lofgren co-founded in 2014. REAL's team of vets and animal care technicians aims to "understand the lived experience of the animal," she says, and to nurture what it has evolved to do. The marbles, for example, might reduce the fish's anxiety by making the tank feel a bit more like the wild. (They're also easier to clean than gravel.)

Stress can affect a wide range of physiologies and behaviors, and researchers are beginning to test whether the additions make the animals better models for depression—and, in the case of these particular fish—retinal regeneration. "If we provide subpar welfare," Lofgren says, "we are also providing subpar science."

Across campus, she and her team are also trying to improve the lives of rabbits. In a fancy, heavily glassed building once owned by biotech giant Pfizer sits a room filled with 50 white bunnies in metal cages the size of large laundry baskets. Most are housed alone, as has been the standard for decades.

"The going theory is that you can't socially house rabbits, because they'll tear each other apart," says Lofgren, even though the animals live in teeming warrens in the wild. For the past few years, her group has been getting some animals to share cages by providing enrichment: hay-filled paper bags they can "forage" through, plastic keys to gnaw on, and other accoutrements. "Now, they're playing together and snuggling up with each other," she says.

Once they've firmed up the enrichments, Lofgren and colleagues will explore how they affect research results. These animals are used in studies of cardiovascular disease, and isolated rabbits sometimes have irregular circadian rhythms, which can influence heart rate, blood pressure, and hormone levels. "We want to study the impact of diet and drugs on atherosclerosis, not the impact of these other variables," says Patrick Lester, the vet in charge of the rabbits. "If we can eliminate them, we can create a cleaner signal."

The bunnies don't appreciate every addition, and there's an easy way to tell. "They'll pee on it, and shove it into a corner," Lofgren says. Enrichments that the animals like are added to a database that REAL shares across campus and with other labs, including those in the United States that house some 150,000 rabbits. Lofgren says a recent webinar on their rabbit work attracted 90 institutions. "They get back in touch and say, ‘Oh my gosh, it actually worked!’"

Other labs are forging their own paths. At the University of Minho in Braga, Portugal, animal facility manager Magda João Castelhano Carlos has helped develop PhenoWorld, a sort of McMansion for rats with exercise rooms fitted with running wheels, dining areas with food and water, and experimental spaces with levers for cognition testing. The rodents must learn how to open the tunnels that lead to each room, giving them daily challenges. The animals engage in more natural play behavior, Carlos says, and are better models for psychiatric disorders because they're not unnaturally depressed or anxious.

Similarly, some rats at the University of British Columbia in Vancouver, Canada, can stand, climb ladders, and burrow in real soil in four-level cages created by biologist Daniel Weary and postdoc Joanna Makowska. "Our dream," Weary says, "is that our animals live a better life with us than if they had never been born."

A case in point is a strategy pioneered by Lofgren's group to ease a major trauma in the life of a lab mouse. Imagine a giant reaching into your house every week, hoisting you up by your legs, and plopping you into a new home. That's what the lab mice in a room stacked with nearly 900 cages on UM's medical campus deal with every time staff pick them up to clean their enclosures. "It's one of the most stressful things you can do to them," Lofgren says.

To ease that stress, her group adds plastic tubes to some cages. The goal is to get the rodents accustomed to the tubes and to spending time in them. Then, when cleaning time comes, the animal care staff wait for the mice to enter the tubes (or gently nudge them in), and transfer the whole shebang to a new enclosure. If it works, Lofgren says her team will apply the practice across campus.

Persuading the doubters will take time, in part because money for studies is scarce. The National Institutes of Health in Bethesda, Maryland, doesn't support enrichment research because it doesn't directly relate to the health and well-being of humans, says Patricia Brown, director of the agency's Office of Laboratory Animal Welfare. "We would if we could," she says. "A happy mouse is a better model."

The REAL program gets the vast share of its financing from UM funds designed to improve animal care and use, and a few small organizations offer grants for such work. Hannan's seminal Huntington study came out of his own pocket. "We never could have gotten a grant to do it," he says, "so we just did it."

Still, the chorus for enrichment is growing. "More and more, people are reaching out to us," Lofgren says. "We're starting to see some real momentum." More than 160 papers were published on rodent enrichment in 2016 versus a handful at the turn of the millennium; at the 2016 meeting of the American Association for Laboratory Animal Science, 83 out of 171 rodent presentations focused on enrichment—more than twice the number at the 2009 meeting.

Meanwhile, REAL continues to explore what makes animals happy. Lofgren plans to line the walls of UM's sheep runs with photos of contented sheep, for example, because studies suggest that the animals recognize each others' faces. She and her fellow enrichment advocates hope that one day, work like this will be become the rule, rather than the exception, both for the sake of science and for the animals themselves. "We owe it to these creatures to give them the best lives possible," Lofgren says. "They're giving us the best they can. So we should be doing the best we can."

Source:  Science, Author - David Grimm


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