Lab mice that ‘touch grass’ are less anxious — and that highlights a big problem in rodent research
The online admonition to “touch the grass” to ease your emotional state may be backed by science – at least in lab mice.
A recent study reveals that mice who live outdoors are less anxious than those who spend their days in safe, shoebox-sized cages. And it could highlight a fundamental flaw in laboratory research, including that used to test the safety and effectiveness of drugs ultimately intended for humans.
“Why is there this huge gap in results between laboratory animal models and real experiments when we test [many] drugs in humans?” said the first author of the study Matthew Zipplepostdoctoral researcher at Cornell University “We think that a lot of this effect can be explained by this really artificial and standardized environment in which the laboratory animals are kept.”
The results were published in December in the journal Current biology.
Less anxious outdoors
Wild mice and humans have rich social environments, and wild mice are constantly on the move, foraging, burrowing, and facing risks, including the many predators that like to nibble on them.
In comparison, laboratory mice sit in small cages with two or three siblings of the same sex. There, food and water are delivered on a regular schedule. Studying drugs in these mice could mean limiting research to prisoners in solitary confinement, Zipple told Live Science.
Zipple and his colleagues set out to compare the psychology of two groups of laboratory mice: a group remaining in a laboratory and a group living with other mice in an outdoor enclosure, filled with grass, dirt and exposed to the sky. They did this using a standard maze, called an “elevated maze,” which has two closed and two open, gateway-style arms.
When first exposed to this maze under bright laboratory lights, laboratory mice typically explore with open arms, find them terrifying, and never venture on again. Instead, they stay in the closed, relatively safe part of the maze. This response is so consistent that researchers use open arms to induce and measure anxiety in laboratory mice.
But mice living in a wild environment weren’t at all frightened by the open arms, Zipple and his team found. They spent as much time exploring these areas on subsequent visits to the maze as the first time, all under bright light.
Meanwhile, caged mice sent to live outside also saw their maze-related anxiety evaporate; Animals that had already shown an apparent fear of open arms and then spent a week outside then spent twice as much time exploring open arms as animals that continued to live in cages.
Using the standardized maze is a “very powerful way of showing the limits of the status quo,” said Andrea Grahaman evolutionary ecologist from Princeton University who was not involved in the research.
Caged Mice Have Other Key Differences
Graham’s lab showed that mice that live in lab cages are also immunologically different from mice that live outside and encounter dirt, plants and a large number of other mice. It’s important, she said.
In one famous case of 2006A drug called TGN1412 appeared to boost the immune system against leukemia in laboratory mice, but caused a near-fatal immune response in the first six healthy human volunteers exposed to the drug. Further research found that, in laboratory mice, the drug activated immune cells that regulate and calm the immune response. However, in mice living in wild-type enclosures, the drug instead activated cells that intensify the immune response to the point that the body attacks itself.
“If we limit ourselves to studying only a few different genotypes [genetic profiles] of laboratory mice in the same immunologically boring and psychologically boring environments, we’re not really going to be able to study the full spectrum of the human immune or nervous system response to the environment,” Graham told Live Science.
Using wild-style enclosures requires upfront cost and effort, and also reduces rigid control over study animals to limit confounding variables in experiments. As such, they pull biomedical scientists out of their comfort zone, Zipple said.
But adding testing in these less confined mice could save a lot of effort and money on the human testing side by identifying drugs most likely to move from the lab to the clinic, the study authors say. Zipple and his colleagues are now studying the ways in which caged and wild mice age differently.
“The broader goal is to compile a list of behaviors, relevant biomedical phenotypes [observable traits] and psychological traits that are similar in the laboratory and in the field,” he said, to help solve the problem of translating the results to humans. They also want to make a “list of traits that look very different,” he said.
