Lab mice that ‘touch grass’ have less anxiety – highlighting a big problem in rodent research

Online advice to “touch grass” to calm your emotional state may be backed up by science, at least in lab mice.

A recent study found that mice that live outdoors are less anxious than mice that spend their days in secure shoebox-sized cages. And that could ultimately highlight fundamental flaws in laboratory research, including research used to test the safety and effectiveness of drugs in humans.

Drugs that seem to work in lab mice don’t necessarily work in human patients, and some scientists believe that drugs can fail because of how strange and isolating life in the lab is for rodents.

you may like

“Why is there such a large gap between animal models in the laboratory and results in real experiments? [many] “We think much of this effect may be explained by this really artificial, standardized environment in which the laboratory animals are kept,” said Matthew Zipple, a postdoctoral fellow at Cornell University and first study author.

The findings were published in Current Biology in December.

Reduces anxiety outdoors

Both wild rats and humans have rich social environments, and wild rats are constantly on the go, foraging for food, digging holes, and facing dangers such as many predators who like to snack.

In comparison, lab mice sit in small cages with two or three same-sex siblings. There, food and water are delivered regularly. Studying drugs in these mice could be similar to 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. One group remained in the laboratory, and the other group lived with other mice in an outdoor enclosure with grass, soil, and exposure to the sky. They did this using a standard maze called an “elevated plus maze” with two closed arms and two open catwalk-style arms.

When exposed to this maze for the first time under the bright lights of a laboratory, laboratory mice typically explore the open arms, become frightened, and essentially never set foot in that maze again. Instead, they remain in a relatively safe enclosed part of the maze. This response is so consistent that researchers use open arms to induce and measure anxiety in laboratory mice.

Image 1/2

Mice in a wild-type environment not only behave differently than mice living in cages, but also have different immunological profiles.

Mice that were allowed to roam outside spent more time exploring the “open” arms of the maze.

However, Zipple and his team found that mice living in a wild-type environment were not at all surprised by the outstretched arms. They spent the same amount of time exploring these areas under bright lights as they did the first time they visited the maze.

you may like

Meanwhile, caged mice sent to live outdoors also saw their fear of mazes disappear. Animals that had already shown a clear fear of open arms and then spent a week outdoors spent twice as much time exploring open arms afterwards compared to animals that continued to live in cages.

Andrea Graham, an evolutionary ecologist at Princeton University who was not involved in the study, said the use of standardized mazes was “a really powerful way to show the limits of business as usual.”

There are other important differences between caged mice

Graham’s lab has shown that mice that live in lab cages are immunologically different from mice that encounter dirt, plants, and a host of other mice outdoors. That’s important, she said.

In a famous case in 2006, a drug called TGN1412 seemed to strengthen the immune systems of laboratory mice against leukemia, but it caused a near-fatal immune response in the first six healthy human volunteers exposed to the drug. Subsequent studies showed that in laboratory mice, the drug activated immune cells that regulate and quiet the immune response. But in mice living in wild-type enclosures, the drug instead activated cells and boosted the immune response until the body attacked itself.

“If we limit ourselves to studying just a few different genotypes, [genetic profiles] “If you experiment on lab mice in the same immunologically and psychologically boring environment, you won’t really be able to study the full range of human immune and nervous system responses to that environment,” Graham told Live Science.

The use of wild-type enclosures requires some initial cost and effort, and also reduces the strict controls imposed on research animals to limit confounding variables in experiments. So they’re pushing biomedical scientists out of their comfort zones, Zipple said.

However, the study authors argue that adding these less restrictive mouse studies could save significant effort and money on the human testing side by pinpointing the drugs most likely to make it from the lab to the clinic. Zipple and his colleagues are currently studying how caged mice age differently than mice in the wild.

“The broader goal is to create a list of biomedically relevant behaviors and phenotypes. [observable traits] The researchers also said they wanted to create a “list of traits that look quite different.”