The millions of mice used in labs are extremely important for medical research. But for them, life is almost always miserable. Imagine spending your entire life in a shoebox-sized cell, with stagnant air, fluorescent lights, and almost nowhere to move (not to even mention the procedures themselves). This is the reality for laboratory mice in biomedical research.
Unsurprisingly, their mind suffers terribly. Researchers thought anxiety was a permanent problem in this context. But when postdoctoral researcher Matthew Zipple took a cage of these sheltered animals and carried them outside, he was stunned to see the results. When the mice touched grass for the first time in their lives, and when they could move around freely, their mental health improved massively within days.
“We release the mice into these very large, enclosed fields where they can run around and touch grass and dirt for the first time in their lives,” said senior author Michael Sheehan, associate professor of neurobiology. “It’s a new approach to understanding more about how experiences shape subsequent responses to the world, and the hope is that what we learn from these mice will have more generalizability to other animals and to ourselves as well.”
Fear Factory
To measure mouse fear and anxiety, scientists use a classic tool called the “elevated plus maze.” It looks just like it sounds: a “plus” sign raised off the ground. Two arms of the maze are enclosed by high walls — a safe, dark tunnel. The other two arms are open planks, suspended in the air with nothing to stop a fall.
Put a standard lab mouse in this maze, and it will cautiously explore. But mice are smart. They learn quickly that the open arm is scary. If you put that same mouse back in the maze later, it will remember and refuse to go out onto the plank. When a mouse is brought back to this type of maze, it hides in the walled section. It has learned to be anxious.
This standard test reliable and you can do it over and over. But as it turns out, it’s potentially misleading.
Zipple and senior author Michael Sheehan, a professor of neurobiology, wanted to see what happens when you get the rewilded mice to do the test. They took groups of mice that had already learned to fear the maze and had high levels of anxiety. After just one week of touching grass, the researchers brought them back inside and put them back on the maze.
“The rewilded mice show either no fear response or a much, much weaker response,” said Zipple, first author and a Klarman Fellow in the College of Arts and Sciences. Their anxiety dwindled.
“We put them in the field for a week, and they returned to their original levels of anxiety behavior,” Zipple said. “Living in this naturalistic environment both blocks the formation of the initial fear response, and it can reset a fear response that’s already been developed in these animals in the lab.”
The Agency of Anxiety
Researchers tried to explain how it is that just one week makes such a big difference. The researchers believe the answer lies in a concept called “agency.”
Agency is the ability to act purposefully, make choices, and influence one’s own life. Mice, like us, suffer when they feel they have no control over their outcomes. They experience “learned helplessness,” a state where they stop trying to improve their situation, leading to increased feelings of anxiety and depression.
In a cage, a mouse has zero agency. Food appears. Water appears. The bedding is changed when a giant hand decides to change it. The mouse solves no problems. It overcomes no obstacles. Its “library of experiences” is virtually empty.
When that mouse encounters a threat, even one as bland as an open plank, it has no context. It panics and gets very anxious.
“If you experience lots of different things that happen to you every day, you have a better way to calibrate whether or not something is scary or threatening,” Sheehan said. “But if you’ve only had five experiences, you come across your sixth experience, and it’s quite different from everything you’ve done before, that’s going to invoke anxiety.”
But in the field, mice spent 168 hours solving problems. They built tunnels, found food, and navigated wind and rain. They built a massive library of experiences. When they returned to the maze, the open plank was just another manageable challenge in a life full of them. They had learned to calibrate risk.
Useful for Mice, Useful for Us
For decades, some researchers have cautioned that lab mice are poor models for human health.
We cure cancer in mice all the time, but those cures rarely work on humans. This study suggests a reason why: we are testing drugs on animals that are psychologically broken. We are studying the biology of prisoners in solitary confinement and assuming it applies to the general population. This psychological environment has major repercussions on the immune system and multiple bodily functions.
The implications here stretch far beyond rodent research. This offers some important context for anxiety in general. This finding suggests that what we call “anxiety” might often be a rational response to an irrational lack of experience. Without the ability to change our environment through our own behavior, we lose the ability to judge safety. We become hyper-sensitized to threat.
Sheehan points out that the “rewilding” effect mirrors conversations we are having about our own species. We see rising rates of anxiety in children and young adults. Simultaneously, we see a decline in unstructured play, independent roaming, and exposure to physical risk. We’re reducing the experiences young generations can have, and this could leave them predisposed to anxiety.
The science is still early. We need to know how long the effect lasts and if it works on older animals as well as young ones. The classic caveat (this is a mouse study, it doesn’t necessarily apply to humans) also has to be mentioned. But the core message is striking in its simplicity.
Resilience isn’t a genetic trait you are born with. It is a skill you practice. It requires a world large enough to be scary, and the freedom to face it. Sometimes, you just need to go outside and touch the grass.
The study was published in Current Biology.
