Toxoplasma gondii exerts a strange sort of mind control on rodents: Once infected with the brain parasite, they seem to lose their fear of cats and become more likely to get eaten. When they are, the microbe can make its way into the feline intestine to reproduce. But a new study argues that T. gondii’s effects on rodents aren’t cat specific; instead, the parasite simply makes mice more eager to explore and less fearful of any species that might gobble them up.
“It doesn’t make the parasite look to be this genius that many people thought it was,” says William Sullivan, a microbiologist at the Indiana University School of Medicine, Indianapolis, who was not involved in the new work.
T. gondii can infect any warm-blooded vertebrate, including people, but its relationship with cats is special. Only in the feline gut can it reproduce sexually and assume a hardy, infectious form called an oocyst, which gets excreted to infect more animals.
Some researchers suspect the parasite tweaks a rodent’s brain to change how it perceives cats. And some lab tests have revealed infected mice prefer to explore cat urine over that of other potential predators.
But that’s not what parasitologist Dominique Soldati-Favre at the University of Geneva found. When she and colleagues allowed T. gondii-infected mice to explore chambers containing four smells—those of themselves, bobcats, foxes, and guinea pigs (a nonpredator)—the rodents didn’t give the bobcat smell special treatment. Indeed, infected mice spent the most time investigating the guinea pig and fox smells, the team concludes today in Cell Reports. The mice were also willing to venture into a chamber containing a live, anesthetized rat (another potential predator), whereas uninfected control mice almost invariably stayed away.
In several other behavioral tests, the team found that infected mice showed less anxiety and a stronger tendency to explore. For example, they spent more time in the arms of a maze that were open and exposed—areas that mice typically find threatening.
“We realized it wasn’t just about having lost fear against the cat,” Soldati-Favre says. “Really, these mice are very open-minded, and they go everywhere.”
Other studies have found similar changes in anxiety and exploration, notes Joanne Webster, a parasitologist at the Royal Veterinary College, Hawkshead, who was not involved with the work. And the new research hasn’t convinced her that the cat-focused effect of T. gondii is a myth. “I don’t think they’ve got the power to dispute that here.” The researchers, she notes, report the odor preferences of the mice over 10 minutes, whereas some previous odor tests have tracked mice for several hours. She suspects the new test was too short to pick up a subtle tendency to explore the bobcat odor more intently than the others.
Other experts embrace the new finding. T. gondii “clearly manipulates the crap out of the host,” says Laura Knoll, a parasitologist at the University of Wisconsin, Madison, and there’s no evolutionary reason this manipulation needs to focus on cats. Sexual reproduction may depend on the cat, but the parasite is transmitted any time an animal eats infected prey. A generally bold, curious mouse is “more likely to be out and about and get eaten. And every time it’s eaten—whether it’s [by] a fox or a bobcat—[T. gondii] does get passed on.”
Knoll’s team recently published a method to get T. gondii to reproduce in laboratory mice. Like that study, she says, this new one supports the idea that “there’s nothing that special about the cat.”
Soldati-Favre and colleagues propose that an immune response provoked by T. gondii cysts in the brain underlies the behavior changes. Unlike some previous studies suggesting the cysts concentrate in particular regions and may act on specific brain circuits, this one finds a roughly even distribution of cysts across the mouse cortex—the brain’s outer layer. And genetic analysis of brain tissue revealed certain markers of inflammation. Both cyst number and level of inflammation correlated with the degree of behavior change in infected mice, they report.
Up to one-third of humans are thought to harbor a T. gondii infection, known as toxoplasmosis, and some research has linked it to schizophrenia and other mental illness. Soldati-Favre speculates that, because the parasite seems to produce fewer and smaller cysts in healthy humans than in mice, it may drive less inflammation and very minor behavioral change in people. The authors propose future studies to test whether infected humans show signs of inflammation, which is thought to contribute to certain neurodegenerative diseases.
If researchers ever decide they do want to combat the effect of T. gondii infection in the human brain, the new results suggest reducing inflammation might help, Sullivan says. His team recently found that dosing T. gondii-infected mice with an anti-inflammatory drug could reverse some of their behavioral changes.
The new results suggest the parasite has found a “sweet spot,” he says: invading the brain enough to provoke an immune response that drives the animal toward predators, but not enough to kill its host right away. It may not be an ultraprecise tweak to the perception of cats, but it’s still “a very smart strategy,” he says. “In a way, that is kind of mad genius.”