You don’t have to watch Tom and Jerry cartoons to know that mice run away from cats. Mice and rats are born with an innate, hardwired fear of their feline predators, and the very scent of a cat is terrifying to them. So it was quite a surprise when in 2000, parasitologist Joanne Webster found rats that had not only lost their fear of cat urine, they were attracted to it. The key feature of these rats? They were infected by the parasite Toxoplasma gondii.

This phenomenon, which Webster dubbed “fatal feline attraction,” is particularly fascinating given the peculiarities of the parasite. Toxoplasma, or Toxo for short, is seemingly able to infect just about any warm-blooded animal anywhere in the world—dogs, cows, kangaroos, koalas, chickens, pigeons, sea otters, dolphins, et al.

Yet despite its ubiquity, Toxoplasma reproduces sexually only in cats. One idea is that if Toxo-infected mice and rats become easier prey, the parasite can get into cats and complete its lifecycle. It’s a compelling story, and one made even more so by the fact that Toxo also hangs out in the brain cells of its hosts—a great location for a mind-manipulating parasite.

The more researchers have investigated how this peculiar parasitic puppetmaster can influence behavior, the more complicated the story becomes. But it’s an enigma worth figuring out, because Toxo infection has been associated with a lot of neurological problems in another species it infects—us. Toxo’s been associated with all kinds of behaviors and disorders, including schizophrenia, suicide attempts, traffic accidents, and even personality and cultural differences. (As for any theories about Toxo being the reason we like cats, or being responsible for crazy cat ladies, feel free to take those with a huge grain of salt.)

It’s still unclear how convincing some of these associations are, and figuring out how the parasite operates has taken a long and winding path with multiple dead ends. These days, researchers may finally have some promising leads about the mechanism behind Toxo’s behavioral effects. “There was a period of confusion, and kind of a wild goose chase,” said Ajai Vyas, a neurobiologist at Nanyang Technological University in Singapore. “I think that period is now gone.”

Toxo in the brain

Vyas first read about Toxoplasma’s behavioral effects in a New York Times article by Carl Zimmer. For a freshly minted PhD looking for his next research project, “it was love at first sight,” he told Ars. He decided to replicate the behavioral work with lab strains of parasites and rodents. In his experiments, Vyas typically released rats into a circular arena where opposite ends had been laced with rabbit urine or bobcat urine.

(Believe it or not, bobcat urine is commercially available and easier to get than an alternative: “With house cats, it’s very difficult to collect urine from them,” Vyas said.)

Uninfected rats avoided the bobcat urine, whereas Toxo-infected ones didn't.

Vyas found that Toxo specifically affected fear of cat odors, but not learned fear or anxiety. But if you’re imagining infected rodents throwing themselves at cats and begging to be eaten, well, Toxo’s effects are considerably subtler. “They are not fearless, they’re just a little bit less fearful,” said Vyas. “That’s exactly what you’d expect—it’s not a magic wand so that there’s no fear at all.” When Vyas used a stronger source of cat odors, such as a cat collar, the fear became overpowering and the effects disappeared. “I’m very sure if we used a real cat, we probably will not see the effect,” he said.

When trying to explain how Toxo produces this effect, Vyas initially focused on the obvious: the parasite’s presence in the brain. When Toxo infects, it barricades itself in thick-walled cysts to evade the immune system, and these cysts can remain for decades in a few sites, including the brain. If Toxo forms cysts in specific parts of the brain, it could do something there to affect behavior. But so far, different studies have found cysts in many different locations with no obvious pattern to their distribution, so it’s unclear if cyst location can influence behavior.

Another hypothesis is that Toxo affects behavior by influencing the levels of dopamine, a major neurotransmitter involved in attraction and reward behaviors. Studies suggested that Toxo infection increases dopamine levels in the brain, and it may do so by producing enzymes that are related to those involved in dopamine synthesis. This idea is particularly exciting given that increased dopamine is associated with many of the same psychological conditions—such as schizophrenia—associated with Toxo infection.

But a recent study has questioned whether Toxo infection actually increases dopamine levels, and some researchers suggest that these enzymes may not get involved in dopamine synthesis at all. Instead, some believe the enzymes provide some other function relevant to Toxo, such as building its cyst wall. So the jury’s still out on the dopamine hypothesis.

To make things even more confusing, other experiments have even questioned whether Toxo needs to form cysts in the brain in order to influence behavior.



What a difference a strain makes

Wendy Ingram was initially quite skeptical of Toxo’s ability to manipulate behavior. As a graduate student at UC Berkeley, “I actually set out to prove this whole thing wrong,” she told Ars. “Much to my surprise, it’s amazing, it’s really shocking how consistent it is that uninfected mice have an incredible aversion to cat urine, and when you infect them with Toxoplasma, there’s a loss of aversion,” said Ingram, who’s now a post-doctoral fellow at Geisinger Health System in Danville, California.

But the real breakthrough came when Ingram decided to test the effects of different strains of Toxoplasma. Toxo parasites in Europe and the US belong primarily to three distinct strains, cleverly called Type I, II and III. Most previous experiments were conducted with the Type II strain—the Type I strain was too lethal to use for behavioral experiments in mice. “You can’t study them; dead mice tell no tales,” Ingram joked.

But just in time for Ingram’s experiments, other researchers created a mutant Type I strain that, despite missing just one set of genes, displayed radically different behavior. It was now completely unable to kill mice and, unlike the Type II and Type III strains, the mutated Type I strain didn’t form cysts and hang out in the brain for the long term. Accordingly, Ingram expected it to have no effect on behavior.

To her surprise, infection with any of the three Toxo strains caused mice to lose their fear of bobcat urine. In fact, the behavior persisted even a month after infection with the type I strain, when there were no signs of Toxo cysts in their brains. The parasite appeared to have made some long-term change to behavior during its initial infection phase, which lasted just a few days. “That was kind of the most striking and most exciting thing that led us to totally rethink what everyone’s saying is true about what the mechanism could be,” said Ingram. “In the context of my results with the Type I parasite not forming cysts in the brain and getting completely cleared from the brain, from what we can tell, it has nothing to do with cysts.”

How might Toxo influence behavior without being camped out in the brain? Some intriguing new work suggests that the parasite injects its proteins into many neurons without ever forming cysts there. It’s possible that these proteins might be making some permanent changes to the neurons that influence behavior, but that’s still pretty speculative.

Nanyang Technological University’s Vyas has an alternative idea based on a completely different behavior: Toxo makes male rodents more sexually attractive.

Listing image by Wendy Ingram