Key Points
- Toxoplasma gondii infection is associated with altered behavior in intermediate and secondary hosts like rodents and humans.
- Behavioral changes include reduced fear of predators, greater impulsivity and increased risk-taking.
- The parasite can only reproduce sexually in cats; behavioral shifts associated with infection may increase the chances of an infected intermediate host being consumed by a cat.
- There are several mechanisms by which T. gondii may impact host behavior, including altering dopamine levels in the brain, miRNA signaling and dysregulating hormones.
Rats and mice don't usually like cat pee. It's a warning sign: stay away if you want to live another day.
But sometimes the rodents don't take the hint. In fact, they may be attracted to the odor-and, as a result, end up in the clutches of the cat who did the peeing. There's a reason this phenomenon is called fatal feline attraction.
What comes over these seemingly self-destructive rodents? It turns out, they don't have much choice in the matter. Their brain has been hijacked.
Toxoplasma Made Me Do It
The hijacker is Toxoplasma gondii, a parasite that can infect all warm-blooded animals-including humans. Different stages of the parasite's multi-part life cycle occur in its extensive list of intermediate or secondary hosts, though it can only reproduce sexually in the guts of domestic cats and their wilder relatives as definitive hosts.
The cats shed oocytes in their feces that contaminate the environment and are ingested by other creatures. The oocytes transform into tachyzoites that invade host cells in neural (brain) and muscle tissue, transforming into cyst-forming bradyzoites that can persist for a host's lifetime. Cats that consume bradyzoites (e.g., eat an infected mouse) become infected, and the parasite's lifecycle continues.
It is estimated that 1/3 of the human population harbors T. gondii, often without overt signs of infection. However, in certain populations, such as those who are infected for the first time while pregnant and immunocompromised individuals, T. gondii can have severe impacts.
But there's more to the story than the potentially catastrophic effects from congenital transmission in humans and livestock, or havoc caused in the brains of immunocompromised patients. A large body of research suggests that, due to its localization in the brain, T. gondii may also be able to subtly influence how intermediate and other secondary host species behave.
For example, T. gondii-infected rodents have lower anxiety, are less averse to predators (not just cats) and are more explorative. Hyena cubs approach lions more closely than uninfected peers-and die more often because of it. Wolves harboring the parasite are more likely to make high-risk decisions, like becoming a pack leader, whereas chimpanzees lose their innate aversion to leopard urine.
And then there are people. T. gondii infection has been linked to cognition, personality traits and disorders like schizophrenia in humans. Research suggests there is an association between infection by the parasite and increased aggression and impulsivity, a heightened risk for motor vehicle accidents and a reduced response to monetary rewards after completing challenging cognitive tasks. One study of over 16,000 Danish women showed that T. gondii infection was associated with an increased probability of becoming an entrepreneur-a decidedly risky move.
These are associative studies, which have limitations. As Laura Knoll, Ph.D., a professor of medical microbiology & immunology at the University of Wisconsin-Madison, puts it, "How do you differentiate that people that are just bigger risk takers [and are] going to do behaviors that are more likely to give them parasites, [like] drink unfiltered water or eat undercooked meat? How do you know that risky people just aren't more likely to have Toxo, period?"
Even so, the preponderance of positive correlations, combined with data from controlled laboratory studies in rodents, signals an interplay between T. gondii and host behavior. This overlap shows up in many other parasite-host interactions, too. For instance, hairworms drive infected insects to jump into water. Ophiocordyceps fungi force their ant hosts to leave their colonies, climb high into vegetation, clamp onto leaves and die; the fungus grows out of the dead ant's back, releasing spores to facilitate transmission. The fluke Euhaplorchis claiforniensis infects the brains of killfish, causing them to "dance" in a way that catches the eyes of predators. And the list goes on.
Why Does Toxoplasma Infection Alter Host Behavior?
The ability of T. gondii infection to change host behavior, including overriding hard-wired responses like fear of predators, is a little mind-boggling. But researchers think it-and other forms of parasite-mediated host control-has a relatively simple reason: reproduction.
For T. gondii to complete its life cycle, it must find its way into the gut of a feline. It bides its time in an intermediate host, which ideally will be eaten by a cat to produce a new population of T. gondii. But this waiting game is not a passive process. Parasite-induced behavioral modifications can increase the chances of host consumption by cats (e.g., reducing fear of cat urine, increasing risk-taking behavior).
"Wherever we go, we have this very large intermediate host reservoir of rodents. And there's a selective advantage of the parasite to get to the cat final host," said Joanne Webster, Ph.D., a professor in the Royal Veterinary College at the University of London. "Having cysts in various organs, most commonly the brain, puts the parasite in an ideal position in which to achieve this manipulation."
But how does T. gondii know it's in a cat and not a person, mouse or wolf? "Cats have really interesting, weird metabolism," Knoll said. "They evolved as carnivores in desert or low-nutrient situations [and] have several aspects of their metabolism that are very different [from] other mammals." Her lab determined that, unlike all other mammals, cats do not express an enzyme in their guts that metabolizes the fatty acid linoleic acid, likely to avoid wasting calories on costly lipid mediators. "So, the linoleic acid in the guts is a signal [to the parasites] that says, 'Oh, I'm in a cat. This is where we have sexual reproduction.'"
Even if a host isn't gulped down by a cat, but a different animal instead, the parasite is passed on-and that is a net positive overall. That said, it's rare for humans to be eaten by cats, or anything for that matter. Why does the parasite affect us at all? It's possible that parasite-associated behavioral modifications in people evolved when feline predation was a significant threat to humans. They may also have evolved in other, more frequently consumed hosts and are just a side effect of infection in people.
Webster noted that some of the more severe T. gondii-associated pathologies, like schizophrenia, may arise because people and other animals live longer than rodents. That is, host-parasite interactions look 1 way in hosts like wild rodents that live for 2-3 years (if they're lucky), but very different in those that live for decades.
How Does T. gondii Manipulate Its Host?
Understanding how T. gondii infection alters host behavior has long been an important research topic. Over the years, scientists have uncovered a spate of mechanisms tied to parasitic factors and host responses, many of which likely interact and overlap with one another.
The Role of Dopamine
One prominent hypothesis is that T. gondii infection modifies levels of neurotransmitters involved in host functioning and behavior. Dopamine-a molecule that helps us feel pleasure, regulates mood, contributes to learning and attention and more-is of particular interest.
Rodents infected with T. gondii and patients with schizophrenia have altered dopamine levels. Moreover, dopamine receptor antagonists used to treat schizophrenia also prevent behavioral changes from developing in T. gondii-infected rats. Curiously, scientists discovered that the parasite itself produces an enzyme (tyrosine hydroxylase) that is central to dopamine production.
For Webster, this raised a question: are behavioral effects from T. gondii infection caused by parasite-produced dopamine, rather than just changes to host dopamine? Working with colleagues at Leeds University, her lab engineered strains of T. gondii to overexpress tyrosine hydroxylase at medium and high levels, testing how they impact the behavior of infected rats. To do this, they used a classic feline fatal attraction assay, in which rodents are placed in a box where 1 corner contains cat urine. Each of the other corners contain alternative odors, such their own urine, water or that of a non-definitive host urine (e.g., rabbits), thereby controlling for any response to smells in general. Researchers then measure how often the rats entered "the cat zone," and how long they spent there.
"We saw this sort of dose-dependent curve with the higher levels of overexpression [associated with] more time spent within the cat zone," Webster shared. "It is evidence that parasite-produced dopamine, and the tyrosine hydroxylase gene, is at least 1 component in parasite-altered behavior."
Next steps involve measuring dopamine levels in the brains of infected animals, and testing T. gondii strains with naturally varying levels of tyrosine hydroxylase production. Scientists are also exploring the roles of other neurotransmitters, like glutamate and gamma-aminobutyric acid (GABA), too.
Extracellular Vesicles and miRNAs
Host cells (and parasites) produce other products, not just neurotransmitters, that shape how the brain works-and may also be altered in the context of T. gondii infection. One example gaining attention among T. gondii researchers is microRNAs (miRNAs). These non-coding RNA fragments interact with mRNA to suppress expression of genes. MiRNAs can be packaged in extracellular vesicles (EVs) that blip off and are transported between host cells; EVs are known to be key mediators in T. gondii-induced neuronal alterations.
In a recent study, scientists found that human neuronal cells infected with T. gondii produced EVs harboring distinct miRNAs compared to non-infected cells. The miRNAs were associated with genetic pathways involved in neuronal excitability, synaptic plasticity (which is essential for learning and memory) and behavioral adaptation.
A separate study identified an EV-packaged miRNA that alters the microtubule and actin filaments of the cytoskeleton in both T. gondii infected and bystander cells, with implications for neuronal function. As such, EVs may facilitate the diffusion of molecular factors with behavioral ties. 
Hormones, the Microbiome and Co-Infections
Dopamine and EVs aside, the catalogue of potential mechanisms for parasite-associated behavioral changes also includes entries that are hormonal and microbial in nature. Indeed, like neurotransmitters and miRNAs, dysregulated hormone levels (e.g., testosterone) may alter neural processes tied to behaviors like predator aversion.
In addition, scientists are exploring how the gut microbiome modulates infection outcomes and plugs into existing hypotheses about altered behavior (e.g., neurotransmitter changes), perhaps by way of the gut-brain axis. The idea that other microbes shape T. gondii infection extends beyond the gut, too-one study found that rats co-infected with T. gondii and Porphyromonas gingivalis, a periodontal pathogen, had increased anxiety-like behavior and reduced cognitive function.
Infections by viral pathogens, like HIV-1 and cytomegalovirus, may also play a role. In an example from the animal world, Webster's team showed that Dopey Fox Syndrome-a condition in which foxes show reduced fear and increased affection-may stem from T. gondii infection in conjunction with other neurotropic agents, such as circovirus. How exactly these different agents interact to influence host responses and behavior requires additional investigation.
Studying One to Understand Many
There are a lot of reasons why illuminating the mechanisms of T. gondii-mediated behavioral changes is worthwhile. From a practical standpoint, it may give us a clearer understanding of the "how" and "why" behind certain animal and human behaviors, while offering new therapeutic touchpoints for mitigating the most severe T. gondii-associated pathologies (e.g., schizophrenia).
"It's still such a black box, because we don't even know how the brain works fully," Webster said. "If you look at the standard textbooks, and even some of the old clinical textbooks, they'll still say latent toxoplasmosis in people is asymptomatic … But if this is doing something to our risk behavior and our modulation, the implications could be really quite huge."
The implications extend beyond T. gondii, too. "There're lots of different intracellular pathogens, and a lot of them have evolved similar mechanisms," Knoll said, highlighting that phenomena like T. gondii's ability to form a parasitophorous vacuole that helps shield it from host responses are shared by other pathogens. T. gondii is also relatively easy to work with and genetically manipulatable. "Being able to understand the mechanisms that Toxoplasma uses will help us to understand how other intracellular pathogens manipulate their host as well."
But perhaps the simplest-and most relatable-reason why these insights are valuable: they're fascinating. That a microbe can evolve to transmit between and manipulate multiple organisms that are completely distinct from itself is an impressive biological feat. And in a time when public perception of science is on shaky ground, Knoll thinks the wonky world of parasites like T. gondii may be a way to bring people into the fold.
"Parasite interactions [are just] really cool," she said. "I think we all need to think about how we can make our science engaging. And I think parasites and host parasite interactions is really a field that can do that."
Parasites make our skin crawl-they can also eat it. Check out this next article to learn how international scientific collaboration halted the flesh-eating parasite New World screwworm, and how ongoing cooperation and unity is vital to continue protecting food, public health and economies.
