TOXO [ROBERT SAPOLSKY:] In the endless sort of struggle that neurobiologists have — in terms of free will, determinism — my feeling has always been that there's not a whole lot of free will out there, and if there is, it's in the least interesting places and getting more sparse all the time. But there's a whole new realm of neuroscience which I've been thinking about, which I'm starting to do research on, that throws in another element of things going on below the surface affecting our behavior. And it's got to do with this utterly bizarre world of parasites manipulating our behavior. It turns out that this is not all that surprising. There are all sorts of parasites out there that get into some organism, and what they need to do is parasitize the organism and increase the likelihood that they, the parasite, will be fruitful and multiply, and in some cases they can manipulate the behavior of the host. Some of these are pretty astounding. There's this barnacle that rides on the back of some crab and is able to inject estrogenic hormones into the crab if the crab is male, and at that point, the male's behavior becomes feminized. The male crab digs a hole in the sand for his eggs, except he has no eggs, but the barnacle sure does, and has just gotten this guy to build a nest for him. There are other ones where wasps parasitize caterpillars and get them to defend the wasp's nests for them. These are extraordinary examples. The parasite my lab is beginning to focus on is one in the world of mammals, where parasites are changing mammalian behavior. It's got to do with this parasite, this protozoan called Toxoplasma. If you're ever pregnant, if you're ever around anyone who's pregnant, you know you immediately get skittish about cat feces, cat bedding, cat everything, because it could carry Toxo. And you do not want to get Toxoplasma into a fetal nervous system. It's a disaster. The normal life cycle for Toxo is one of these amazing bits of natural history. Toxo can only reproduce sexually in the gut of a cat. It comes out in the cat feces, feces get eaten by rodents. And Toxo's evolutionary challenge at that point is to figure out how to get rodents inside cats' stomachs. Now it could have done this in really unsubtle ways, such as cripple the rodent or some such thing. Toxo instead has developed this amazing capacity to alter innate behavior in rodents. If you take a lab rat who is 5,000 generations into being a lab rat, since the ancestor actually ran around in the real world, and you put some cat urine in one corner of their cage, they're going to move to the other side. Completely innate, hard-wired reaction to the smell of cats, the cat pheromones. But take a Toxo-infected rodent, and they're no longer afraid of the smell of cats. In fact they become attracted to it. The most damn amazing thing you can ever see, Toxo knows how to make cat urine smell attractive to rats. And rats go and check it out and that rat is now much more likely to wind up in the cat's stomach. Toxo's circle of life completed. This was reported by a group in the UK about half a dozen years ago. Not a whole lot was known about what Toxo was doing in the brain, so ever since, part of my lab has been trying to figure out the neurobiological aspects. The first thing is that it's for real. The rodents, rats, mice, really do become attracted to cat urine when they've been infected with Toxo. And you might say, okay, well, this is a rodent doing just all sorts of screwy stuff because it's got this parasite turning its brain into Swiss cheese or something. It's just non-specific behavioral chaos. But no, these are incredibly normal animals. Their olfaction is normal, their social behavior is normal, their learning and memory is normal. All of that. It's not just a generically screwy animal. You say, okay well, it's not that, but Toxo seems to know how to destroy fear and anxiety circuits. But it's not that, either. Because these are rats who are still innately afraid of bright lights. They're nocturnal animals. They're afraid of big, open spaces. You can condition them to be afraid of novel things. The system works perfectly well there. Somehow Toxo can laser out this one fear pathway, this aversion to predator odors. We started looking at this. The first thing we did was introduce Toxo into a rat and it took about six weeks for it to migrate from its gut up into its nervous system. And at that point, we looked to see, where has it gone in the brain? It formed cysts, sort of latent, encapsulated cysts, and it wound up all over the brain. That was deeply disappointing. But then we looked at how much winds up in different areas in the brain, and it turned out Toxo preferentially knows how to home in on the part of the brain that is all about fear and anxiety, a brain region called the amygdala. The amygdala is where you do your fear conditioning; the amygdala is what's hyperactive in people with post-traumatic stress disorder; the amygdala is all about pathways of predator aversion, and Toxo knows how to get in there. Next, we then saw that Toxo would take the dendrites, the branch and cables that neurons have to connect to each other, and shriveled them up in the amygdala. It was disconnecting circuits. You wind up with fewer cells there. This is a parasite that is unwiring this stuff in the critical part of the brain for fear and anxiety. That's really interesting. That doesn't tell us a thing about why only its predator aversion has been knocked outwhereas fear of bright lights, et cetera, is still in there. It knows how to find that particular circuitry. So what's going on from there? What's it doing? Because it's not just destroying this fear aversive response, it's creating something new. It's creating an attraction to the cat urine. And here is where this gets utterly bizarre. You look at circuitry in the brain, and there's a reasonably well-characterized circuit that activates neurons which become metabolically active circuits where they're talking to each other, a reasonably well-understood process that's involved in predator aversion. It involves neurons in the amygdala, the hypothalamus, and some other brain regions getting excited. This is a very well characterized circuit. Meanwhile, there is a well-characterized circuit that has to do with sexual attraction. And as it happens, part of this circuit courses through the amygdala, which is pretty interesting in and of itself, and then goes to different areas of the brain than the fear pathways. When you look at normal rats, and expose them to cat urine, cat pheromones, exactly as you would expect, they have a stress response: their stress hormone levels go up, and they activate this classical fear circuitry in the brain. Now you take Toxo-infected rats, right around the time when they start liking the smell of cat urine, you expose them to cat pheromones, and you don't see the stress hormone release. What you see is that the fear circuit doesn't activate normally, and instead the sexual arousal activates some. In other words, Toxo knows how to hijack the sexual reward pathway. And you get males infected with Toxo and expose them to a lot of the cat pheromones, and their testes get bigger. Somehow, this damn parasite knows how to make cat urine smell sexually arousing to rodents, and they go and check it out. Totally amazing. So on a certain level, that explains everything. Ah ha! It takes over sexual arousal circuitry. This is utterly bizarre. At this point, we don't know what the basis is of the attraction in the females. It's something we're working on. Some extremely nice work has been done by a group at Leeds in the UK, who are looking at the Toxo genome, and we're picking up on this collaboratively. Okay, Toxo, it's a protozoan parasite. Toxo and mammals had a common ancestor, and the last they did was God knows, billions of years ago. And you look in the Toxo genome, and it's got two versions of the gene called tyrosine hydroxylase. And if you were a neuro-chemistry type, you would be leaping up in shock and excitement at this point. Tyrosine hydroxylase is the critical enzyme for making dopamine: the neurotransmitter in the brain that's all about reward and anticipation of reward. Cocaine works on the dopamine system, all sorts of other euphoriants do. Dopamine is about pleasure, attraction and anticipation. And the Toxo genome has the mammalian gene for making the stuff. It's got a little tail on the gene that targets, specifies, that when this is turned into the actual enzyme, it gets secreted out of the Toxo and into neurons. This parasite doesn't need to learn how to make neurons act as if they are pleasurably anticipatory; it takes over the brain chemistry of it all on its own. Again that issue of specificity comes up. Look at closely related parasites to Toxo: do they have this gene? Absolutely not. Now look at the Toxo genome and look at genes related to other brain messengers. Serotonin, acetylcholine, norepinephrine, and so on, and you go through every single gene you can think of. Zero. Toxo doesn't have them, Toxo's got this one gene which allows it to just plug into the whole world of mammalian reward systems. And at this point, that's what we know. It is utterly cool. Of course, at this point, you say well, what about other species? What does Toxo do to humans? And there's some interesting stuff there that's reminiscent of what's going on in rodents. Clinical dogma is you first get a Toxo infection. If you're pregnant, it gets into the fetal nervous system, a huge disaster. Otherwise, if you get a Toxo infection, it has phases of inflammation, but eventually it goes into this latent asymptomatic stage, which is when these cysts form in the brain. Which is, in a rat, when it stops being anything boring like asymptomatic, and when the behavior starts occurring. Interestingly, that's when the parasite starts making this tyrosine hydroxylase. So what about humans? A small literature is coming out now reporting neuropsychological testing on men who are Toxo-infected, showing that they get a little bit impulsive. Women less so, and this may have some parallels perhaps with this whole testosterone aspect of the story that we're seeing. And then the truly astonishing thing: two different groups independently have reported that people who are Toxo-infected have three to four times the likelihood of being killed in car accidents involving reckless speeding. In other words, you take a Toxo-infected rat and it does some dumb-ass thing that it should be innately skittish about, like going right up to cat smells. Maybe you take a Toxo-infected human and they start having a proclivity towards doing dumb-ass things that we should be innately averse to, like having your body hurdle through space at high G-forces. Maybe this is the same neurobiology. This is not to say that Toxo has evolved the need to get humans into cat stomachs. It's just sheer convergence. It's the same nuts and bolts neurobiology in us and in a rodent, and does the same thing. On a certain level, this is a protozoan parasite that knows more about the neurobiology of anxiety and fear than 25,000 neuroscientists standing on each other's shoulders, and this is not a rare pattern. Look at the rabies virus; rabies knows more about aggression than we neuroscientists do. It knows how to make you rabid. It knows how to make you want to bite someone, and that saliva of yours contains rabies virus particles, passed on to another person. The Toxo story is, for me, completely new terrain — totally cool, interesting stuff, just in terms of this individual problem. And maybe it's got something to do with treatments for phobias down the line or whatever it is to make it seem like anything more than just the coolest gee whiz thing possible. But no doubt it's also a tip of the iceberg of God knows what other parasitic stuff is going on out there. Even in the larger sense, God knows what other unseen realms of biology make our behavior far less autonomous than lots of folks would like to think. With regard to parasite infections like Toxo in humans, there is a big prevalence in certain parts of the world. There's a higher prevalence in the tropics, where typically more than 50 percent of people are infected. Lower rates in more temperate zones for reasons that I do not understand and do not choose to speculate on. France has really high rates of Toxo infection. In much of the developing world, it's bare feet, absorbing it through soil, where cats may have been. It's food that may not have been washed sufficiently and absorption through hands. It's the usual story that people in the developing world are more subject to all sorts of infectious stuff. A few years ago, I sat down with a couple of the Toxo docs over in our hospital who do the Toxo testing in the Ob/Gyn clinics. And they hadn't heard about this behavioral story, and I'm going on about how cool and unexpected it is. And suddenly, one of them jumps up, flooded with 40-year-old memories, and says, "I just remembered back when I was a resident, I was doing a surgical transplant rotation. And there was an older surgeon, who said, if you ever get organs from a motorcycle accident death, check the organs for Toxo. I don't know why, but you find a lot of Toxo." And you could see this guy was having a rush of nostalgic memories from back when he was 25 and all because he was being told this weird factoid ... ooh, people who die in motorcycle accidents seem to have high rates of Toxo. Utterly bizarre. What is the bottom line on this? Well, it depends; if you want to overcome some of your inhibitions, Toxo might be a very good thing to have in your system. Not surprisingly, ever since we started studying Toxo in my lab, every lab meeting we sit around speculating about which people in the lab are Toxo-infected, and that might have something to do with one's level of recklessness. Who knows? It's very interesting stuff, though. You want to know something utterly terrifying? Here's something terrifying and not surprising. Folks who know about Toxo and its affect on behavior are in the U.S. military. They're interested in Toxo. They're officially intrigued. And I would think they would be intrigued, studying a parasite that makes mammals perhaps do things that everything in their fiber normally tells them not to because it's dangerous and ridiculous and stupid and don't do it. But suddenly with this parasite on board, the mammal is a little bit more likely you go and do it. Who knows? But they are aware of Toxo. There are two groups that collaborate in Toxo research. One is Joanne Webster, who was at Oxford at the time that she first saw this behavioral phenomenon. And I believe she's now at University College London. And the other is Glenn McConkey at University of Leeds. And they're on this. She's more of a behaviorist, he's more of an enzyme biochemist guy. We're doing the neurobiology end of it. We're all talking lots. There's a long-standing literature that absolutely shows there's a statistical link between Toxo infection and schizophrenia. It's not a big link, but it's solidly there. Schizophrenics have higher than expected rates of having been infected with Toxo, and not particularly the case for other related parasites. Links between schizophrenia and mothers who had house cats during pregnancy. There's a whole literature on that. So where does this fit in? Two really interesting things. Back to dopamine and the tyrosine hydroxylase gene that Toxo somehow ripped off from mammals, which allows it to make more dopamine. Dopamine levels are too high in schizophrenia. That's the leading suggestion of what schizophrenia is about neurochemically. You take Toxo-infected rodents and their brains have elevated levels of dopamine. Final deal is, and this came from Webster's group, you take a rat who's been Toxo-infected and is now at the state where it would find cat urine to be attractive, and you give it drugs that block dopamine receptors, the drugs that are used to treat schizophrenics, and it stops being attracted to the cat urine. There is some schizophrenia connection here with this. Any time Toxo's picked up in the media, and this schizophrenia angle is brought in, the irresistible angle is the generic crazy cat lady, you know, living in the apartment with 43 cats and their detritus. And that's an irresistible one in terms of Toxo psychiatric status: cats. But God knows what stuff is lurking there.