Cave fish have long fascinated biologists because of their missing eyes and pale skin. Now, one researcher is studying them for another reason: Their behavior may provide clues to the genetic basis of some human psychiatric disorders. Last week at the 23rd International Conference on Subterranean Biology in Fayetteville, Arkansas, he demonstrated how drugs that help people with schizophrenia and autism similarly affect the fish.
“I think there is a lot of potential” for these fish to teach us about mental disorders, says David Culver, an evolutionary biologist at American University in Washington, D.C., who was not involved in the study. Culver adds that—like other work on the cause of cave fish blindness—the new research may also have implications for human disease.
A decade ago, the lead author on the new study, Masato Yoshizawa, wanted to understand brain evolution by investigating the effects of natural selection on behavior. The Mexican tetra (Astyanax mexicanus), a cave fish with very close surface relatives, seemed an excellent prospect for that work. Because the two populations can interbreed, it’s easier to pin down genes that might be related to the neural defects underlying behavioral differences. Such breeding studies are not possible in humans.
The blind cave fish differ from their surface relatives in several notable ways. They don’t have a social structure and they don’t school. Instead, they lead solitary lives—a behavior that makes sense given their lack of natural predators. They also almost never sleep. They are hyperactive, and—unlike other fish—they are attracted to certain vibrations in the water. Finally, they tend to do the same behavior over and over again and seem to have higher anxiety than their surface relatives.
Yoshizawa, now an evolutionary developmental biologist at the University of Hawaii, Manoa, has been testing whether these fish might be useful in understanding the genetic basis of schizophrenia or autism. Studies in typical model animals—mice—are rarely illuminating, because the rodents often still behave normally when researchers manipulate genes that should cause these disorders. But even without genetic tinkering, the fish already show certain "symptoms" of the diseases, such as sleeplessness, hyperactivity, and asocial behavior.
What’s more, 90% of the 101 classic risk factor genes for human psychiatric diseases are also found in the cave fish genome, according to Yoshizawa’s comparison of genomes and transcriptomes—surveys of active genes—in cave fish and humans. Fully one-third of those genes are more or less active in the cave fish than they are in the surface fish.
As a first step toward assessing this new model, Yoshizawa and others have treated cave fish with several psychiatric drugs. Three years ago, a French team showed that the antidepressant Fluoxetine (commonly known as Prozac) caused the fish to become more aggressive toward each other. Yoshizawa has now shown that Fluoxetine—along with the antipsychotic Clozapine—made the fish sleep more and swim around less. "Overall, these drug responses in cave fish are very similar to what you see in human patients," he said last week at the meeting in Fayetteville. "These are strong evidence that cave fish could be a good model for human psychiatric disease."
Now, he and his colleagues are studying larger numbers of cave fish with variation in these behaviors, in the hopes that they can tease out which versions of which genes are associated with the extremes of these behaviors. From there, they plan to study how those genes interact with each other and the environment to alter fish behavior. Combined with insights into gene expression, nerve connections, and imaging the neural activity, the work could help prune the long list of genes implicated in autism and schizophrenia, Yoshizawa says.
Of course, Yoshizawa faces a long road ahead. “As with any model system, cave fish has limitations,” says Houmam Araj, a program officer at the National Eye Institute in Bethesda, Maryland, who was not involved with the work. Fish and humans are separated by 400 million years of evolution, so the control of these behaviors may not be the same in humans and fish. Still, Culver says, “I think this is really exciting stuff.”