High in the cloud forests of Costa Rica, there's a species of mouse that sings call-and-response duets, similar to the high-speed back and forth humans engage in with conversation. Now scientists have pinpointed the precise brain circuit responsible for this behavior, which may lead to fresh insights into how humans converse, according to a new paper in Science.

Co-author Michael Long of New York University's School of Medicine calls this conversational back and forth "turn talking," likening it to hitting a tennis ball back and forth over a net between two players. "If I were to summarize [the results] in one sentence, I'd say this is the first demonstration of the neural mechanisms that lead to coordinated vocal turn-talking in the mammalian brain," he said. "Our strong prediction from the mouse study is that a similar kind of vocal coordination center may exist in the human brain as well."

Long's lab specializes in the study of vocal communication, something at which human beings excel. We don't often stop to think about the intricate neural processing even a simple conversation requires. The pause time between when one speaker finishes and another begins—called "floor transfer time"—is just 200 milliseconds. But one in ten people experiences some form of communication disorder, whether due to a stroke or a developmental disorder like autism.

It's difficult to study this with humans because of the enormous complexity of the human brain. But certain animal species also exhibit turn-talking, including frogs, bottlenose dolphins, Bush crickets, and a few primates. Alas, the standard species of laboratory mouse (Mus musculus) does not exhibit this behavior. "They don't have vocal coordination in any meaningful way," said Long.

Then an evolutionary biologist at the University of Texas, Austin, named Steve Phelps told him about the singing mice he'd encountered doing field work in the cloud forest of Costa Rica. It's less singing and more of a chirping call and response behavior, or "counter singing." (It would be easy to mistake them for insects.) And it's loud, which is unusual in mice. Typical lab mice occasionally make vocalizations in the ultrasound range, but "it's just kind of random wheezing," said Long. "What is clear here is a kind of purposeful conversational interchange," likely as a means of marking territory.

They're “kind of divas”

So they brought several of the singing mice to New York City. Long admits the mice require a bit more luxurious accommodation: "They're singers, they're kind of divas." But give them bigger cages with better exercise equipment so they don't get fat, and a special diet of mealworms and insects, and they will thrive, even breed in captivity, all the while singing their little rodent hearts out.

Long and his team carefully documented the singing behavior, noting the elaborate dueting in particular. Not only do the mice take turns, but each mouse's song will change slightly in response to that of the other. Keen to uncover the brain mechanism behind this behavior, the team first had to figure out which parts of the brain were involved. They used a technique called electromyography, stimulating different parts of the cortex and recording the activity of vocal muscles at the same time.

That's how Long et al. identified a "hot spot": a motor region in the front of the brain called the orofacial motor cortex (OMC) that seems to be responsible for flexing the vocal muscles. Along with the region telling the muscles to make notes, there are other, separate circuits in the motor cortex that make the fast starts and stops possible—that is, the ability of the mice to engage in "turn talking" and have a "conversation."

"The mouse actually breaks this complex problem into two parts," said Long. "There's one part of the brain that creates the song itself, and another part, the OMC, which is important for vocal coordination."

"Two individual mice can be like Simon and Garfunkel and create a duet with each other."

To test this hypothesis, Long's postdoc and co-author Arkarup Banerjee dosed the "hot spot" with muscimol, a psychoactive component found in certain kinds of mushrooms. This turned the hot spot off for several minutes. Once that happened, the mice could still sing but could no longer coordinate their songs into a turn-talking duet with other mice.

They also made use of a technique called focal cooling. They used it to selectively cool a small part of a bird's brain to determine whether that region could be serving as a kind of "timer" for the birdsong. "We're not turning it off, we're taking what we think is acting like a clock and making it run more slowly," said Long. "Imagine running in molasses or something like that." And the birds did indeed start singing in slow motion, slower each time Long and his cohorts lowered the temperature a few degrees. Focal cooling has also been used on epileptic human subjects undergoing neurosurgery, when Long's lab partnered with neurosurgeon Dr. Jeremy Greenlee of the University of Iowa.

With the singing mice, they cooled just the OMC region—the part acting as a coordinator for the song. "When we do that, the mice can still sing the same song, but now they're getting through it much more slowly," said Long. That's strong evidence that the song itself is indeed stored in a different place, and the OMC is regulating the song. "It's a way of having executive control over how the song works, so that two individual mice can be like Simon and Garfunkel and create a duet with each other," he said.

"From an evolutionary perspective, the study... supports the hypothesis that cortical control over vocal motor networks has gradually increased during the evolution of vocal motor systems in mammals," Steffan Hage of the University of Tubingen in Germany wrote in an accompanying perspective on the implications the study's findings. "However, it appears to have started much earlier than previously thought." Hage believes the singing mouse "adds a novel model system" for further research into vocal communication in animals.

This doesn't mean they have found the solution to complicated communication disorders resulting from stroke or autism. "Have we solved these kinds of disorders? We haven't. Do we have a new tool in the fight? We sure do," said Long. "That's what fills me with hope."

So what's next for Long and his team? "We've been studying the human brain for a few years now, and what the mouse study has taught us is that we really need to study the human brain in the context of interaction," said Long. His lab is currently working with human subjects, recording brain activity as the subjects are talking to one another, rather than simply repeating a syllable or string of words, or similar trained linguistic tasks commonly used when studying language in the brain. "Just tell me what you had for lunch today," said Long. "Let's talk back and forth and see how the brain actually creates this kind of conversational exchange."

Long laments that over the last couple of decades, the diversity of lab animals studied by researchers has narrowed to focus largely on the standard laboratory mouse, driven in part by the fact that a lot of technology has been specifically designed to work with these creatures. Had he not looked to a different rodent, these new insights might have never been gleaned. "I think over-fitting to one animal is dangerous," said Long. "Here's a clear case where the laboratory mouse doesn't have the behavior that we find to be absolutely fascinating. I hope that in the ensuing years, people will take bigger risks and re-embrace the larger world of biology."

DOI: Science, 2019. 10.1126/science.aau9480 (About DOIs).