Is a transparent fish the future of brain science? This center is betting on it

Fluorescent proteins, seen inside this transparent Danionella fish, allow scientists to track processes in its brain and body. Researchers at a major brain science center hope that studying Danionella fish will reveal new information about the brain-behavior connection. Chie Satou/HHMI

Chie Satou/HHMI

One of the world's top centers for brain science is taking a huge gamble on a tiny, transparent fish.

The Howard Hughes Medical Institute's Janelia Research Campus near Washington, D.C., has announced an effort to use artificial intelligence and an unusual fish called Danionella to understand how the brain controls complex behaviors like social interaction.

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"It's a big, risky bet," says Gerry Rubin, Janelia's founding executive director and head of biology. "But that's what makes it interesting."

Janelia plans to triple the space dedicated to fish to 6,000 square feet, which will make room for thousands of new tanks. Leaders expect that the number of scientists working on Danionella is likely to rise from about 10 to 100 or more.

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The payoff, they say, will be worth it — because by watching an entire fish brain function in real time, researchers at Janelia hope to learn about exactly how the brain drives behavior in other species, including humans.

"We all evolved from fish, and our brains share many features of the brains of fish," says Nelson Spruston, Janelia's executive director.

The brain as a black box

In the race to understand our brains, Danionella has some key advantages over other more common lab critters like rodents.

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In most species, the brain is hidden by a skull and skin, making it hard to observe. Danionella fish, in contrast,lack the top part of their skull and have see-through skin.

But Danionella isn't nearly as well understood as other lab models, like zebra fish, which are larger and only transparent in their larval stage.

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That's in part because Danionella cerebrum, the species favored by neuroscientists, wasn't officially identified as a separate species until 2021. In recent years, though, it has begun appearing in more labs.

"Having an animal that has a clear head and a clear body [is] extremely useful for neuroscience," says Matt Lovett-Barron, a scientist who studies Danionella at the University of California, San Diego.

From flies to fish

Janelia is famous for its work on fruit flies, especially a 2024 project that led to the mapping of all 54.5 million connections in the insect's brain.

Now it's time for Janelia to take on a bold new challenge, says HHMI President Erin O'Shea — one that could help solve one of the fundamental mysteries of biology.

It's known as the brain-behavior question, and it asks how physical processes, like the firing of a neuron, can give rise to things like memory, experiences and decision-making.

Scientists at Janelia think the question can't be answered by just studying bits of an animal's brain.

"If you really want to understand how the brain is working as a whole, you really need to see all the neurons firing at once," Rubin says.

A transparent fish makes that easier, he says, but it also means researchers will be dealing with three times as many neurons as they did in fruit flies.

"This is going to produce so much data that we're going to need something like artificial intelligence to analyze it," Rubin says.

A new kind of science

Part of Janelia's plan is to create tools that will make it easier for scientists everywhere to study Danionella.

This means the center will have to create a map of every connection in the fish brain, much like the one that the center did for the fruit fly. It also means developing ways for scientists to work in partnership with artificial intelligence to make discoveries more quickly.

Right now, for example, scientists often immobilize Danionella fish to study their brains. Spruston says the scientists at Janelia want to change that.

"The ultimate goal is to do these experiments in freely swimming animals," he says. "That's going to require that we tackle some serious engineering challenges."

Scientists already studying Danionella would welcome those advances.

Lovett-Barron, for example, says new tools would help him study how the fish use visual information to synchronize their activity when they school.

"We place our animals into, effectively, virtual reality environments — like little video games with virtual social partners," he says.

Then the scientists watch as the fish brains manage the animals' busy social lives.

Better tools and techniques to monitor those brains would make the work go faster, Lovett-Barron says.

Even then, answering the brain-behavior question is a long-term goal, O'Shea says.

"I would be ecstatic if in 10 years we [understand] just one complex behavior in the fish, like schooling," she says.

Already, she says, Janelia scientists are making progress on other fronts, like monitoring the activity of lots of neurons simultaneously.

They've succeeded with larval zebra fish, which have about 80,000 neurons, she says. So it should be possible to scale up for adult Danionella fish, which have about 650,000.

Human brains, by comparison, have about 86 billion neurons.