The brain of mammals is known to be equipped with a built-in GPS system: “place cells” in the hippocampus that are selectively activated when an animal enters a particular location and enable spatial perception.

A comparable navigation system had not previously been described in fish.

It turns out that zebrafish larvae also have place cells that integrate multiple sources of information and create new cognitive maps when the animal’s environment changes. This is the result of a study published today in Nature.

The search for these cells in fish became “almost a kind of myth,” says study co-leader Jennifer Li, a research group leader at the Max Planck Institute for Biological Cybernetics. She and her team were initially hesitant to look for place cells in fish, Li says, “because we thought if nobody sees them after all this time,” they might not exist.

But Li and her colleagues had already developed a custom-built microscope that tracks calcium signals in the brains of zebrafish larvae as they freely swim. This device allowed them to precisely locate the place cells in the larvae’s telencephalon.

“I certainly find this work extremely interesting because it shows that you can find place cells in at least some fish,” says Ronen Segev, a professor of biological sciences at Ben-Gurion University of the Negev who was not involved in the study.

The finding also suggests that spatial perception has its origins deep in the vertebrate evolutionary tree, Li says. There is a notion that “the hippocampus and cortex are these structures that evolved at some point to enable flexible behavior,” but evolutionarily “it was never clear when that happened.”

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Free-roaming rats first led the way to the discovery of place cells in 1971 (for which John O’Keefe received the Nobel Prize in Physiology or Medicine in 2014). The cells were found in other mammals in the 2000s and, as recently as 2021, in sperm-storing birds.

But finding similar cells in fish has proved more difficult – in part because it is not even clear whether fish have a hippocampal analogue in their brains. And because there is no easy way to track neural activity while the fish are moving freely in the water, there have been few attempts to use electrophysiology in adult fish. For zebrafish larvae, researchers often immobilize the animals in an agarose gel under a microscope.

Li’s tracking microscope, however, could overcome this second hurdle. “In hindsight, we asked ourselves: Why didn’t we look for place cells earlier?” says Drew Robson, a research group leader at the Max Planck Institute for Biological Cybernetics, who co-led both the new work and the microscope development with Li (Robson and Li share a lab).

The team focused on the telencephalon, Li says, because in fish, when this structure is removed, spatial learning is impaired, although other forms of learning are preserved, as experiments from the 1990s show.

Certain cells in the telencephalon region appeared to show “spatial specificity” when the zebrafish larvae swam for 90 minutes in a transparent chamber the size of a matchbox with two visible landmarks. Moreover, they found that the activity of these cells could be predicted based on the animal’s position in the chamber.

However, to be sure that one of these cells was a place cell, the team had to demonstrate “that it responds to different things in its environment, but does not fall apart when one of them is disturbed,” says Robson.

In fact, the cells maintained their spatial activity map even after the researchers removed or altered the chamber’s visual landmarks or changed the chamber’s boundaries. This suggests that these cells do not rely exclusively on visual cues. Similar to mammals, the experiments showed, zebrafish larvae integrate both visual and non-visual information in their place cells.

The zebrafish’s place cells also remapped when the visual environment was drastically changed, as is the case in the classic mammalian species. This finding supports the idea that the place cells “may form a flexible memory or prediction system,” the researchers wrote in the paper.

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The work with zebrafish larvae is just the beginning, Li says. “This has to be a collaborative effort, because if many different fish and reptile species actually all have place cells, then I would say we are probably dealing with an initial state. Something like a primitive hippocampal cortex structure,” she says.

According to a study published last year, goldfish do not appear to have place cells in the telencephalon; instead, they have cells for spatial calculation, so-called boundary vector cells.

But “it could be that we haven’t yet challenged the goldfish in the right environment to see (place cells),” says Segev, who led that study. Or different species may not have the same place cell types, he says, “so you’ll find different behaviors and different coding schemes in different animals.”

More behavioral studies could help guide future work, says Luigi Petrucco, a postdoctoral fellow at the Italian Institute of Technology who was not involved in the place cell study but recently published a study on head direction cells in zebrafish larvae. “I didn’t expect to find (place cells), and the fact that we found them is actually super, super exciting,” he adds.