Rat cells grew in mice brains, and helped sniff out cookies

Chimeric mice are helping to reveal the biology of flexible brain development

A photograph of two mice looking in the direction of the camera, one brown mouse on the left and one brown and white mouse on the right.

A mouse (right) was genetically tweaked to have no forebrain, usually a lethal condition. But rat cells helped populate its brain, a new study shows. Rat cells were less likely to integrate into the mouse on the left, which didn’t have the genetic tweak.

J. Huang et al/Cell 2024

What does it feel like to be a rat? We will never know, but some very unusual mice may now have an inkling.

In a series of new experiments, bits of rat brain grew inside the brains of mice. Donor stem cells from rats formed elaborate — and functional — neural structures in mice’s brains, despite being from a completely different species, researchers report in two papers published April 25 in Cell.

The findings are “remarkable,” says Afsaneh Gaillard, a neuroscientist at INSERM and the University of Poitiers in France. “The ability to generate specific neuronal cells that can successfully integrate into the brain may provide a solution for treating a variety of brain diseases associated with neuronal loss.”

These chimeric mice are helping to reveal just how flexible brain development can be (SN: 3/29/23). And while no one is suggesting that human brains could be grown in another animal, the results may help clarify biological details relevant to interspecies organ transplants, the researchers say.

The success of these rat-mouse hybrids depended on timing: The rat and mouse cells had to grow into brains together from a very young stage. Stem cells from rats that had the potential to mature into several different cell types were injected into mouse embryos. From there, these rat cells developed alongside mice cells in the growing brain, though researchers couldn’t control exactly where the rat cells ended up.

In one set of experiments, researchers first cleared the way for these rat cells to develop in the young mouse brains. Stem cell biologist Jun Wu and colleagues used a form of the genetic tool CRISPR to inactivate a mouse gene that instructs their brain cells to build a forebrain, a large region involved in learning, remembering and sensing the world. This left the mice without forebrains — normally, a lethal problem.

But rat stem cells could fill the void in these mice. “The chimeras can live a normal life, up to two years that we analyzed,” says Wu, of the University of Texas Southwestern Medical Center in Dallas. These mice seemed to behave normally, and their forebrains were the right size and shape. Gaillard points out, however, that more detailed studies are needed to say how similar these rat cells are to the mouse cells they replace.

This colorful slice of a mouse brain shows where rat brain cells have taken hold in the animal's structures that detect smells. Structures that show up as red circles in the image were formed by the rat cells.
Structures made of rat nerve fibers (red circles) that help animals sense particular odor molecules formed in the brains of mice, alongside a mix of structures made of rat and mouse nerve fibers (orange) or just mouse (green). This hybrid mouse-rat smell system can help scientists understand how flexible brains can be.Ben Throesch

In other experiments, mice put rat cells to good use by sniffing out buried cookies.

In this work, neuroscientist Kristin Baldwin of Columbia University and her colleagues focused on brain areas that handle smells (SN: 6/18/20). The team put donor rat stem cells into embryos of mice engineered to have damaged smell systems. To their surprise, in some mice, these rat cells knit themselves into neural circuits that allowed the mice to sniff out and dig up a buried Oreo cookie.

Some clusters of nerve cell endings that help animals sense odors were built solely from rat cells in these mice, the researchers found. And in some animals, random chance had made it so half the brain was made strictly of mouse cells while the other half had rat cells. In these cases, “the rat [cells were] really driving the brain to respond,” Baldwin says. “That was pretty cool that half of its brain was smelling, and half of it wasn’t.”

In both studies, a close look at the rat donor cells showed that they adopted many of the traits of surrounding mouse cells. Rat cell size, growth timing and cellular targets looked less like rat cells and more like mouse cells, the researchers found. That suggests the environment the cell grows up in can strongly influence the cell, regardless of its species identity.

Cells in a mouse's hippocampus make up a swirly pattern. Rat cells appear red, and all cells are labeled with blue.
In many ways, rat cells (red) behaved like the resident mouse cells, researchers found. Here, the rat cells make cellular connections in the mouse’s hippocampus, a memory and navigation center in the mouse’s brain. All cells’ nuclei are marked with blue.Ben Throesch

The results tug at deep philosophical questions about what it might be like to have part of another species’ brain, Baldwin says. She points to an essay by philosopher Thomas Nagel, “What is it like to be a bat?” Without a bat’s brain, Nagel argues, it’s impossible to ever really know. “We gave the mouse basically a version of that: What is it like to be a rat?” Baldwin says. “So it’s got some of a rat’s brain, and it is using it to do its most fundamental task, which is to find food.”

The results go beyond the philosophical. By figuring out the details of interspecies cell transfers, researchers hope to learn more about how brains evolve and develop. Wu is keen to study the brains of wild rodents, including the African pygmy mouse. It has a tiny brain, commensurate with a body that’s about 6 to 8 centimeters long. Wu wonders if stem cells from this minuscule mouse would grow larger forebrains if grown inside the head of a regular house mouse.

The new results could also lead to insights on brain cells’ flexibility, Baldwin says. “We were very delighted to find out that there were unknown aspects of brain plasticity.” And those insights “lead us to think this kind of approach would be very informative for future attempts to fix human brains.”

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

More Stories from Foogue on Neuroscience