Rat neurons thrive in a mouse brain world, testing ‘nature versus nurture’

Some questions about neurons, such as how they give rise to behavior, are tricky to answer when those cells are embedded within their natural milieu.

“Is residence in a nervous system sufficient to allow synapses to form?” says Kristin Baldwin, professor of genetics and development at Columbia University. “Are synapses that we can see sufficient to allow communication? And is synaptic communication sufficient to actually endow an animal with a set of behaviors that would be appropriate for it?”

The best way to answer those questions is to put the cells in a new environment where their extrinsic and intrinsic influences can be teased apart, says Xin Jin, assistant professor of neuroscience at the Scripps Research Institute.

For a long time, Jin says, that new environment was the unnatural setting of a petri dish. But two new studies that make use of chimeric mice—animals with both mouse and rat cells in their brain—point to another option: One demonstrates how rat stem cells can restore a mouse’s ability to smell, whereas the other shows how rat stem cells can give rise to a forebrain in mice that would otherwise lack one. The studies were published last month in Cell. Because rat brains are larger than mouse brains and develop at a different rate, the chimeras enable researchers to probe the competing forces of a cell’s intrinsic programming and its external environment.

The work opens up doors for new research and the ability to explore the origins of species-specific cellular behaviors, says Jin, who was not involved in either study.

“It’s sort of a fundamental ‘nature versus nurture,’” says Baldwin, who led one of the new studies.

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aldwin and her colleagues engineered mice with olfactory sensory neurons—the cells in the nose that detect odors—that had been either genetically killed or, through expression of a neurotoxin, synaptically silenced. They then injected both groups of developing mouse blastocysts with embryonic stem cells from rats—a technically challenging feat, Jin says.

The rat cells successfully integrated themselves into olfactory circuits whether the mouse’s olfactory sensory neurons were absent or silent, Baldwin and her colleagues found. But animals with silenced olfactory neurons could not find a buried cookie by scent alone, whereas those that lacked those cells could put those new rat neurons to use.

The distinction may point to some competition between remaining mouse cells and the introduced rat cells, Baldwin says. “That alone gives us a new handle on what are the pathways and molecules and cellular responses that are consistent with a functional rescue, and those maybe that are not,” she adds.

Rat stem cells can also grow to replace entire structures missing in a mouse brain, according to the second study. Researchers injected the cells into the blastocysts of mice engineered to lack the gene HESX1, which is essential for the development of the forebrain. On their own, mice lacking HESX1 have no forebrain and do not survive past birth. But when the rat cells are present, the team found, they grow alongside mouse cells and help form a forebrain—and the mice survive and behave typically.

Both studies point to the fact that “the rat and mouse neurons can functionally connect to each other,” says Jun Wu, associate professor of molecular biology at the University of Texas Southwestern, who contributed to the olfactory sensory neuron study and led the forebrain study.

Rat-cell-generated forebrains grow to standard mouse size and at standard mouse rate, Wu and his team found, suggesting that the environment drives their development. “You would expect there is some incompatibility or differences in differentiation, speed and pace that may disrupt the formation of the proper forebrain. But we did not observe that,” he says.

Rat cells that grew in the environment of the mouse brain also adopted the birth dates of their surrounding tissues, Baldwin and her colleagues found.

In other cases, however, the cells’ intrinsic programming seemed to win out. For example, compared with rats, mice have fewer clusters of odor-receptive neurons, called glomeruli, in their olfactory system. But the chimeric mice developed extra glomeruli, suggesting that the rat cells are influencing that aspect of development. Although the researchers did not test whether these glomeruli were functional, “they have rat-specific potential for coding for information that mice might not normally sense,” Baldwin says.

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hese chimeric approaches could be useful for understanding cell-environment interactions that happen in cell therapies, says Ruslan Rust, assistant professor of research in physiology and neuroscience at the Keck School of Medicine of the University of Southern California, who was not involved in the work.

Rust and his colleagues recently identified molecular signals from grafts of human stem cells that influence the surrounding brain tissue in a mouse model of stroke. “There are certain limitations to xenograft transplantations” that chimeras could help overcome, he says.

The development of these chimeras also raises ethical questions, especially if human neurons are introduced, Wu says, but “I don’t think this is the direction that this particular research is going. We don’t think we want to—or anybody ever wants to—generate human brain tissue in pigs.”

Instead, the goal is to gain insight into the origins of species differences, he adds. He says he hopes to test whether neurons from diurnal species influence the sleep habits of a nocturnal species, like mice, for example—all without having to house full colonies of the other species.

“That’s exciting to me,” Wu says. It makes it possible for researchers “to have access to brain tissue from other species that are not traditionally housed in a laboratory setting.”