Researchers have developed a new way to install millions of human brain cells into mice, as a way of creating better scientific models for studying neurodegenerative disease. Using genetic tools, the scientists bred mice that were missing most of their cerebral cortexes – the outermost layer of the brain involved with reasoning, memory and consciousness. Then, they replaced a large part of those missing mouse cells with lab-grown human brain cells, creating mice with human neurons that can be altered to approximate human brain conditions researchers are eager to study.
"For the past two decades, there's been a quest to try to build models of the human brain outside of the human body," says Sergiu Pașca, professor of psychiatry and behavioral sciences at Stanford University and senior author on the paper, published in the journal Nature. "This is not going to replace all the models we had before, but it's going to provide us access to other aspects of human brain function that would be very difficult to study otherwise." Pașca says this research was conducted with strong ethical oversight and pushes research forward. At the same time, outside researchers point out that the development raises significant questions about where it could lead.
"It's really a powerful technology to study human neurons and how human brain circuits can form in a more natural environment" than a petri dish, says Hongkui Zeng, executive vice president and director of brain science at the Allen Institute in Seattle, Washington, who was not affiliated with the study. But "going forward, there will be some considerations, if not concerns," she added — such as the implications of deploying this technique in larger and longer-living animals. While it's not the first time human brain cells have been installed in mice, this new effort manages to connect significantly more human cells than before.
Previous attempts were limited by an enduring biological reality: Human brain cells develop at least 20 times slower than those in mice, Pașca says. That meant that neurons in a regularly developing mouse formed a rapid network, outcompeting the human cells that were dropped in. "By the time the human cells managed to extend a few millimeters, mice cells had already formed most of the connections, and brain development closed," Pașca says.
The team solved for this by breeding genetically engineered mice that were missing specific parts of their brains. "We thought we could provide the human cells more opportunities to connect by removing parts of the nervous system of the mouse in a very precise, very clean way," he says. To their surprise, the mice they bred were still quite functional: "They actually have quite good locomotion," Pașca says, "They don't do that well in memory tasks…[but] you wouldn't be able to tell when you look at these animals that they're lacking half of the volume of their brain." This part of the experiment shows the remarkable adaptability of developing brains, says Keng of the Allen Institute.
Animals missing their cerebral cortex — which governs higher-order brain function — aren't expected to do well on challenging tasks. These mice, however, developed alternative strategies using the remaining parts of the brain. "Surprisingly, the animal can adapt," she says, "It's incredible to see that." Next, the research team added small clumps of human neurons to the depleted mouse brains.
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