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To Make Mice Smarter, Add A Few Human Brain Cells

For more than a century, neurons have been the superstars of the brain. Their less glamorous partners, glial cells, can't send electric signals, and so they've been mostly ignored.

Now scientists have injected some human glial cells into the brains of newborn mice. When the mice grew up, they were faster learners. The study, published Thursday in Cell Stem Cell, not only introduces a new tool to study the mechanisms of the human brain, it supports the hypothesis that glial cells — and not just neurons — play an important role in learning.

These drawings by Santiago Ramon y Cajal, published in 1899, show cortex neurons.
Santiago Ramon y Cajal / Wikimedia Commons
Wikimedia Commons
These drawings by Santiago Ramon y Cajal, published in 1899, show cortex neurons.

The scientific obsession with neurons really began at the end of the 19th century. Spanish anatomy professor Santiago Ramon y Cajal used a special dye to stain brain tissue. Under the microscope, neurons were revealed in exquisite detail. "A dense forest," Ramón y Cajal called it — a field of little branching cells that would soon be named neurons.

With beautiful ink drawings, Ramón y Cajal painstakingly mapped neural networks and slowly developed the theory that neurons are the telegraph lines of thought (an idea later embraced by Schoolhouse Rock). Every idea and memory — every aspect of learning — could be traced back to the electric signals sent between neurons.

Ramón y Cajal won the Nobel Prize for his work, and scientists focused on neurons for the next century.

But neurons aren't the only cells in the brain.

"We've overlooked half the brain," says Douglas Fields, a neuroscientist at the National Institutes of Health. "We've only been studying one kind of cell in the brain."

The other kind of cell — glial cells — are at least as abundant as neurons. But early scientists thought they were so boring they didn't even merit a singular noun.

"Glia is plural — there is no singular," Fields says. "We have 'neuron' but we don't have 'glion.' "

Glial cells lacked the ability to send electric signals, and most scientists thought they were housekeeping cells, helping provide nutrients and insulation.

It was only in the last decade or so that scientists realized glial cells were more than that. Special types of glial cells, called astrocytes, which are named for the star-like patterns of their cellular structure, have their own form of chemical signaling. They have the potential to coordinate whole groups of neurons.

"Glia are in a position to regulate the flow of information through the brain," Fields says. "This is all missing from our models."

And there's something else. This type of glial cell, these astrocytes, have changed a lot as humans have evolved, while neurons have pretty much stayed the same. A mouse neuron and a human neuron look so much alike, even experienced neuroscientists can't tell them apart.

"I can't tell the differences between a neuron from a bird or a mouse or a primate or a human," says Steve Goldman, a neuroscientist at the University of Rochester who has studied brain cells for decades.

But Goldman says glial cells are easy to tell apart.

"Human glial cells — human astrocytes — are much larger than those of lower species," he says. "They have more fibers and they send those fibers out over greater distances."

The thought is maybe these glial cells have played a role in making humans smarter. So Goldman teamed up with this wife, Maiken Nedergaard, to test this idea.

They injected some human glial cells into the brains of newborn mice. The mice grew up, and so did the human glial cells. The cells spread through the mouse brain, integrating perfectly with mouse neurons and, in some areas, outnumbering their mouse counterparts. All the while Goldman says the glial cells maintained their human characteristics.

"They very much thought that they were in the human brain, in terms of how they developed and integrated," he says.

So what are these mice like, the ones with brains full of functioning human cells? Their neural circuitry is still just the same, so they act completely normal. They still socialize with other mice and still seem interested in mousey things.

But the researchers say these mice are measurably smarter. In classic maze tests, they learn faster. "They make many fewer errors, and it takes them less time to come to the appropriate answer," Goldman says.

It might take a normal mouse four or five attempts to learn the correct route, for example. But a mouse with human brain cells could get it on the second try. Glial cells — those boring glial cells — somehow enhance learning.

In fact, they could be changing what it means to be a mouse, and that raises ethical questions for this kind of research.

"Maybe bioethicists have been a little bit too cavalier assuming that a mouse with some human brain cells in it is just your normal old mouse," says Robert Streiffer, a bioethicist from the University of Wisconsin-Madison. "Well, it's not going to be human, but that doesn't mean it's a normal old mouse either."

Streiffer says it's not just that these mice can get through a maze more quickly — they're better at recognizing things that scare them. And perception of fear is one of the things bioethicists must weigh when they decide the types of experiments you can do on an animal.

"So you have to sort of step back and do some hardcore philosophy," he says. Like, will these types of human-animal hybrids eventually get close enough to humanity that we would feel uncomfortable performing experiments on them?

The researchers in this study say we're really, really far from that point. And if you want to investigate the role of glial cells, these hybrid mice are the best tools available.

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