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The smart mouse with the half-human brain

• 12:45 01 December 2014 by Andy Coghlan
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What would Stewart Little make of it? Mice have been created whose brains are half human. As a result, the animals are smarter than their siblings.

The idea is not to mimic fiction, but to advance our understanding of human brain diseases by studying them in whole mouse brains rather than in dishes.

The altered mice still have mouse neurons – the "thinking" cells that make up around half of all their brain cells. But practically all the glial cells in their brains, the ones that support the neurons, are human.

"It's still a mouse brain, not a human brain," says Steve Goldman of the University of Rochester Medical Center in New York. "But all the non-neuronal cells are human."

Rapid takeover

Goldman's team extracted immature glial cells from donated human fetuses. They injected them into mouse pups where they developed into astrocytes, a star-shaped type of glial cell.

Within a year, the mouse glial cells had been completely usurped by the human interlopers. The 300,000 human cells each mouse received multiplied until they numbered 12 million, displacing the native cells.

"We could see the human cells taking over the whole space," says Goldman. "It seemed like the mouse counterparts were fleeing to the margins."

Astrocytes are vital for conscious thought, because they help to strengthen the connections between neurons, called synapses. Their tendrils (see image) are involved in coordinating the transmission of electrical signals across synapses.

Human astrocytes are 10 to 20 times the size of mouse astrocytes and carry 100 times as many tendrils. This means they can coordinate all the neural signals in an area far more adeptly than mouse astrocytes can. "It's like ramping up the power of your computer," says Goldman.

Intelligence leap

A battery of standard tests for mouse memory and cognition showed that the mice with human astrocytes are much smarter than their mousy peers.

In one test that measures ability to remember a sound associated with a mild electric shock, for example, the humanised mice froze for four times as long as other mice when they heard the sound, suggesting their memory was about four times better. "These were whopping effects," says Goldman. "We can say they were statistically and significantly smarter than control mice."

Goldman first reported last year that mice with human glial cells are smarter. But the human cells his team injected then were mature so they simply integrated into the mouse brain tissue and stayed put.

This time, he injected the precursors of these cells, glial progenitor cells, which were able to divide and multiply. That, he says, explains how they were able to take over the mouse brains so completely, stopping only when they reached the physical limits of the space.

Species cross

"It would be interesting to find out whether the human astrocytes function the same way in the mice as they do in humans," says Fred Gage, a stem cell researcher at the Salk Institute in La Jolla, California. "It would show whether the host modifies the fate of cells, or whether the cells retain the same features in mice as they do in humans," he says.

"That the cells work at all in a different species is amazing, and poses the question of which properties are being driven by the cell itself and which by the new environment," says Wolfgang Enard of Ludwig-Maximilians University Munich in Germany, who has shown that mice are better at learning if they have the human Foxp2 gene, which has been linked with human language development.

In a parallel experiment, Goldman injected immature human glial cells into mouse pups that were poor at making myelin, the protein that insulates nerves. Once inside the mouse brain, many of the human glial cells matured into oligodendrocytes, brain cells that specialise in making the insulating material, suggesting that the cells somehow detected and compensated for the defect.

This could be useful for treating diseases in which the myelin sheath is damaged, such as multiple sclerosis, says Goldman, and he has already applied for permission to treat MS patients with the glial progenitor cells, and hopes to start a trial in 12 to 15 months.

Still a mouse

To explore further how the human astrocytes affect intelligence, memory and learning, Goldman is already grafting the cells into rats, which are more intelligent than mice. "We've done the first grafts, and are mapping distributions of the cells," he says.

Although this may sound like the work of science fiction – think Deep Blue Sea, where researchers searching for an Alzheimer's cure accidently create super-smart sharks, or Algernon, the lab mouse who has surgery to enhance his intelligence, or even the pigoons, Margaret Atwood's pigs with human stem cells – and human thoughts – Goldman is quick to dismiss any idea that the added cells somehow make the mice more human.

"This does not provide the animals with additional capabilities that could in any way be ascribed or perceived as specifically human," he says. "Rather, the human cells are simply improving the efficiency of the mouse's own neural networks. It's still a mouse."

However, the team decided not to try putting human cells into monkeys. "We briefly considered it but decided not to because of all the potential ethical issues," Goldman says.

Enard agrees that it could be difficult to decide which animals to put human brain cells into. "If you make animals more human-like, where do you stop?" he says.

Journal reference: Journal of Neuroscience, DOI: 10.1523/JNEUROSCI.1510-14.2014