Human genes make mice smarter – gene promotes growth of the cerebral cortex and flexibility of memory

Turbo for the brain: By introducing only one human gene, researchers have given mice a higher level of intelligence and a larger brain. In behavioral tests, the animals showed more flexible memory and were less anxious. At the same time, their cerebral cortex was also significantly thicker – the part of the brain that controls higher mental functions. This suggests that this human-specific gene played a crucial role in the spiritual development of our ancestors.

We humans have an unusually large brain in relation to the body. Above all, the neocortex, the cerebral cortex, is as well developed in our species as it is not even in our closest relatives among the primates. The increase in volume of the cerebral cortex and the cerebellum, together with a better energy supply for the thinking organ, is therefore the basis of our intelligence. This raises the question of how the typical human brain developed.

Gene variant promotes neuronal formation

Scientists have long suspected that some gene variants that were active for only a few million years contributed to making the brains of our ancestors larger. One of these variants is the human-specific gene ARHGAP11B, which stimulates the increased formation of neuronal progenitor cells in the embryo: If it is introduced into the embryos of mice, ferrets or monkeys, their brains also become larger and richer in neurons.

Difference in size of neocortex between normal mouse (left) and the 11B mouse with human gene. © Xing et al./ EMBO Journal, CC-by-nc-nd 4.0

So far, however, it has not been clear whether this brain growth will continue into adulthood and whether this also gives the carriers of this gene a higher level of intelligence. Lei Xing from the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden and his colleagues have now investigated this in more detail. To do this, they smuggled the ARHGAP11B gene into mouse embryos and first observed how this affects the volume and the number of neurons in their developing brain.

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Larger neocortex and more gray cells

In fact, the mice with the human gene developed a permanently thicker and larger neocortex. The researchers report that there was an increase in the neurons in the top layer of the cerebral cortex in particular. In the next step, Xing and his team tested the intelligence of these mice. To do this, they put the animals through several behavioral tests that require different types of learning and memory.

These included classic labyrinth tests of spatial memory, but also tests of anxiety and mental flexibility. For the latter, the mice had to learn the pattern according to which access to different drinking bottles changed over time. “This test primarily tests long-term memory, which is based more on the neocortex than on the hippocampus,” the researchers explain.

Mentally more flexible and less anxious

The result: “We found that the ARHGAP11B mice, with their larger brain, made fewer mistakes when finding the water bottle than the wild-type mice,” reports Xing. “This indicates that the 11B mice have a more flexible memory and are better able to adapt to new conditions and rules.” While spatial learning per se hardly changed in these mice, the processing of what was learned in the cerebral cortex was apparently optimized .

At the same time, the 11B mice were also less anxious than their normal conspecifics: “Wild-type mice were more scared and tried to get out of the brightly lit center of the test facility into the protective edge zone as quickly as possible, while ARHGAP11B mice were more relaxed and longer stayed in the center, ”reports Xing.

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Decisive advantage for our ancestors

According to the researchers, this proves that the human-specific gene variant ARHGAP11B has a decisive influence on brain development and cognitive abilities. Because it only developed around five million years ago, after the human lineage was separated from that of the chimpanzees, it could have contributed to our ancestors increasingly cognitively differing from their primate relatives.

“Our study suggests that the enlargement of the neocortex caused by ARHGAP11B actually leads to better cognitive performance, which gives important clues about the role of this human-specific gene in human evolution,” says Xing’s colleague Wieland Huttner. (EMBO Journal, 2021; doi: 10.15252 / embj.2020107093)

Source: Max Planck Institute for Molecular Cell Biology and Genetics

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