The mouse brain has served as a workhorse for the study of synaptic circuits and connectomics. However, the human cerebral cortex houses 1,000 times more neurons than that of a mouse. And the differences in the connectome between these species are still poorly understood.

Now, neuroscientists have gained insights into human neural circuitry using tissue obtained from neurosurgical interventions. They used 3D electron microscopy to study the cell type composition and synaptic circuit architecture of mouse, macaque, and human cortical samples. The data revealed a novel expanded network of interneurons in humans compared to mouse. The discovery of this prominent network in the human cortex encourages further detailed analysis of its function in health and disease.

This work is published in Science in the paper, “Connectomic comparison of mouse and human cortex.

In some ways, the brains of mouse and human are similar: the neurons have similar shapes and properties, the molecular mechanisms of electrical excitation are highly conserved, and many biophysical phenomena found in other species seem to also apply to human brains.

“So, is it primarily the fact that our brains are 1,000-fold larger, house 1000-fold more nerve cells that allows us to play chess and write children’s books, which mice arguably cannot do?” asks Moritz Helmstaedter, MD, director of the department of connectomics at the Max Planck Institute for Brain Research in Frankfurt.

By analyzing the connectomes of mice, monkeys, and humans, the team discovered that human cortical networks have evolved a novel neuronal network type that is essentially absent in mice.

Using biopsies from neurosurgical interventions, the researchers applied 3D electron microscopy to map about a million synapses in human brain samples. Their data revealed, in humans, an unexpected bias of interneurons (enriched in humans) connecting with each other, while the innervation to principal neurons remained largely similar.

More specifically, they found that a 2.5-fold increase in interneurons in humans, compared to mouse, was compensated by a change in axonal connection probabilities. Therefore, the authors wrote, it “did not yield a commensurate increase in inhibitory-vs-excitatory synaptic input balance on human pyramidal cells.”

Rather, they continued, “Increased inhibition created an expanded interneuron-to-interneuron network, driven by an expansion of interneuron-targeting interneuron types and an increase in their synaptic selectivity for interneuron innervation.”

“Interneurons make about a fourth to a third of cortical nerve cells that behave in a very peculiar way: they are highly active, however, not to activate other neurons, but rather to silence them. Just like kindergarten caretakers, or guards in the museum: their very laborious and highly energy consuming activity is to keep others peaceful, quiet,” explained Helmstaedter. “Now imagine a room full of museum guards, all mutually silencing each other. This is what the human brain has developed!”

Theoretical work has suggested that such networks of silencers can prolong the time over which recent events can be kept in the neuronal network: expand the working memory. “In fact, it is highly plausible that longer working memory will help you deal with more complex tasks, expand your ability for reasoning,” said Helmstaedter.

The new discovery suggests a first clear network innovation in humans that deserves intense further study. He added: “It could also be a site of pathological change and must be studied in the context of neuropsychiatric disorders. And last but not least: none of today’s main AI methods uses such interneuron-to-interneuron networks.”

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