Wiring the Brain: Columbia’s Mind Brain Behavior Institute

What makes us human?

This conundrum, a perennial challenge to poets and philosophers, was the subject of a talk last Wednesday hosted by Columbia University’s Zuckerman Mind Brain Behavior Institute and sponsored by the Dana Foundation.

From a neuroscientist’s perspective, the question becomes “What’s human-specific about our brains that allows the emergence of higher cognitive abilities?” said Franck Polleux, who recently joined the Columbia faculty as professor of neuroscience. On a genetic level, “[it] can be rephrased: ‘what happened in the genome since we [and chimpanzees] diverged from a common ancestor some six million years ago?’”

Polleux introduced his listeners to a body of research that combines these perspectives. He has spent much of his career investigating the molecular and cellular events that contribute to the brain’s wiring. Most recently, he has turned his attention to the evolutionary roots of this hugely complex system.

The sequencing of the human genome put us in a unique position to explore the brain’s emergence, Polleux said. But technical challenges remain daunting: among thousands of human-primate differences that have been identified, “we have to ask which could have allowed the brain to get wired in a human-specific way.”

Although our brains tripled in volume (from 500 to 1500 cc) since we and non-human primates went our separate ways, size alone is not the answer; other mammals have a higher brain/body size ratio. New cortical areas and increased connectivity (human neurons receive up to 30% more synapses than those of other primates) are probably more to the point. “What happened at a genome level that allowed emergence of these features?” he asked.

Polleux described two key processes. Mutations that occur in non-coding sequences (so-called “junk DNA”) can change when and where a single gene is expressed, giving it a dramatically different function.

Gene duplications have been another driving force in evolution, he said: a copy of a gene appears elsewhere on the genome, sometimes with altered coding.

Discoveries in this latter area have been “big news,” Polleux said. In the last six to seven years, researchers have mapped 30 duplications specific to the human lineage.

His talk focused on one instance, the gene SRGAP2. An “ancestral” version (SRGAP2A) is shared by all primates. Its first duplication (SRGAP2B) occurred some 3.4 million years ago, but is essentially non-functional. The second (SRGAP2C), which expresses messenger RNA and a protein, appeared 2.4 million years ago—just when the first representative of genus homo arose. “The timing is remarkable: its appearance corresponds to the emergence of the human lineage,” he said.

When they were first identified, no one knew what these genes did. Polleux and his colleagues established that the ancestral version “plays an absolutely essential role in synaptic development.” And the human-specific copy? Studies in his lab, with mice genetically modified to express SRGAP2C, demonstrated that it inhibits the ancestral gene, delaying maturation of synapses to substantially increase their total number.

“These findings were stunning,” Polleux said. “A single gene duplication is responsible for two central aspects of human synaptic development… we were able to move from genetic manipulation to analyzing consequences at the circuit level.”

The implications of this work could be profound, he said. “We’re convinced that understanding what’s unique about the human brain will transform our ability to understand human diseases, such as autistic spectrum disorders.” Abnormalities in synaptic development and function are believed central to autism, he pointed out, and SRGAP2C appears to modify synapses by interacting with proteins known to be involved in the disorder.

Looking ahead, Polleux suggested that genetic studies might illuminate the evolution of such uniquely human cognitive capacities as creativity. “Some genes we have identified could play a role establishing connectivity in brain areas that underlie the emergence of language,” he said.

–Carl Sherman

Carl Sherman is a science writer in New York City.

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