What distinguishes the human brain from that of all other animals — including our closest primate relatives? In an analysis of cell types in the prefrontal cortex of four species of primates, Yale researchers identified species-specific — particularly human — traits, they reported in the Aug. 25 journal science.
And they found that what makes us human may also make us susceptible to neuropsychiatric illness.
For the study, the researchers looked specifically at the dorsolateral prefrontal cortex (dlPFC), a brain region that is unique to primates and essential for higher-order cognition. Using a single-cell RNA-sequencing technique, they profiled gene expression levels in hundreds of thousands of cells collected from the dlPFC of adult humans, chimpanzees, macaques, and marmosets.
“Today, we see the dorsolateral prefrontal cortex as the core component of human identity, but we still don’t know what makes this unique in humans and what sets us apart from other primate species.” said Nenad Sestan, Harvey Professor of Neuroscience and Yale’s Kate Cushing Professor of Comparative Medicine, Genetics. and psychiatry, and the paper’s lead senior author. “Now we have more data.”
To answer this, the researchers first asked whether there are any cell types uniquely present in humans or the other non-human primate species analyzed. After grouping cells with similar expression profiles, they discovered 109 common primate cell types, but also five that were not common across species. These included a type of microglia, or brain-specific immune cell, that was only present in humans and a second type shared only by humans and chimpanzees.
The human-specific type of microglia exists throughout development and adulthood, researchers found, suggesting the cells play a role in brain maintenance rather than disease-fighting.
“We humans live in a very different environment with a unique lifestyle compared to other primate species; and glia cells, including microglia, are very sensitive to these differences,” Sestan said. “The type of microglia found in the human brain may represent an immune response to the environment.”
An analysis of gene expression in microglia revealed another human-specific surprise – the presence of the FOXP2 gene. This discovery raised great interest because FOXP2 variants have been linked to verbal dyspraxia, a condition in which patients have difficulty producing language or speech. Other studies have also shown that FOXP2 is associated with other neuropsychiatric diseases, such as autism, schizophrenia and epilepsy.
Sestan and colleagues found that this gene exhibits primate-specific expression in a subset of excitatory neurons and human-specific expression in microglia.
“FOXP2 has intrigued many scientists for decades, but we still had no idea what makes it unique in humans versus other primate species,” said Shaojie Ma, a postdoctoral fellow in Sestan’s lab and co-lead author. We are extremely excited about the FOXP2 findings because they open new directions in the study of language and disease.”
The research was funded by the National Institutes of Health and the National Institute of Mental Health.
Other authors include co-lead author Mario Skarica, associate research scientist in neuroscience at Yale School of Medicine; co-senior author Andre Sousa, assistant professor of neuroscience at the University of Wisconsin-Madison; and co-senior author Stephen M. Strittmatter, Vincent Coates Professor of Neurology and Professor of Neuroscience at Yale, chair of the Department of Neuroscience and director of the Kavli Institute for Neuroscience.
Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.