Yale scientists uncover clues about what makes the human brain different

Yale researchers have identified human-specific features in the prefrontal cortex.

What sets the human brain apart from that of all other animals—including even our closest primate relatives? Yale researchers identified species-specific — particularly human-specific — characteristics in an analysis of cell types in the prefrontal cortex of four primate species. They reported their findings on August 25, 2022 in the journal Science.

What makes us human, they found, may also make us susceptible to neuropsychiatric illness.

For the study, the scientists looked specifically at the dorsolateral prefrontal cortex (dlPFC). This is a brain region that is unique to primates and is essential for higher-order cognition. Using a single cell[{” attribute=””>RNA-sequencing technique, the researchers profiled expression levels of genes in hundreds of thousands of cells collected from the dlPFC of adult humans, chimpanzees, macaque, and marmoset monkeys.

“Today, we view the dorsolateral prefrontal cortex as the core component of human identity, but still we don’t know what makes this unique in humans and distinguishes us from other primate species,” said Nenad Sestan. He is the lead senior author of the paper, the Harvey and Kate Cushing Professor of Neuroscience at Yale, professor of comparative medicine, of genetics, and of psychiatry.  “Now we have more clues.”

To answer this, the scientists first asked whether there are there any cell types uniquely present in humans or other analyzed non-human primate species. After grouping cells with similar expression profiles they revealed 109 shared primate cell types. They also discovered five that were not common to all species. These included a type of microglia, or brain-specific immune cell, that was present only in humans and a second type shared by only humans and chimpanzees.

The human-specific microglia type exists throughout development and adulthood, the researchers found. This suggests that the cells play a role in the upkeep and maintenance of the brain rather than combatting disease.

“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 might represent an immune response to the environment.”

Another human-specific surprise was revealed in an analysis of gene expression in the microglia — the presence of the gene FOXP2. This discovery raised great interest among researchers because variants of FOXP2 have been linked to verbal dyspraxia, a condition in which patients have difficulty producing language or speech. Other research has also shown that FOXP2 is associated with other neuropsychiatric diseases, such as autism, schizophrenia, and epilepsy.

Sestan and colleagues discovered 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 still we had no idea of what makes it unique in humans versus other primate species,” said Shaojie Ma. He is a postdoctoral associate 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 diseases.”

Reference: “Molecular and cellular evolution of the primate dorsolateral prefrontal cortex” by Shaojie Ma, Mario Skarica, Qian Li, Chuan Xu, Ryan D. Risgaard, Andrew T. N. Tebbenkamp, Xoel Mato-Blanco, Rothem Kovner, Željka Krsnik, Xabier de Martin, Victor Luria, Xavier Martí-Pérez, Dan Liang, Amir Karger, Danielle K. Schmidt, Zachary Gomez-Sanchez, Cai Qi, Kevin T. Gobeske, Sirisha Pochareddy, Ashwin Debnath, Cade J. Hottman, Joshua Spurrier, Leon Teo, Anthony G. Boghdadi, Jihane Homman-Ludiye, John J. Ely, Etienne W. Daadi, Da Mi, Marcel Daadi, Oscar Marín, Patrick R. Hof, Mladen-Roko Rasin, James Bourne, Chet C. Sherwood, Gabriel Santpere, Matthew J. Girgenti, Stephen M. Strittmatter, André M. M. Sousa and Nenad Sestan, 25 August 2022, Science.
DOI: 10.1126/science.abo7257

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, an 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, the 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.

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