Neuroscientists have unveiled their most comprehensive and detailed map of cell types across the entire mouse brain, delivering the latest results of a six-year-long scientific effort in which Seattle’s Allen Institute has played a leading role.
Nine studies published today in the journal Nature document the identification of 5,322 different types of brain cells, and trace the similarities and differences found in a variety of mammalian species — including humans.
The work expands upon previous studies from the BRAIN Initiative Cell Census Network, including earlier surveys of cells in various regions of the mouse brain, as well as cross-species comparisons of cell functions. Researchers from the Allen Institute joined forces with colleagues from the Broad Institute, Harvard, the Salk Institute for Biological Studies, the University of California at San Diego, UC-Berkeley and other institutions to add to their “parts list” for the brain.
“Now we have the cell-type atlas of all the cells in the brain,” Hongkui Zeng, executive vice president and director of the Allen Institute for Brain Science, said in an explanatory video. “This is really a landmark achievement. … It marks the completion of a kind of work that strives for completeness. But it also marks the beginning of the next phase of the journey. It just opens up the door for the next generation of investigations.”
Zeng, who is the senior author of one of the papers in Nature and a co-author of five others, said the next step will be to figure out exactly what all those different cell types do, how their functions are affected by disease, and whether there might be yet-to-be-discovered ways to restore those proper functions.
“It’s not just about a catalog, a list of cell types and where they are — reference information which by itself is already important — but we begin to see how a brain is organized,” Zeng said.
The studies relied on genetic sequencing data plus spatial maps of gene expression, gathered from millions of cells.
Researchers found a strong correlation between the characteristic gene expression patterns for cell types and their location in the brain. In the upper regions of the brain, also known as the dorsal regions, there was a small number of widely diverse cell types. In contrast, the brain’s lower or ventral regions contain a large number of distinct cell types that are more closely related to each other.
“Our hypothesis is an evolution-based explanation,” Zeng told GeekWire in an email. “The evolutionally more ancient, ventral part of the brain (especially the hypothalamus / midbrain / hindbrain) is mainly involved in the survival function of the animal (including feeding, reproduction, metabolism, etc.), and thus it is subject to more evolutionary constraints, and its cell types are more numerous but haven’t diverged much.”
In contrast, the dorsal part of the brain — including the cortex, thalamus and cerebellum — is mainly involved in fast-changing adaptive functions, such as sensory-motor specialization and cognition. “Thus it has expanded and diversified faster, even with fewer millions of years of evolution,” Zeng said.
Another study compared gene regulation in the primary motor cortex of humans, macaques, monkeys and mice. Researchers found that patterns of gene expression that were specific to particular cell types seem to have evolved much more rapidly than patterns that are shared across different cell types.
They said nearly 80 percent of the regulatory elements that are unique to humans are transposable elements — that is, small sections of DNA that can easily change position within the genome.
The analysis also pointed to features that are highly conserved across species in genetic variants that have been linked to multiple sclerosis, anorexia nervosa and tobacco addiction. The researchers said their results demonstrate the value of brain maps for identifying genetic factors that play a part in neurological conditions.
“Humans have evolved over millions of years, and much of that evolutionary history is shared with other animals,” Joseph Ecker, a professor at the Salk Institute who helped lead the cross-species study, explained in a news release. “Data from humans alone is never going to be enough to tell us everything we want to know about how the brain works. By filling in these gaps with other mammalian species, we can continue to answer those questions and improve the machine learning models we use by providing them more data.”
Now that researchers have filled out the parts list for the mouse brain, they’ll be devoting even more attention to the human brain. The Allen Institute is spearheading a five-year effort to create a human cell-type atlas with $173 million in funding from the BRAIN Initiative.
Zeng said cell-type maps are likely to point to new strategies for treating diseases. In that sense, having an accurate map could be the first step toward putting a wayward brain back on the right track.
“We know that many of the diseases originated actually in specific parts of the brain, and probably in specific cell types in those parts of the brain,” she said. “With the map in hand, now we can find out exactly how genes changed in those cell types, in those parts of the brain. … We can then create genetic tools or other kinds of tools, like pharmacological tools, to target those specific cell types.”
John Ngai, director of the BRAIN Initiative, suggested that the best is yet to come.
“Where we previously stood in darkness, this milestone achievement shines a bright light, giving researchers access to the location, function, and pathways between cell types and cell groups in a way we couldn’t imagine previously,” Ngai said. “This product is a testament to the power of this unprecedented, cross-cutting collaboration and paves our path for more precision brain treatments.”
A special section on Nature’s website highlights research from the BRAIN Initiative Cell Census Network relating to the mouse brain-cell atlas, including the nine papers published today as well as a paper that was published in September.
