A New Cell Atlas Helps Researchers Navigate the Developing Brain

The brain is the most complicated organ in the human body. With billions of cells that create trillions of connections to allow an individual to move, think, and remember, many of its innerworkings remain mysterious to researchers.

To help unravel these processes, the National Institutes of Health (NIH) launched the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative in 2013. As part of this effort, the BRAIN Initiative launched a series of projects to explore the diverse cell types in the mammalian brain.¹

Hongkui Zeng, a neuroscientist at the Allen Institute, and her team joined this BRAIN Initiative project at its start. Previously, they created a whole brain atlas for cell types in the adult mouse brain using single cell transcriptomic data.² She said, “[Now], we are expanding that work in two directions. One is to create same scale, whole brain level cell type atlases for human and nonhuman primate brains. And the other aim is to create cell type atlases for the developing brains across species, from mouse to human.”

Recently, Zeng, her team, and other researchers from the third phase of this project, the BRAIN Initiative Cell Atlas Network (BICAN), released a package of studies that details the most comprehensive map of the developing brain in mice, nonhuman primates, and humans so far. Beyond the enormous advancement in neuroscience knowledge that the project provided, the collaboration sets a precedent for future efforts and provides trainees with invaluable learning experiences.

Creating Connections to Characterize the Brain

Embarking on a goal as extensive as characterizing the mammalian brain required multiple skillsets from several research groups tackling different parts of the larger project. While Zeng and her team delved into the development of the mouse brain, other researchers carried out studies on developing nonhuman primate and human brains.

Even within these individual working groups, collaboration abounded. For example, Arnold Kriegstein, a neurologist and neuroscientist at the University of California, San Francisco, partnered with researchers across the country to define and compare the development of the human and nonhuman primate brains. “By getting these experts in different realms together with complimentary expertise and technologies, I might add, has been really enlightening,” he said.

Of course, such a large endeavor with so many moving parts required extensive amounts of coordination as well. “We had to establish mechanisms for transferring data as well as samples back and forth. It took quite a bit of logistical work to make sure everything was coordinated,” Kriegstein said. The various teams also held regular meetings to update the others about their progress, challenges, and nomenclature. “We want to make sure we're all speaking the same language,” Kriegstein said.

Zeng added that, when exploring features across species, this type of communication was imperative for proper data analysis. “It's very important to integrate data across species, so we understand the similarity and difference right between species. We understand what can be modeled in the maps, whereas what properties are really unique to the human brain itself,” she said. She added that that the BICAN groups’ example of scientific collaboration, including data sharing and standardization, can serve as a model for future efforts in the field.

New Cells in the Developing Brain and New Opportunities for Budding Researchers

While the work required extra organization and communication, Zeng and Kriegstein agreed that it is an example of how the whole is greater than the sum of its parts. Across the entire BICAN team, the researchers developed the most comprehensive atlases of mouse, nonhuman primate, and human cell types in the developing brain of these species to date.

Zeng’s group showed that neuronal cell types in the mouse visual cortex are not fixed upon their generation and instead continue to diversify after the animal’s birth.³ “It just really suggests the importance of the cell type diversification coupled with the maturation of the circuit through the extensive postnatal stages that can be influenced by environment,” she said.

Separately, her team explored neurons that exert their effects through the neurotransmitter GABA (GABAergic) in the telencephalon, the largest region of the brain that includes the cortex. They showed that this region is home to several diverse types of cells with a variety of functions and that many of them migrate extensively during brain development.⁴

“All this work can be applied into cross species comparison as well [and] lay the foundation for us to begin to understand the development of cell types in a human brain, which is much harder to study comprehensively,” Zeng said.

Meanwhile, while studying human brain development, Kriegstein’s group identified a type of progenitor cell that gave rise to one of three distinct cell types: GABAergic neurons, oligodendrocyte precursors, and astrocytes.⁵ Intriguingly, the team noticed that the gene expression pattern for this tripotential cell matched that of cancer stem cells in glioblastoma.

“With that insight, we're now trying to propose to look more carefully at mechanisms involved in the production of those cell types to see if we can find some therapeutic opportunities where we might be able to manipulate the cells in a way that would prevent or slow down the growth of the tumors,” Kriegstein said.

Another exciting outcome, Kriegstein noted, was the positive benefits the collaborative projects provide for trainees. “It's wonderful to see these young people who are really energized and creative and so smart. So, that's been one of the real pleasures of this collaboration,” he said. He added that the BICAN project and its predecessors have allowed trainees among the different teams to write manuscripts and organize and run annual meetings with each other. “It’s a wonderful opportunity for us to energize this next generation and give them some guidance and actually let them flourish in a way that they may not in their individual labs,” Kriegstein said.

Taking Normal Brain Findings to Disease

In 2027, the BICAN project will wrap up. “It's been a huge effort, but very rewarding,” Kriegstein said. “This effort, which is NIH funded, will have an impact that extends well beyond ourselves, the investigators who are generating the data.”

The researchers on the BICAN project regularly upload their findings to an online atlas that others can access. “That really gives everybody the opportunity to look over the data and come up with their own insights,” Kriegstein said.

Additionally, Zeng and Kriegstein said that the future directions for the BRAIN Initiative are to apply the findings from BICAN and its predecessors, which studied normal brains and their development, and apply that to neurological disorders and variations. Zeng added that researchers also hope to explore functional aspects of neuron maturation, such as their connectivity and measuring circuit functions, and applying cell type information to in vitro models.