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When scientists first looked at brain tissue under a microscope, they saw an impenetrable and jumbled mess. Santiago Ramon y Cajal, the father of modern neuroscience, likened the experience to walking into a forest with a hundred billion trees, “looking each day at blurry pieces of a few of those trees entangled with one another, and, after a few years of this, trying to write an illustrated field guide to the forest,” according to the authors of The Beautiful Brain, a book about Cajal’s work.
Today, scientists have a first draft of that guide. In a set of 21 new papers published across three journals, the teams report that they've developed large-scale whole-brain cell atlases for humans and non-human primates. This work, part of the National Institutes of Health BRAIN Initiative, is the culmination of five years of research. “It's not just an atlas,” says Ed Lein, a neuroscientist at the Allen Institute for Brain Science and one of the lead authors. “It's really opening up a whole new field, where you can now look with extremely high cellular resolution in brains of species where this typically hasn't been possible in the past.”
Welcome back to The Checkup. Let’s talk brains.
What is a brain atlas, and what makes this one different?
A brain atlas is a 3-D map of the brain. Some brain atlases already exist, but this new suite of papers provides unprecedented resolution of the whole brain for humans and non-human primates. The human brain atlas includes the location and function of more than 3,000 cell types in adult and developing individuals. “This is far and away the most complete description of the human brain at this kind of level, and the first description in many brain regions,” Lein says. But it’s still a first draft.
The work is part of the BRAIN Initiative Cell Census Network, which kicked off in 2017 with the aim of generating a comprehensive 3-D reference brain cell atlas for mice (that project is still in the works). The results reported on October 12 were part of a set of pilot studies to validate whether the methods used in mice would work for bigger brains. Spoiler: those methods did work. Really well, in fact.
What did these initial studies find?
The human brain is really, really complex. I know, shocker! Thus far, the teams have identified more than 3,300 cell types. And as the resolution gets even higher (that’s what they’re working on now), they’re likely to uncover many more. Efforts to develop an atlas of the mouse brain, which are further along, have identified 5,000 cell types. (For more, check out these preprints: 1 and 2)
But underneath that complexity are some commonalities. Many regions, for example, share cell types, but they have them in different proportions.
And the location of that complexity is surprising. Neuroscience has focused much of its research on the outer shell of the brain, which is responsible for memory, learning, language, and more. But the majority of cellular diversity is actually in older evolutionary structures deep inside the brain, Lein says.
How did they make these atlases?
The classic neuroscience approach to classifying cell types relies on either cell shape–think of star-shaped astrocytes–or the cells’ type of activity–such as fast-spiking interneurons. “These cell atlases capitalize on a new suite of technologies that come from genomics,” Lein says, primarily a technique known as single-cell sequencing.
First, the researchers start with a small piece of frozen brain tissue from a biobank. “You take a tissue, you grind it up, you profile lots of cells to try to make sense of it,” Lein says. They make sense of it by sequencing the cells’ nuclei to look at the genes that are being expressed. “Each cell type has a coherent set of genes that they typically use. And you can measure all these genes and then cluster all the types of cells on the basis of their overall gene expression pattern,” Lein says. Then, using imaging data from the donor brain, they can put this functional information where it belongs spatially.
How can scientists use these brain cell atlases?
So many ways. But one crucial use is to help understand the basis of brain diseases. A reference human brain atlas that describes a normal or neurotypical brain could help researchers understand depression or schizophrenia or many other kinds of diseases, Lein says. Take Alzheimer’s as an example. You could apply these same methods to characterize the brains of people with differing levels of severity of Alzheimer’s, and then compare those brain maps with the reference atlas. “And now you can start to ask questions like, ‘Are certain kinds of cells vulnerable in disease, or are certain kinds of cells causal,” Lein says. (He’s part of a team that’s already working on this.) Rather than investigating plaques and tangles, researchers can ask questions about “very specific kinds of neurons that are the real circuit elements that are likely to be perturbed and have functional consequences,” he says.
What’s the next step?
Better resolution. “The next phase is really moving into very comprehensive coverage of the human and non-human primate brain in adults and development.” In fact, that work has already begun with the BRAIN Initiative Cell Atlas Network, a five-year, $500 million project. The aim is to generate a complete reference atlas of cell types in the human brain across the lifespan, and also to map cell interactions that underlie a wide range of brain disorders.
It’s a level of detail that Ramon y Cajal couldn’t have imagined.
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