Most detailed atlas of the human brain created
When scientists first looked at brain tissue under a microscope, they saw an impenetrable and disordered mess. Santiago Ramon y Cajal, the father of modern neuroscience, compared the experience to going into a forest with a hundred billion trees, “looking at blurry parts of some of these trees intertwined every day, and after a few years trying to “to write an illustrated field guide for the forest,” as the authors write about Cajal’s work in the book “The Beautiful Brain.”
Advertisement
Scientists now have the first draft of this travel guide. In 21 new papers published in three journals, the teams involved report that they have created large-scale whole-brain cell atlases for humans and non-human primates. This work is the culmination of five years of research. “It’s not just an atlas,” says neuroscientist Ed Lein of the Allen Institute for Brain Science, who is one of the lead authors. “It really opens up a whole new field where you can now look at extremely high cellular resolution into the brains of species where that wasn’t possible in the past.”
What is a brain atlas and what makes it so different?
A brain atlas is a 3D map of the brain. There are already some brain atlases, but this new series of articles provides unprecedented resolution of the entire brain of humans and non-human primates. The Human Brain Atlas contains the location and function of more than 3,000 cell types in adult and developing individuals. “This is by far the most complete description of the human brain at this level and the first description for many brain regions,” says Lein. However, it is still a first draft.
The work is part of the BRAIN Initiative Cell Census Network of the US National Institutes of Health. It was launched in 2017 with the aim of creating a comprehensive 3D reference brain cell atlas for mice. This project is still in progress. The results, presented on October 12, come from pilot studies designed to test whether the methods used in mice would also work in larger brains. The result: They actually worked very well.
What have these initial studies revealed?
The human brain is very complex. So far, the teams have identified more than 3,300 cell types. If the resolution gets even higher, which researchers are currently working on, they will likely discover many more species. During the creation of the mouse brain atlas, which is already more advanced, even 5,000 cell types were identified. (Further information can be found in these preprints: 1 and 2)
But behind this complexity there are some similarities. For example, many regions have the same cell types, but in different proportions. Furthermore, the location of this complexity is surprising. Neuroscience has largely focused its research on the outer covering of the brain, which is responsible for memory, learning, language and much more. However, most of the cellular diversity is found in older evolutionary structures deep inside the brain, says Lein.
How were the brain cell atlases created?
The classic neuroscientific approach to classifying cell types relies on either the shape of the cell (think star-shaped astrocytes) or the type of cell activity (such as fast-spiking interneurons). “These cell atlases use a new range of technologies that come from genomics,” says Lein, particularly so-called single-cell sequencing.
The genetic testing begins with a small piece of frozen brain tissue from a biobank. “You chop up the tissue and profile a lot of cells to try to understand it,” says Lein. To do this, the DNA of the cell nuclei is sequenced to see which genes are expressed. “Each cell type has a coherent set of genes that it typically uses. You can record all of these genes and then group all cell types based on their general gene expression pattern,” says Lein. They can then spatially assign this functional information using the imaging data from the donor brain.
How can scientists use these brain cell atlases?
There are many options for this. However, an important area of application is understanding the basics of brain diseases, a long-term goal that was also pursued by the recently completed “Human Brain Project”. A reference human brain atlas that describes a normal or so-called neurotypical brain could help researchers understand depression, schizophrenia or many other diseases, says Lein. One could use roughly the same methods to characterize the brains of people with varying degrees of Alzheimer’s disease, and then compare those brain maps with the reference atlas. “And now you can ask questions like: Are certain cell types susceptible to the disease or are certain cell types the cause,” says Lein.
Instead of studying plaques and twisted fibrils (tangles), researchers can ask questions about “very specific types of neurons that are among the circuit elements that are likely to be disrupted and have functional consequences,” he says.
What is the next step?
Next, the researchers want to improve the resolution even further. “The next phase is a very detailed survey of human and non-human primate adult brains.” In fact, this work has already begun with the BRAIN Initiative’s Cell Atlas Network, a five-year, $500 million project. The aim is to create a complete reference atlas of the cell types in the human brain across the lifespan and also to map the cell interactions that underlie a wide range of brain disorders. This is a level of detail that Ramon y Cajal could not have imagined.
(vs.)
To home page