A Milestone in Mapping the Brain
By Joshua Gordon, M.D., Ph.D., and Walter Koroshetz, M.D., director of the National Institute of Neurological Disorders and Stroke
The brain is the most complex organ in the body—and perhaps the most complex object in the universe. It is made up of billions of cells linked through trillions of networked connections. Yet, if we want to make progress in the understanding and treatment of neurological and psychiatric illnesses, we must unravel this complexity. Key to this effort is to figure out how many and what types of cells there are in the brain. We’re excited to tell you about a first step in this direction: a comprehensive description of the cell types in the motor cortex of mice, monkeys, and humans. This landmark achievement, described in a series of 27 papers in Nature, Nature Neuroscience, and other journals, will dramatically and broadly accelerate progress in neuroscience research and presages a more complete census of brain cell types to come in the near future.
The effort to count and characterize all the cell types of the brain grew out of the NIH Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, an effort supported in part by the bipartisan 21st Century Cures Act that was passed in 2016. The NIH component of the BRAIN Initiative represents a collaboration of ten institutes and centers, including the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, among others*. Through the BRAIN Initiative, NIH has been supporting the Cell Census Network (BICCN), a collaboration of over 250 scientists at nearly 50 institutions located across three continents. Founded in 2017, the BICCN was originally built off of a group of three-year pilot projects. This network is tasked with developing novel technologies to identify and characterize brain cell types; to use those technologies to develop a brain-wide census of cell types; to create an atlas of these cell types for the mouse, monkey, and human brains; and to collate and share their data with the greater neuroscience community.
One reason the BICCN is able to do such cutting-edge research is because of technological methods created through the BRAIN Initiative that have enhanced our ability to examine both the molecular machinery present in single cells and the mechanisms by which expression of this machinery is governed. We can now look into a single nucleus of a single cell in the brain and measure the expression of thousands of messenger RNA transcripts—the instructions read off the DNA that determine what proteins a cell produces. We can also read the structure of the DNA and the chemical marks on the DNA itself—marks that indicate where the instructions for creating specific cell products begin and end—to examine whether these locations show signs of being read. These marks are akin to bookmarks or highlights that tell you where you last opened your favorite book.
Together, these two levels of information—the RNA instructions themselves and the chemical marks on the DNA—provide independent streams of information that can tell us what kind of a cell that nucleus belongs to. And the remarkable thing about the technology used to gather this information is not just that it works, but that it can be used over and over again, rapidly collecting these data from millions of cells.
Indeed, the data that the BICCN is now publishing—and sharing freely across the globe—are derived from 450 thousand cells from a single brain region, the motor cortex of mice, monkeys, and humans. And the findings are every bit as remarkable as the technology. Some highlights:
- In the motor cortex alone, there are over 100 different cell types, divided roughly into six major subclasses of inhibitory neurons and eight major subclasses of excitatory neurons
- Most of these subtypes are present and identifiable in all three species, but the specific RNA transcripts present in each species vary a lot; only by studying the expression of thousands of RNA transcripts can scientists see the similarities and differences
- The RNA “instructions” and chemical marks on the DNA that allow the instructions to be read are in general agreement, suggesting that both methods are accurate and giving scientists hints about how we might use this information to direct specific therapies (especially genetic therapies) to specific cell types
- The locations of these cell types within the motor cortex can be determined with exceptional resolution using optical methods, which will permit the construction of detailed three-dimensional maps of where cell types are in the brain
There is much more to be learned from the data sets collected through the BICCN, which are available to scientists through the BICCN data catalog. The promise is tremendous. By characterizing the different cell types in the brain and understanding their functional contributions, we can construct better theories and models about how they work together to produce behavior and what might go wrong in specific illnesses like schizophrenia or dementia. The approaches used are already revolutionizing our ability to study postmortem brain samples from people diagnosed with a variety of psychiatric and neurologic disorders. What’s more, a detailed understanding of cell types will suggest novel targets for therapies aimed at treating these illnesses, as well as clues to how those therapies might be delivered to the specific brain area where they are needed. Congratulations to the hundreds of scientists involved in the creation of these first initial products of BICCN and to the dozens of NIH BRAIN Initiative staffers who helped shepherd this awesome project along.
*The NIH BRAIN Initiative is managed by 10 institutes whose missions and current research portfolios complement the goals of The BRAIN Initiative®: National Center for Complementary and Integrative Health, National Eye Institute, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute of Biomedical Imaging and Bioengineering, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute on Deafness and other Communication Disorders, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke.