The brain is the most complex organ in the human body, making all of our movements, thoughts and other body functions possible through the transmission of signals throughout our nervous system. Fully understanding the inner workings of the brain down to the cellular level is a monumental task, one that hundreds of scientists have now undertaken as part of the BRAIN Initiative Cell Census Network (BICCN). This week, the BICCN has begun rolling out its first results after five years of extensive research, with 17 papers comprising hundreds of scientists’ work representations the beginnings of a comprehensive atlas of the mammalian brain.
The rollout of papers, including a flagship paper co-authored by more than 250 researchers, provide a multimodal cell census and atlas of the primary motor cortex in mice, marmosets and humans. The studies identified up to 116 different cell types based on shape, size, electrical properties and gene expression. Many of these are subtypes of well-known cell types, distinguishable by their specific gene expression and electrical firing patterns.
The research effort involved about a dozen different experimental methods for characterizing cell types, including scRNA-seq, electrophysiological patch clamp recordings, biocytin staining and multiplexed error-robust fluorescence in situ hybridization (MERFISH). CRISPR-Cas9 edited knock-in reporter mice were used to track the connections between newly identified cell types, and machine learning and artificial intelligence were also applied to help distinguish cell types based on shape, connectivity, location, fire action potential and epigenetics.
The researchers said that distinguishing between cell clusters and determining which could truly be considered different subtypes was challenging, but consistency and overlap in results between many different methods helped highlight distinctions between specific clusters, according to UC Berkeley researcher Dirk Hockemeyer, one of the co-authors of the flagship paper. The research provides a consensus taxonomy of cell types based on many different properties rather than just gene expression or morphology. The papers, including the open-access flagship study, were published in Nature.
“Even among biologists, there are vastly different opinions as to how much resolution you should have for these systems, whether there is this very, very fine clustering structure or whether you really have higher level cell types that are more stable,” said Sandrine Dudoit, chair of the Department of Statistics at UC Berkeley and co-author of the flagship paper. “Nevertheless, these results show the power of collaboration and pulling together efforts across different groups. We’re starting with a biological question, but a biologist alone could not have solved that problem. To address a big challenging problem like that, you want a team of experts in a bunch of different disciplines that are able to communicate well and work well with each other.”
The BICCN endeavors to ultimately map all of the cell types throughout the entire brain. With a more complete understanding of cell properties and connections, scientists can better develop therapies for neurologic and neuropsychiatric disorders.
Photo: Brain slice from a transgenic mouse, in which genetically defined neurons in the cerebral cortex are labeled with a red fluorescent reporter gene. Credit: Tanya Daigle, Courtesy of the Allen Institute