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Mammalian Brain Cortex Cell Populations Characterized by Single-Cell Sequencing

NEW YORK (GenomeWeb) – A team led by researchers from the Allen Institute for Brain Science has characterized more than 100 cell types in the mammalian brain neocortex — a region tasked with complex cognitive functions — using RNA sequencing on individual mouse brain cells.

"This is by far the most comprehensive, most in-depth analysis of any regions of the cortex in any species," senior author Hongkui Zeng, executive director of structured science at the Allen Institute, said in a statement. "With all these data in hand, we can start to learn new principles of how the brain is organized — and ultimately, how it works."

In a paper published online today in Nature, Zeng and her colleagues presented data for more than 23,800 individual cells from the primary visual cortex and anterior lateral motor cortex areas of the mouse neocortex, identifying 133 cell types with distinct transcriptomic patterns. Some of these cell types turned up in both brain areas, they reported, while others appeared to be specific to one or the other.

"When we see not only cell types that people have identified before, but a number of new ones that are showing up in the data, it's really exciting for us," Zeng said. "It's like we are able to put all the different pieces of the puzzle together and suddenly see the whole picture."

In an effort to build on a study of RNA sequences from around 1,600 cells in the mouse visual cortex that Zeng and her colleagues published in Nature Neuroscience in 2016, the researchers used SMART-seq kits and Illumina HiSeq 2500 instruments to do RNA-seq on 14,249 individual cells from the mouse primary visual cortex and 9,573 cells from the anterior lateral motor cortex. The researchers clustered the cells based on their expression profiles and identified 56 types of excitatory, glutamatergic neurons; 61 inhibitory, gamma-aminobutyric acid (GABAergic) neurons; and 16 types of non-neuronal neocortex cells.

The anterior lateral motor cortex contained 101 of these cell types, and the primary visual cortex was home to 79 of these cell types. While most of the non-neuronal cell types and GABAergic neurons turned up in both of the neocortex areas, the team noted that the glutamatergic neurons were more likely to be specific to either the primary visual cortex or anterior lateral motor cortex.

"Ultimately, we are also working to study not only gene expression, but many of the cells' other properties — including their function, which is the most elusive, the most difficult to define," first and co-corresponding author Bosiljka Tasic, associate director of the Allen Institute's molecular genetics program, said in a statement.

In a subset of 2,204 cells, for example, the group used a method called retro-seq to assess the transcriptional properties of cells subjected to retrograde labeling injections, which made it possible to trace their projections into different parts of the brain.

For a related study, also appearing in Nature, a team led by investigators at the Howard Hughes Medical Institute's Janelia Research Campus, the Allen Institute, and the National Institute of Mental Health focused in on two types of movement-related neurons in layer 5 of the descending pyramidal tract, using axonal reconstruction and single-cell RNA-seq on nearly 9,600 anterior lateral motor cortex cells to identify a population of neurons contributing to movement planning and another that triggers the movement.

"The motor cortex study is the first salvo in a different type of cell type classification, where gene expression information, structural information and measurements of neural activity are brought together to make statements about the function of specific cell types in the brain," corresponding author Karel Svoboda, a researcher at the Janelia Research Campus, said in a statement.

In an accompanying News and Views article in Nature, University of California, San Francisco regeneration medicine and stem cell researchers Aparna Bhaduri and Tomasz Nowakowski noted that "the two studies highlight the transformative potential of atlas-scale data sets in modern neuroscience. They make a strong case for conducting similar studies of more cell types and of the brains of animals of different species, including humans, at various ages."