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Neuroscientists used a new, gene-based classification of mouse brain cell types and additional information about neuron shape to uncover two new types of neurons involved in movement. (Credit: Michael Economo, Janelia Research Campus / Lucas Graybuck, Allen Institute)

How many different kinds of cells are there in the brain? At least 133 kinds, including two types of neurons not recognized before, according to a pair of studies featured on the cover of this week’s issue of the journal Nature.

The “parts list” builds on 15 years of work at Seattle’s Allen Institute, focused on analyzing genetic activity in nearly 24,000 of the 100 million brain cells in the mouse cortex. Each cell type exhibited a different combination of genes that were turned on or off.

“This is by far the most comprehensive, most in-depth analysis of any regions of the cortex in any species,” senior study author Hongkui Zeng, executive director of structured science at the Allen Institute for Brain Science, said in a news release. “We can now say that we understand the distribution rules for its parts list.”

Nature cover
The cover of this week’s issue of the journal Nature features brain cells. (Michael Economo / Jayaram Chandrashekar via Nature)

The region of the cortex that Zeng and her colleagues studied is responsible for processing visual and motor function. Other regions should follow similar rules of organization, the researchers said.

“With all these data in hand, we can start to learn new principles of how the brain is organized — and ultimately, how it works,” Zeng said.

Researchers at the Howard Hughes Medical Institute’s Janelia Research Campus in Virginia used the Allen Institute’s gene expression data as well as the physical shapes of brain cells to identify two new types of pyramidal tract neurons involved in movement. Then they monitored the cells’ activity in live mice to figure out their function.

One of the neuron types plays a role in preparing for a movement — for example, the lick of a tongue. The other type works to trigger the movement itself.

Janelia’s Karel Svoboda, senior author of the motor neuron study, said that tracking gene expression is “a very efficient way of getting at cell types.”

“That’s really what the Allen Institute is at the core,” Svoboda said. “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.”

The newly published study could well point the way to a comprehensive catalog of brain cells, which will help researchers get a better grip on how all those different types of cells work together to give rise to sensory input, motor function and ultimately consciousness.

Neuroscientists use a variety of methods to characterize brain cells, including their physical shape and the pattern of their electrical activity. But analyzing gene expression is arguably the best way to do a cell-by-cell characterization.

“It’s only through recent advances in technology that we can measure the activity of so many genes in a single cell,” said Bosiljka Tasic, associate director of molecular genetics at the Allen Institute of Brain Science and principal author of the cell-type study. “Ultimately, we are also working to study not only gene expression, but may of the cells’ other properties — including their function, which is the most elusive, the most difficult to define.”

In a Nature commentary, Aparna Bhaduri and Tomasz Nowakowski of the Broad Center for Regeneration Medicine and Stem Cell Research say the two studies demonstrate the “transformative potential” of brain cell atlases like the ones that are the Allen Institute’s specialty.

“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,” Bhaduri and Nowakowski write. One recent study, based in part on Allen Institute data, identified a type of brain cell called the “rosehip neuron” that doesn’t seem to exist in mice and may be linked to higher-order cognition.

Bhaduri and Nowakowski say such studies could yield fresh insights into the vulnerability of different types of cells to different diseases, and guide stem-cell researchers as they create brain cells in the lab for research into those diseases as well as new types of drugs.

Tasic, Zeng and Svoboda are among 48 authors of the Nature paper titled “Shared and Distinct Transcriptomic Cell Types Across Neocortical Areas.” Janelia’s Michael Economo is the principal author of the second paper, titled “Distinct Descending Motor Cortex Pathways and Their Roles in Movement.” Co-authors include Tasic, Zeng and Svoboda and 11 other researchers.

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