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Mice turning tiny steering wheels to move shapes on a screen have helped scientists produce the first brain-wide map of decision-making at single-cell resolution in a mammal.

For decades, most neuroscience studies have focused on small clusters of cells in isolated brain regions.

"But this method is flawed," said Ilana Witten, Ph.D., a professor of neuroscience at Princeton University and a Howard Hughes Medical Institute investigator.

"The brain is constantly making decisions during everyday life, and we've come to realize that there are many brain regions, rather than just one or two regions, contributing to decision-making."

Witten, working with the International Brain Laboratory (IBL)—a global consortium of 22 labs across Europe and the U.S.—combined the reach of multiple laboratories to better understand the complexity of decision-making in the brain by using a shared, standardized approach to track neural activity during behavior.

The resulting datasets, published in two papers in the journal Nature, reveal the activity of more than 600,000 neurons across 279 brain regions in 139 mice, offering an unprecedented view of how distributed neural networks work together to guide decision-making.

A collaborative leap forward for neuroscience

Mapping an entire brain in action, even one as small as a mouse's, is an immense challenge.

"This had never been done before," said Alejandro Pan Vazquez, Ph.D., an associate research scholar in the Witten lab, and a contributing author on both papers.

"There was a lot of innovation on the organizational side of things for this project in order to integrate the data from different labs. This turned out to be the first time such a large collaboration like this had ever been done in neuroscience."

To overcome this challenge, three Princeton University labs—one headed by Witten and the others by Tatiana Engel, Ph.D., an associate professor of neuroscience, and Jonathan Pillow, Ph.D., professor of neuroscience—helped support this collaboration by coordinating efforts among the participating laboratories and establishing rigorous quality-control metrics, designing experimental parameters, collecting data, and developing standardized analysis pipelines that allowed the data to be combined into a single resource for everyone to analyze.

Steering wheels and flashing circles

The task was a deceptively simple task. Mice sat in front of a screen that intermittently displayed a black-and-white striped circle for a brief amount of time on either the left or right side. A mouse could earn a sip of sugar water if they quickly moved the circle toward the center of the screen by operating a tiny steering wheel in the same direction, often doing so within one second.

On some trials, the circle was faint, requiring the animal to rely on past experience to make a guess, which allowed researchers to study how expectations influence future decisions.

While the mice performed the task, researchers recorded brain activity using high-density electrodes that allowed them to monitor hundreds of neurons across many regions simultaneously. The work was divided across the participating labs, so that each lab mapped a particular region of the mouse brain. The pooled dataset covers 620,000 neurons recorded from 139 mice in 12 labs, encompassing nearly the entire brain.

Surprising findings

The resulting map revealed that decision-making activity is distributed across the brain, including in areas traditionally associated with movement rather than cognition.

"One of the important conclusions of this work is that decision-making is indeed very broadly distributed throughout the brain, including in regions that we formerly thought were not involved," Witten said.

The published findings are also "in a sense advertising this unique dataset," Witten said. "They describe what the dataset is composed of, what it looks like, and provide a resource for the field to use for further analyses. We hope these papers inspire others to investigate the data and make new discoveries with it."

Ultimately, the researchers believe that the results of their work can be used as a benchmark for testing new theories about decision making, thereby advancing the field of neuroscience.

A map made across the world

Above all, just getting 22 globe-spanning labs to work towards a common goal is a success in itself. It also demonstrates the power of large-scale, coordinated neuroscience.

"The brain-wide map is undoubtedly an impressive achievement, but it marks a beginning, not the grand finale," Engel said.

"The IBL has shown how a global team of scientists can unite, pushing each other beyond comfort zones into uncharted territories no single lab could reach alone."