Scientists reveal advance in brain research once thought impossible

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Using a speck of mouse brain matter the size of a grain of sand, scientists have created the first precise, three-dimensional map of a mammal’s brain.

The map details the form, function and activity of 84,000 neurons, branched structures that fire off messages down a long arm, called an axon, and then through more than 500 million synapses, as well as 200,000 brain cells. The tiny piece of tissue contained 3.4 miles (5.4 kilometers) of neuronal wiring — nearly one and a half times the length of New York City’s Central Park.

The work is the culmination of almost a decade of research by 150 scientists at 22 institutions led by the Allen Institute for Brain Science, the Baylor College of Medicine and Princeton University.

“One byproduct of this whole project shows us just how incredibly beautiful the brain is,” said Dr. Forrest Collman, associate director of data and technology at the Allen Institute, in a video shared by the organization.

“Just looking at these neurons shows you their detail and scale in a way that makes you appreciate the brain with a sense of awe in the way that when you look up, you know, say, at a picture of a galaxy far, far away,” he added.

The astonishing map represents only 1/500 of the full volume of a mouse’s brain yet the team ended up with 1.6 petabytes of data — a staggering amount equivalent to 22 years of nonstop HD video, which the project, known as The Machine Intelligence from Cortical Networks (MICrONS) program, has already made publicly available.

Researchers described the work in several papers published in the journal Nature on April 9.

Building out brain activity

To make the map, scientists at Baylor College of Medicine in Houston began by using specialized microscopes to record the brain activity in a 1-cubic-millimeter portion of tissue in a lab mouse’s visual cortex — where the animal processes what it sees — over the course of a few days.

The researchers made sure the mouse was awake and visually stimulated during the imaging by having the animal run on a treadmill and watch 10-second scenes from various movies, including “The Matrix” and “Mad Max: Fury Road.” YouTube clips of extreme sports such as motocross, luge and BASE jumping were also part of the viewing rotation, according to a Princeton University news release.

Next, after euthanizing the mouse, researchers from the Allen Institute in Seattle took that same cubic millimeter of brain and sliced it into more than 28,000 layers, each 1/400 the width of a human hair, and took images of each slice along the way. They then reconstructed the images into a composite.

“That took us about 12 days and 12 nights with the team taking shifts around the clock; not because we were cutting it by hand, it’s a machine that is automated,” said Dr. Nuno Maçarico da Costa, an associate investigator at the Allen Institute.

“We needed to be there to stop at any point in time if we thought we’re going to lose more than a section in a row.” If that happened, da Costa said the experiment would have to start from scratch, adding that the whole process was very “stressful.”

A team at Princeton University in New Jersey subsequently deployed machine learning and artificial intelligence tools to trace the contour of every neuron through the slices, coloring the neurons to illuminate them individually in a process called segmentation. The AI-generated information is validated or proofread by the scientists involved, a process that is still ongoing.

The work has culminated in a unified view of what scientists are calling the mouse brain “connectome” that shows how specific parts of the mouse brain are organized and offers insight into how different cell types work together.

“The connectome is the beginning of the digital transformation of brain science,” said Dr. Sebastian Seung, Princeton University’s Evnin Professor in Neuroscience and a professor of computer science.

“With a few keystrokes you can search for information and get the results in seconds. Some of that information would have taken a whole Ph.D. thesis to get before. And that’s the power of digital transformation,” he said in a news release.

Impossible challenge?

Mapping the brain in this way had long been thought an impossible challenge. Molecular biologist Francis Crick, who won the Nobel prize for describing the structure of DNA, suggested neuroscientists would never be able to achieve such a detailed understanding of the brain.

“It is no use asking for the impossible, such as, say, the exact wiring diagram for a cubic millimeter of brain tissue and the way all its neurons are firing,” he wrote in Scientific American in 1979.

The mouse brain “connectome” builds on similar work on even smaller creatures: The connectome of the nematode worm C. elegans was completed in 2019, and scientists revealed a map of all the fruit fly brain neurons in 2024.

One cubic millimeter of mouse brain is about 20 times bigger than the complete fruit fly brain, and much more complex, the researchers said. Nonetheless, the goal is to be able to map the entire mice brain connectome in the near future.

“I think right now the answer is no, it is not feasible, but I think everyone has really clear ideas about how they could break through those barriers. We’re hoping in three or four years, we can say, yes, it is possible,” Collman told CNN.

However, he said mapping the human brain connectome in similar synaptic resolution would be a dramatically more difficult endeavor. “The human brain is another factor of 1,500 or so larger than a mouse brain, and so that brings a whole host … of technical and ethical barriers to doing that,” he said.

However, it might be possible to trace axons throughout the human brain, if not synaptic connections, added Dr. Clay Reid, a senior investigator in brain science at the Allen Institute.

“The prospect of reconstructing the entire human brain at the level of all of the connections, that’s something for the distant future.”

A new way to study Alzheimer’s

The neocortex is particularly interesting to study, because this region of the brain is what distinguishes mammal brains from those of other vertebrates, said Dr. Mariela Petkova, a research associate, and Dr. Gregor Schuhknecht, a postdoctoral fellow, both in the department of molecular and cellular biology at Harvard University. Petkova and Schuhknecht weren’t involved in the creation of the mouse brain map.

“The researchers focused on this region because it is generally considered to be the seat of higher cognition and plays a key part in sensory perception, language processing, planning and decision-making,” they wrote in an article published alongside the research.

“Remarkably, these seemingly different functions are made possible by a blueprint that can be found, with some modifications, in all cortical areas and in all mammals.”

Lab mice are already widely used to understand human diseases, and a better comprehension of the mouse brain’s form and function will present new possibilities for studying human brain disorders such as Alzheimer’s, Parkinson’s, autism and schizophrenia that involve disruptions in neural communication.

“If you have a broken radio and you have the circuit diagram, you’ll be in a better position to fix it,” da Costa said in a news release. “We are describing a kind of Google map or blueprint of this grain of sand. In the future, we can use this to compare the brain wiring in a healthy mouse to the brain wiring in a model of disease.”

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