The human brain is so complex that the scientific brain has a hard time understanding it. Nerve tissue, the size of a grain of sand, could be packed with hundreds of thousands of cells connected by miles of wiring. In 1979, Nobel Prize-winning scientist Francis Crick concluded that the anatomy and activity of only a cubic millimeter of brain material would forever surpass our understanding.
“It's no waste to seek the impossible,” wrote Dr. Crick.
46 years later, a team of over 100 scientists achieved that impossible by recording cell activity and mapping the structure of cubic millimeters of the mouse brain. In achieving this feat, they accumulated 1.6 petabytes of data. This is equivalent to 22 years of non-stop high-resolution video.
“This is a milestone,” said University of Vermont neuroscientist Davi Bock, who was not involved in the study published in Journal Nature on Wednesday. Dr. Bock said that it enabled advances that allowed it to cover the cubic bones of the cubic brain to map the entire brain wiring of a mouse.
“It's completely doable and I think it's worth doing,” he said.
Over 130 years have passed since Spanish neuroscientist Santiago Ramon y Kajal first spyed on individual neurons under a microscope to create unique branching shapes. Scientists from subsequent generations have resolved many of the details about how neurons send voltage spikes into long arms called axons. Each axon makes contact with small branches or dendrites of adjacent neurons. Some neurons excite their neighbors and fire their own voltage spikes. Some quiet other neurons.
Human thinking emerges in some way from this combination of excitation and inhibition. But how this happens remains a ridiculous mystery as scientists could only study a small number of neurons at a time.
Over the past few decades, technological advances have allowed scientists to begin mapping the whole brain. In 1986, British researchers published a circuit for a small worm consisting of 302 neurons. The researchers then charted larger brains, including 140,000 neurons in the fly's brain.
After all, is Dr. Crick's impossible dream possible? In 2016, the US government launched a $100 million effort to scan cubic meters of mouse brains. The project was called Cortical Network (or Mechanical Intelligence from Microns) and was led by scientists from the Allen Institute of Brain Science, Princeton University, and Baylor School of Medicine.
Researchers have zeroed into part of the mouse's brain, which receives signals from the eyes and reconstructs what the animal is seeing. In the first phase of the study, the team recorded the neuronal activity in that area as they showed mouse videos of different landscapes.
The researchers then dissected the mouse's brain and allowed the chemical to harden into cubic millimeters. They then shaved 28,000 slices from blocks of tissue and captured images of each. The computer was trained to recognize the contours of cells within each slice and link the slices to three-dimensional shapes. The team charted 200,000 neurons and other types of brain cells, along with 523 million neural connections.
For Nuno da Costa, a biologist at the Allen Institute and one of the project's leaders, just seeing the cells in shape on his computer screen was breathtaking. “These neurons are absolutely fantastic – it gives me joy,” he said.
To understand how this neuronal mesh worked, Dr. Da Costa and his colleagues mapped the activity recorded when mice watched the video.
“Imagine coming to a party with 80,000 people and being aware of all the conversations. “And now, imagine there's a way to know who you're talking to and who you're talking to. But you don't know what they're saying. If you have these two things, you can tell a better story about what's going on at the party.”
Analyzing the data, researchers discovered patterns of brain wiring that had previously escaped notifications. They identified different types of inhibitory neurons, for example, that link only to certain other types of neurons.
“When you study the brain, it seems like a kind of despair. There's so many connections and very complexity,” said Mariella Petcova, a biophysicist at Harvard University who wasn't involved in the Micron Project. “Finding wiring rules is a victory. Your brain is far less messy than people thought,” she said.
Many Microns researchers are currently taking part in a larger project, mapping the entire brain of mice. With a volume of 500 cubic millimeters, the perfect brain takes to chart in the current way for decades or centuries. Scientists need to find additional tricks to complete the project in 10 years.
“What they already had to do to get here is heroic,” said Gregory Jefferis, a neuroscientist at the University of Cambridge who was not involved in the Microns project. “But we still have mountains to climb.”
Forest Colman, a member of the Allen Institute's Micron Project, is optimistic. He and his colleagues recently discovered a way to make microscopically thin sections from the entire brain of a mouse. “Some of these barriers are beginning to fall,” Dr. Colman said.
However, our own brains are about 1,000 times larger than the mouse brain, presenting a much bigger challenge. “Now, the human brain feels like it's outside of what's possible,” he said. “We won't be going there any time.”
However, Princeton neuroscientist and member of the Micron Project, Sebastian Soon said that the mouse brain and the human brain are sufficiently similar.
“Our current ways of manipulating the nervous system are incredibly blunt,” Dr. Sunn said. “You put in the drugs and go anywhere,” he added. “But it's that you can actually reach and manipulate a cell type. That's accuracy.”
Efforts to map the entire brain of mice are supported by funding from the long-term National Institutes of Health Program, known as The Brain Initiative. However, the future of efforts is uncertain. Last year, Congress cut funding for the Brain Initiative by 40%, and last month President Trump signed an additional 20% support for claim reduction.
Dr. Bock noted that brain mapping efforts like Micron take years. This is because new technology and software inventions are required along the way.
“To realize these long-term goals, we need consistency and predictability in science funding,” Dr. Bock said.
