How live recordings of neural electricity could revolutionize the way we see the brain

The red and blue lights are flashing. A machine swirls like a distant swarm of bees. In a room the size of a booth, Yoav Adam, a microscope and a video projector capture something that no one has ever seen before: real-time flashing neurons, in a living creature walking .

For decades, scientists have been looking for a way to watch a live broadcast of the brain. Neurons send and receive huge amounts of information: itching! Hot fire! The garbage smell! – with impressive speed. Electrical signals can travel from cell to cell at a maximum speed of 270 miles at the time.

But neural electricity is as difficult to see as electricity in a telephone wire: For an unaided eye, the busy brain looks as lifeless as rubber. Thus, to observe how neurons transform information (itching) into thoughts ("scratch powder"), behaviors (scratching) and emotions (anger), we need to change the way we think.

A new study, published in Nature, just do that.

Adam Cohen, professor of chemistry and chemical biology and physics at Harvard, the first author, Dr. Yoav Adam, and his interdisciplinary research team literally illuminate the brain, turning neuronal electrical signals into visible sparks under a microscope.

Deceive nature

In the 1980s, during an ecological study of the Dead Sea, an Israeli ecologist discovered an organism that does a trick: converting sunlight into electrical energy in a primitive form of photosynthesis. But for nearly 30 years, the body and its talented protein (Archaerhodopsin 3) floated undisturbed in the waters of the Dead Sea.

Then, in 2010, researchers at the Massachusetts Institute of Technology (MIT) dusted the protein, introduced it into the brain and got the tiny tool to perform its light tower in the neurons. When they learned how to use the protein-enriched brain, the tool converted light into electricity. Researchers could then modify the onset of neurons and even if they choose to manipulate the behavior of the animal.

Cohen was intrigued. He wondered: can we reverse the trick? Could the protein convert the electrical activity of neurons into detectable flashes? After a few years of hard work, he discovered his answer: yes. It can.

Sharpen the tools

When lit with a red light, archaherodopsin can turn a voltage into light (this tool and other similar tools are called genetically encoded voltage indicators or GEVI). The protein acts as an ultra-sensitive voltmeter that, like the hair on your arm, changes with an electric shock.

The Cohen laboratory associates this protein with a similar protein that, when illuminated by blue light, triggers electrical impulses in the neurons. "So," says Yoav, "we can both control the activity of the cells and record the activity of the cells." Blue light controls; red light discs.

Protein pairs worked well in neurons located outside the brain, in a dish. "But," said Cohen, "the Holy Grail was to make it work in living mice that actually do something."

The "Holy Grail" is elusive after five years of intense interdisciplinary collaboration between 24 neuroscientists, molecular biologists, biochemists, physicists, computer scientists and statisticians. First, they modified the protein to work in live animals; then, with some clever genetic manipulations, they positioned the protein in the right part of the right cells of the mouse brain. Finally, they built a new microscope, customized with a video projector, to project a red and blue light pattern into the living mouse's brain, as well as into specific cells of interest.

"You're basically doing a little movie," says Cohen.

With red and blue light on the brain, Yoav can control when and which neurons trigger and capture their electrical activity as light. To identify individual neural signals in bright chaos, the team has developed a final tool: software capable of extracting specific neuronal sparks, such as individual fireflies from a swarm.

Clarity of chaos

But neural signals travel much faster than fireflies. After a third of the time needed to blink, Cohen's team can capture intimate and precise details of the pattern of a neuron's spikes, such as the changing positions of the wings. a firefly in flight. They can record up to ten neurons at a time, an impossible feat with existing technologies and, three weeks later, find exactly the same neurons to record.

Yoav is not the first to record neural signals: thin glass tubes like hair, inserted into brain tissue, can do the job. But such devices only record one or two neurons at a time and, like a burst, must be removed before causing damage. Other tools monitor calcium, which floods the neurons when they are triggered. But, according to Cohen, "depending on how you do it, it's 200 to 500 times slower than the voltage signal that Yoav is looking at."

Now, Yoav can deepen his vision and examine the impact of behavioral changes on neural chatter. For his first attempt, he simply started: a mouse walked on a treadmill for 15 seconds, then rested for fifteen seconds. During both stages, Yoav projected blue and red light over the hippocampus region of the brain, a hub of learning and memory.

"Even with simple behavioral changes, walking and resting," Yoav said, "we could see sharp changes in electrical signals, which also varied between different types of hippocampal neurons."

"Some go faster, others more slowly," says Cohen.

Yoav also observed different types of activity patterns: some neurons had complex peaks, such as the rolling Appalachian mountain range, while others projected large peaks, such as Mount Everest. These tips can be detected by probes on the outside of cell membranes. But, Yoav can see the smaller voltage signals that ultimately determine whether a neuron is in peak. These sub-threshold details have rarely been seen or studied in live animals: The right tools just did not exist.

Then, Yoav and his team will add complexity to the environment of the mouse treadmill: rough circles of velcro, mustache strips and sugar station. Yoav, in particular, wants to know more about spatial memory. For example, can the mouse remember where to find the sugar station? "Nobody knows what a memory really looks like," says Cohen. Soon, we could.

In the meantime, the interdisciplinary team will continue to sort through complex data and improve its optical, molecular and software tools. Better tools could capture more cells, deeper brain regions and cleaner signals. "A mouse brain contains 75 million cells," says Cohen, "so, from your perspective, we have worked a lot or we still have a long way to go."

But Yoav, who has postponed his five years of development challenges to his "Holy Grail," will continue to move forward. For him, the end result always seemed possible: "I could see the light."