Novel IR microscope can manipulate neural activity in live animals

A team of researchers at the University of California, Berkeley (UC Berkeley) has developed a infrared (IR) microscope that can observe and manipulate neural activity in the brains of live animals at the single-cell level with millisecond precision. With its ability to directly control the firing of individual neurons within complex brain circuits, the device could lead to new insights about healthy brain functioning and neurological disorders.

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Research team leader Hillel Adesnik, Ph.D., a UC Berkeley assistant professor of neurobiology, says that the new microscope will allow scientists to write in a sequence of activity that is needed to understand or correct brain function.

To process inputs, store information, and issue commands, the brain's neurons communicate with each other through on-off electrical signals akin to the ones and zeroes used to encode information in computer programming. Although scientists have long been able to observe these signals with various imaging techniques, without understanding the “syntax” of how that digital code translates into information, the brain’s communication system has been essentially indecipherable. So, Adesnik and his team worked to develop a technology that can offer a general approach to understand the basic syntax of neural signals, which will allow scientists to begin to understand what a given brain circuit is doing and perhaps what has gone wrong with that in the case of a disease, Adesnik says.

The best way to learn that syntax, Adesnik says, is to not simply read the information, but to actually write it by making small tweaks in the code, inputting the new code back into the brain and seeing how it alters a perception or behavior. The new microscope, which Adesnik's team developed by combining and building upon several existing technologies developed by other researchers, can handle and transmit information at a spatial and temporal scale that is relevant to manipulating brain activity.

Adesnik says that he and his team overcame the last technological hurdles to get to the single-cell resolution and, at the same time, get to the temporal scale at which cells operate. This allowed them to develop a prototype microscope that achieves the level of detail needed to actually understand the neural code, he says. The microscope essentially points into the brain of a live mouse, zooms in on a few thousand cells, and uses sophisticated lasers to manipulate electrical signals between individual neurons.

Since the lasers can penetrate brain tissue but not skull, the research team implanted small glass windows into the skulls of the mice used to test the instrument. When positioned atop the window, the microscope uses two different types of high-power IR lasers to create a 3D holographic pattern in a specific area of interest within the brain.

Because the research is done in mice genetically modified to have neurons that respond to light—a technique known as optogenetics—the hologram induces the neurons to send electrical signals in a specific pattern that is pre-determined by the researchers.

So far, the team has conducted preliminary tests of the instrument by mapping the effects of small perturbations, such as wiggling a whisker, and then creating holograms that induce the neurons to fire in the same—or slightly different—patterns. In a series of tests that are still underway, they are working with mice trained to push a specific lever when they see a certain shape to develop holograms that “trick” the mouse into seeing, for example, a circle where none exists, or to make the mouse perceive a square as a circle. In the near future, the team hopes to apply the microscope to studies of memory formation.

Once it is further tested and refined, the most immediate applications for the microscope are likely to be in basic research, but Adesnik says it is conceivable that its core technology could one day be adapted for therapeutic use, for example, to correct neurological problems in a high-tech form of brain surgery. Such an application is still a long way off, however, and applying the device in human beings would require overcoming a whole new set of technological challenges.

President Obama recently named Adesnik as a recipient of a Presidential Early Career Award for Scientists and Engineers, the highest honor bestowed by the U.S. government on science and engineering professionals in the early stages of their independent research careers.

Adesnik presented his findings during the Experimental Biology 2016 meeting on April 5, 2016, as part of the Neurobiology Award Hybrid Symposium (San Diego, CA).