For the first time, researchers have developed a microscope capable of observing -- and manipulating -- neural activity in the brains of live animals at the scale of a single cell with millisecond precision. By allowing scientists to directly control the firing of individual neurons within complex brain circuits, the device could ultimately revolutionize how neuroscience is done and lead to new insights about healthy brain functioning and neurological disorders.
"With this new microscope, we believe we will soon be able to treat the brain as the keyboard of a piano, so to speak, and write in a sequence of activity that is needed to understand or correct brain function," said Hillel Adesnik, Ph.D., assistant professor of neurobiology at the University of California, Berkeley, who led the research team. "After more refinements, this instrument may be able to function as a sort of Rosetta Stone to help us crack the neural code."
Adesnik will present this research at the American Association of Anatomists Annual Meeting during Experimental Biology 2016.
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.
"If you want to learn a language, you need a dictionary, and if you want to understand how a machine works, you need to know its parts," said Adesnik. "We wanted to develop a technology that can offer a general approach to understand the basic syntax of neural signals, so that we can begin to understand what a given brain circuit is doing and perhaps what's gone wrong with that in the case of a disease."
The best way to learn that syntax, Adesnik said, 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, is the first to be able to handle and transmit information at a spatial and temporal scale that is truly relevant to manipulating brain activity.
"The brain is an enormous collection of single cells, and cells right next to each other could be doing entirely different things," Adesnik said. "The resolution of our technique is key, because if you aren't looking at a single cell you could be scrambling your code, so to speak, and you won't be able to correctly interpret it. By overcoming the last technological hurdles to get to that single cell resolution, and at the same time getting to the temporal scale that cells operate at, we have developed a prototype microscope that achieves the level of detail needed to actually understand the neural code."
The tool they have devised is essentially a microscope that 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-powered infrared lasers to create a 3-dimensional 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 called optogenetics -- the hologram induces the neurons to send electrical signals in a specific pattern that is pre-determined by the researchers.
"We're adapting holographic display technology, optogenetics and sensory biology and behavior into one complete system that allows an all-optical approach to image and manipulate the nervous system," said Adesnik. "We've essentially put a lot of disparate existing pieces together to achieve something nobody had yet achieved."
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 in order 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 said 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.
Materials provided by Federation of American Societies for Experimental Biology (FASEB). Note: Content may be edited for style and length.
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