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Study Sees Brain in Process of Seeing
Laser Imaging Provides View of Every Cell at Once in a Visual Circuit
Applying a new microscopy technique that detects the activity of individual neurons in the brain of a living animal, HMS researchers have gotten the first close-up look at the neural circuits that produce vision in action.
A see change. This functional map of the visual cortex in a living rat shows a group of single cells selectively responding to a particular visual stimulus. The cells are stained with a calcium indicator to reflect cell activity. (Image courtesy of R. Clay Reid)
“Put simply, this technique allows us to see the brain seeing,” said R. Clay Reid, HMS professor of neurobiology, a member of the systems neuroscience initiative at the School, and principal investigator on the project. “It’s an entirely new way of looking at brain function.” The study appeared online Jan.19 in the journal Nature (doi: 10.1038/nature03274).
The method, the first to track the responses of all the neurons in a visual circuit simultaneously, promises to rapidly advance the understanding of how the brain is wired for complex image processing. Lessons learned by studying the visual system may eventually apply to brain functions like movement, thinking, and learning, as well as to neurodegenerative diseases.
Firing Squads
Reid, research fellow Kenichi Ohki, and their colleagues captured pictures of nerve cells firing in the visual cortex, the region of the brain that processes neuronal input from the eye. Decades of work by David Hubel and Torsten Wiesel, both Harvard neurobiologists and Nobel laureates, revealed how neurons in the visual cortex respond to image fragments: some fire only when they see horizontal or vertical lines, others react specifically to leftward or rightward movement. But a deeper understanding of how the neurons coordinate to produce a complex image has been elusive, partly because techniques to examine neural circuits were limited to tapping into just a few cells among many or making fuzzy pictures of many cells at once.
Research by R. Clay Reid and his colleagues has revealed microscale organization of visual neurons in cats that had not previously been seen by other mapping methods. (Photo by Steve Wimberly)
To get a higher resolution picture of how visual cortex neurons are organized, the researchers used a technique to fill neurons in cats or rats with a dye that glows brightly when calcium rises, a tip-off that the nerves are firing; the method was developed by German researchers led by Arthur Konnerth. The HMS team then illuminated the cells with a high-powered laser and used a sophisticated microscope to make time-lapse images of hundreds of neurons blinking on and off while the animals viewed a computer screen showing black and white bars moving in various directions.
| “The ability to visualize what individual neurons in a circuit are doing while that circuit is functioning opens up new roads to understanding the neural basis of visual perception.” |
The result surprised researchers, since the fine mosaic of functional segregation in cats looks more precise than current models demonstrate. While the bodies of nerves that respond together are seen bunched tightly, their dendrites branch out over a much larger area to pick up incoming signals, overlapping the territory of other neurons. And in the rat, the observed microarchitecture was completely different than in the cat. Instead of being segregated, neurons that recognized different stimuli were mixed together, suggesting that nature has managed to find different solutions to the same computational problem. As for the overarching mystery of how the cortex works, Reid said, “We still don’t know. Rather than answering a question, this work poses a whole new set of questions.”
Technique Takes Off
Answers are sure to come as the imaging technique is rapidly adopted and improved by a growing number of neurobiologists. “The ability to visualize what individual neurons in a circuit are doing while that circuit is functioning opens up new roads to understanding the neural basis of visual perception,” said David Fitzpatrick, a professor of neurobiology at Duke University who also studies visual cortex function, but is not an author on the paper. “By combining markers for different types of neurons with this calcium imaging technique to look at their activity, we will have a powerful approach to ‘circuit breaking’ in the visual cortex. The same principle will undoubtedly be applied to cortical areas responsible for other sensory modalities, as well as motor functions and higher cognitive processes.”
The applications of single-neuron imaging will be plentiful, according to Alzheimer’s disease researcher Bradley Hyman, the John B. Penney, Jr. professor of neurology at Massachusetts General Hospital. “This is basically a very advanced method for studying neuronal function, and any disease process where neuronal function is involved can be studied with this approach,” he said. “We have rodent models of Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, and this imaging will be a powerful tool to dissect the cellular basis for the cognitive problems we see in these diseases.”
— Pat McCaffrey
A multimedia companion to this story appears in Lab Works