MIT unlocks mystery behind brain imaging

Star-shaped brain cells shown to play key role

Deborah Halber, News Office Correspondent
June 19, 2008

In work that solves a long-standing mystery in neuroscience, researchers at MIT's Picower Institute for Learning and Memory have shown for the first time that star-shaped brain cells called astrocytes--previously considered bit players by most neuroscientists--make noninvasive brain scans possible.

Imaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have transformed neuroscience, providing colorful maps of brain activity in living subjects. The scans' reds, oranges, yellows and blues represent changes in blood flow and volume triggered by neural activity. But until the MIT study, reported in the June 20 issue of Science, no one knew exactly why this worked.

"Why blood flow is linked to neuronal activity has been a mystery," said study co-author Mriganka Sur, Sherman Fairchild Professor of Neuroscience and head of the Department of Brain and Cognitive Sciences at MIT. "Previously, people have argued that the fMRI signal reports local field potentials or waves of incoming electrical activity, but neurons do not connect directly to blood vessels. A causal link between neuronal activity and blood flow has never been shown."

Of the two major cell types in the brain, glia outnumber neurons nine to one. Astrocytes--the most common type of glia--extend their branching tendrils both around synapses--through which neruons communicate--and along blood vessels.

Using a cutting-edge technique, Sur and colleagues found that astrocytes receive signals directly from neurons and provide their own neuron-like responses to directly regulate blood flow. They are the missing link between neurons and blood vessels, he said. When astrocytes are shut down, fMRI doesn't work.

"Astrocytes are implicated in many brain disorders and express a very large number of genes that are in the brain," Sur said. "Their role is crucial for understanding brain dysfunction as well as for developing potential therapeutics."

The MIT study shows that, contrary to prevailing belief, astrocytes influence complex neuronal computations such as the duration and selectivity of brain cell responses to stimuli. But their chemical signals had rendered them invisible to traditional brain research methods that monitor electrical activity.

"Electrically, astrocytes are pretty silent," said study co-author James Schummers, Picower Institute postdoctoral associate. "A lot of what we know about neurons is from sticking electrodes in them. We couldn't record from astrocytes, so we ignored them."

When astrocytes were imaged with two-photon microscopy, "the first thing we noticed was that the astrocytes were responding to visual stimuli. That took us completely by surprise," Schummers said. "We didn't expect them to do anything at all. Yet there they were, blinking just like neurons were blinking. We didn't know if the rest of the world would think we were crazy."

"This work shows that astrocytes--which make up 50 percent of the cells in the cortex but whose function was unknown--respond exquisitely to sensory drive, regulate local blood flow in the cortex and even influence neuronal responses," Sur said. "What's more, astrocytes are arranged in orderly feature maps, exquisitely mapped across the cortical surface in sync with neuronal maps."

Two-photon microscopy uses two infrared photons to emit fluorescence that enables imaging of living tissue up to 1 millimeter deep. Previously, researchers could only see astrocytes in dyed, thin slices of dead brain tissue.

The next step, Schummers said, is to explore exactly how astrocytes work on neurons.

In addition to Sur and Schummers, postdoctoral associate Hongbo Yu is a lead author of the study.

This work is supported by the National Institutes of Health and the Simons Foundation.

videos

Credit: James Schummers, MIT

Click to play. Labeling of neurons and astrocytes. The movie shows a z-stack (250 É m square) taken from the pial surface to a depth of 350 É m, every 2 É m. The depth is indicated every 10 É m in the bottom left corner. The left panel shows labeling with SR101, which selectively labels astrocytes only. The center panel shows the labeling with OGB1, which labels both neurons and astrocytes. The right panel shows merged images of the two channels, color-coded such that neurons appear yellow-green and astrocytes appear purple-white.

Click to play. Astrocyte visual responses are delayed relative to neurons. Movie showing the visual responses of the two cells plotted in text Fig. 1A-B. The movie shows the response to three repetitions of grating presentation, indicated in the bottom left corner. The two cells analyzed in text Fig 1B are circled for reference. Note the delayed response of the astrocyte. The movie plays at 10X real time.

Click to play. Visually evoked responses of neurons and astrocytes at a pinwheel center. Time series of É¢F/F images during presentation of drifting gratings changing in orientation from 0 to 150 degrees at 30 degree intervals. Schematic of the visual stimulus is shown in the bottom right corner. Neurons appear green, and astrocytes appear purple-white. Note that the activated cells rotate around the pinwheel center as the orientation of the stimulus rotates. The delay of the astrocyte response is also apparent.

image

Image / James Schummersand HongboYu, Laboratory of MrigankaSur

A field of neurons (green) and astrocytes(purple) within visual cortex, visualized by high-resolution two-photon imaging in the intact brain. The astrocytesare labeled with the marker dye SR101, and both neurons and astrocytesare subsequently labeled with the calcium indicator OGB1. Enlarge image