A laser-based microscopy technique may have settled a long-standing debate among neuroscientists about how brain cells process energy -- while explaining what's really happening in PET (positron emission tomography) imaging and offering a better way to observe the damage that strokes and neurodegenerative diseases, such as Alzheimer's, wreak on brain cells.
Multi-photon microscopy scans by Cornell University biophysicists of living brain tissue, as reported in the latest issue of Science (July 2, 2004), reveal exactly how and when neurons (the cells that do the thinking) and astrocytes (the starburst-shaped glial cells that service neurons) interact to burn oxygen and glucose, after astrocytes make lactate from glucose in the bloodstream, to meet the extraordinary energy demands of the brain.
Based on imaging of two different energy states of NADH (nicotinamide adenine dinucleotide, a coenzyme involved in brain-cell metabolism), the Cornell biophysicists say they have both confirmed and redefined the controversial "astrocyte-neuron lactate shuttle" hypothesis for brain energy metabolism.
"Over the past decade scientists have passionately debated whether the activated brain burns glucose completely to water or incompletely to lactate," said Karl A. Kasischke, M.D., lead author of the Science paper titled "Neural Activity Triggers Neuronal Oxidative Metabolism Followed by Astrocytic Glycolysis." "Our results unify existing contradictory opinions and should be a win-win situation for both factions," said Kasischke, who is a research associate in the Developmental Resource for Biophysical Imaging and Opto-electronics (DRBIO) laboratory headed by Watt W. Webb. Webb, Cornell's S.B. Eckert Professor in Engineering and a co-inventor of multiphoton microscopy who also is an author on the Science paper, explains: "Multiphoton microscopy imaging of intrinsic fluorescence in NADH shows that early oxidative metabolism in neurons is eventually sustained -- after about 10 seconds -- by late activation of the astrocyte-neuron lactate shuttle. Neurons, even at rest, are always burning glucose and they continue to do so when a signal begins to pass through the neurons. Then the astrocytes 'kick in' to provide lactate fuel that they have converted from glucose."
If that seems like a fine point, it is one that escaped scientists who developed PET and fMRI (functional magnetic resonance imaging) scanning technologies, as well as the medical personnel who use those diagnostic tools everyday without knowing exactly what the images represent. PET and fMRI are not recording neural activity directly, but rather surrogates for activity -- changes in blood flow (in the case of PET) and blood oxygenation (fMRI) -- Kasischke explained. He compares PET and fMRI scans to pictures from cameras with slow shutter speeds and wide-angle lenses, producing a broad view over a relatively lengthy time span. A very different picture emerges from multiphoton microscopy, which can record millisecond changes in microscopic detail. The ultra-fast microscopic technique can image individual nerve cells and even their finest extensions, where important steps in brain-cell metabolism take place.