The single capillary and the active brain

Few methods in neuroscience have attracted wider interest, among scientists and the general public, than those demonstrating patterns of brain activity in relation to behavior. First measuring 2-deoxyglucose (2DG) uptake in animals (1), then positron emission tomography (PET) in humans (2), and most recently functional MRI (fMRI) (3, 4) have provided dramatic views of what appears to be “the brain in action”: sensing, moving, feeling, reading, speaking, and even thinking. Although these patterns have been intriguing, what they actually mean in terms of brain mechanisms has been unclear. That they reflect local energy demands of active nerve cells, dependent on oxygen supplied by the local vasculature, is agreed for all methods. But what kinds of cellular activity are the patterns actually indicating? Are they due to neurons or glia; axons or synapses; action potentials or synaptic potentials; excitatory or inhibitory synaptic potentials? And how is the microvasculature matched to the demands of this activity? These questions are rapidly defining a new frontier in brain scanning (5). Answers to these questions require animal experiments that can image local vasculature in relation to local active cells. A recent method for accomplishing this is two-photon microscopy, which enables observations of functional changes in cellular structures down to a micrometer or less in diameter. This approach has permitted imaging of red blood cell (RBC) flow in capillaries within the cerebral cortex of rats (6). Chaigneau et al. (7) have taken this a step further and, in this issue of PNAS, report the tracking of individual red blood cells within individual capillaries in relation to local areas of high synapse density and of thin unmyelinated axons. The results give …