To succeed, researchers will need to find noninvasive ways to record the firing of individual neurons, because all current methods involve opening the skull and, often, sticking electrodes into brain tissue. “Right now, you’re literally driving posts into the brain. It’s not very sophisticated,” says neurobiologist John Ngai of the University of California at Berkeley.
A few groups are working on new approaches. The MindScope project at the Allen Institute for Brain Science in Seattle aims to map the visual cortex of mice. The team identifies where neurons are firing by injecting the brain with dyes or using genetically engineered proteins that bind to calcium molecules. When a neuron fires, calcium flows into the cell and activates the dye or protein.
While powerful and widely used, calcium imaging alone is too slow to generate the kind of real-time map that the brain activity mapping project requires, says Michael Roukes of the California Institute of Technology. A faster alternative would be to record the electrical activity of neurons, but the wires required to do this are invasive and tend to be relatively large. Roukes’s lab is creating tiny silicon-based nanowires that are connected to an array of electrodes, recording data from multiple neurons at once. Roukes’s team has tested the technology in insects and is now moving on to rats. Eventually, he says, they should be able to locate and record the activity from a million neurons at once.
But such an activity map is meaningless if it only shows connections and firing patterns without giving any clue why a circuit fires, says Karl Deisseroth of Stanford University. One way to show these cause-and-effect relationships is through optogenetics, which involves genetically engineering mice so that their neurons fire when hit with a beam of light shone through the skull. The firing neurons leave a protein trail, allowing researchers to see which circuits responded to the light or other stimuli.
The problem plaguing light-based techniques, some of which would get neurons to emit light, however, is the brain’s density. It is no good having a technology that tells you that a neuron has fired by giving off a flash of light if you cannot detect that light. The best microscopes can detect light from three to four millimeters into the brain, enough to see light signals coming from the cortex of a small animal, but not enough to see deep-seated structures such as the hippocampus. “For this, we will need to redesign the basic concept of the microscope,” says Rafael Yuste of Columbia University.