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In the meantime, other laboratories are trying to refine their understanding of just how neurons forge these connections. Here, too, many long established assumptions don't seem so solid anymore.
For the past 20 years, neuroscientists have been piecing together a story in which the key to linking neurons is a kind of molecular switch called an NMDA receptor. (The letters stand for the polysyllabic name of a chemical used to identify these molecules in experiments.) The mechanism is thought to work like this: if one neuron repeatedly sends signals to a second neuron, its NMDA receptors respond by unleashing a cascade of chemical reactions that strengthen the bond between the two cells. Just how this occurs remains a matter of almost religious debate. But somehow the "volume" of the connection is turned up. In some cases, entirely new connections may be formed.
It has been known for years that mice whose NMDA receptors have been chemically blocked have trouble learning their way around a maze. In the most dramatic demonstration of the power of the idea, Joseph Tsien, another Princeton researcher, developed a genetically engineered breed of "smart mice" with souped-up NMDA receptors and showed that the rodents had enhanced powers of memory.
But just as the pieces were starting to fall together, Tsien's lab did another experiment that complicated matters. Mice were bred with no NMDA receptors in a region of the hippocampus known to be especially crucial to memory. As expected, these mice showed seriously diminished memory power. But when they were exposed to a stimulating environment full of toys and exercise wheels, they got their memory back. When the scientists examined the mice's hippocampal tissue with an electron microscope, they found that new neural connections had been formed without the aid of the seemingly crucial NMDA memory switches. "That was really surprising," Tsien says.
There are a couple of plausible explanations. Neurons in the hippocampus might be making new connections using some entirely different means that has escaped researchers' attention. Or the connections normally forged in the hippocampus were being formed instead in the cortex, where the mice's NMDA receptors remained intact. Brains are so amazingly resilient that it's common for functions lost in one area to be taken over by another. In any case, the neat lines of the old picture have been fuzzed up again.
Zeroing in on the mechanism of imprinting engrams and determining whether or not neurogenesis is involved will be just the first steps in a long progression toward understanding how we remember. If memories are indeed stored as configurations of connected cells, then what do these patterns look like? How many neurons does it take to represent the image of your pet cat, and how is that pattern connected to the patterns that represent the abstract categories of cats, pets, mammals and living things?
And when you read a book, how are the neurons stitched together to record the memorable passages? How are they filed so you know the memory came from a book and not from your own experience? And while you are scanning the pages, how do you call up the patterns that represent the definitions of the words and their sounds, and the rules for unpacking meaning from a sentence?