Reliving the past. Exploring a new cage created clozapine receptors (red) in the brains of genetically engineered mice. Activating these receptors with the drug reawakened the memory.

A. R. Garner et al., Science

Researchers Reawaken Old Memories in Mice

Call it Total Recall for mice. In two new studies, researchers have found a way to stimulate the brains of rodents to activate a specific memory trace. This advance could help explain how we form our own memories, and why competing recollections sometimes make it hard to learn new information.

In recent years, neuroscientists have devised several ways to erase memories in rodents. The new studies take steps in a different direction, using the latest genetic and other tools to activate specific memories on command.

In the first study, cell biologist Mark Mayford of The Scripps Research Institute in San Diego, California, and colleagues genetically engineered mice to be able to relive a memory when injected with the schizophrenia drug clozapine. Certain activities, such as exploring a new environment, cause these mice to create receptors for the drug; and when they're given the drug later, the same neurons fire as did when the mice explored the new environment. In effect, clozapine recreates the memory.

Mayford's team hypothesized that reactivating a memory in this way might interfere with the ability to form new memories. To test the idea, the researchers placed mice in a new cage—one with nondescript, opaque white walls. A day later, they gave the rodents injections of clozapine immediately before placing them in another cage, this one with a wintergreen smell and checkerboard walls. Here the mice received a series of mild foot shocks. If the team's hypothesis is correct, activating the old memory of the bland room would interfere with the mice's ability to form a new memory about the bad cage.

And indeed, when the researchers placed the rodents in the shock cage the next day, the animals showed no fear. Normally, a mouse that's had an unpleasant experience in a particular place will freeze with anxiety the next time it's there. The finding suggests that the mice really had relived an old, bland memory when first introduced to the electric shocks, says Mayford, whose team reports its findings in the 23 March issue of Science.

But a second injection of clozapine appears to have helped the mice effectively separate the good and the bad memories. When Mayford and colleagues gave the mice the drug while they were still in the shock cage, the rodents suddenly froze, as if finally remembering that they were in a bad place. To Mayford, this suggests that when the mice got the drug in the first round of the experiment, it caused a bland memory to be muddled with a bad one, thereby hampering the rodents' ability to learn. But the second injection "demuddled" the memories, perhaps by making the old one more clear and matching the new one against it.

"The relevance to normal learning is that we do this all the time," Mayford writes in an e-mail. "When you learn something new you integrate it with old information that is similar and sometimes it is difficult to separate the two."

In the second study, reported online today in Nature, researchers were also able to reactivate an old memory in mice. In this case, molecular biologist and Nobel laureate Susumu Tonegawa of the Massachusetts Institute of Technology in Cambridge and colleagues added a light-sensitive receptor to a group of cells in a memory nexus called the hippocampus. These cells are known to be involved in fear-related learning. The mice went through the same shock-conditioning process as in the Mayford study and were then returned to their home cage. When the receptors were activated by a pulse of laser light, the animals immediately froze, though there were no cues, visual or otherwise, to remind them of the shock. "Our finding shows that activating these cells is absolutely sufficient to produce recall in the mice," Tonegawa says.

Neuroscientist Howard Eichenbaum of Boston University says both studies are exciting. "Both use state-of-the-art molecular tools to show that activating neuronal networks engaged during learning is a stand-in for the original experience." He adds that "the findings support the idea that reengaging the neural networks activated during learning allows mental time travel."

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