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'Total Recall' for Mice

25 July 2013 2:00 pm
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Evan Wondolowski/Collective Next

Warped recall. Scientists labeled brain cells of a mouse in context A (left). The mouse received shocks in context B (center) while those cells were stimulated to recall context A. When returned to context A, it showed a fear response, though it had never been shocked in that context (right).

Our imperfect memory is inconvenient at the grocery store and downright dangerous on the witness stand. In extreme cases, we may be confident that we remember something that never happened at all. Now, a group of neuroscientists say that they’ve identified a potential mechanism of false memory creation and have planted such a memory in the brain of a mouse.

Neuroscientists are only beginning to tackle the phenomenon of false memory, says Susumu Tonegawa of the Massachusetts Institute of Technology in Cambridge, whose team conducted the new research. “It’s there, and it’s well established,” he says, “but the brain mechanisms underlying this false memory are poorly known.” With optogenetics—the precise stimulation of neurons with light—scientists can seek out the physical basis of recall and even tweak it a bit, using mouse models.

Like us, mice develop memories based on context. When a mouse returns to an environment where it felt pain in the past, it recalls that experience and freezes with fear. Tonegawa’s team knew that the hippocampus, a part of the brain responsible for establishing memory, plays a role in encoding context-based experiences, and that stimulating cells in a part of the hippocampus called the dentate gyrus can make a mouse recall and react to a mild electric shock that it received in the past. The new goal was to connect that same painful shock memory to a context where the mouse had not actually received a shock.

First, the team introduced a mouse to a chamber that it had never seen before and allowed it to explore the sights and smells: a black floor, dim red light, and the scent of acetic acid. In this genetically modified variety of mouse, neurons in the hippocampus will produce a light-sensitive protein when they become active. Because only the neurons involved in the mouse’s experience of this chamber became sensitive to light, these cells were essentially labeled for later reactivation.

The next day, the mouse found itself in a decidedly more unpleasant chamber: The lights, colors, and smells were all different, and it received a series of mild electric shocks to its feet. While the mouse was getting shocked, the scientists used optical fibers implanted in its brain to shine pulses of blue light on its dentate gyrus, reactivating specific cells that had been labeled the day before as the mouse explored the first, less painful chamber. The hope was that the mouse would form a new (and totally false) association between the first room and the painful shocks.

Even though the mouse never got shocked in the red-and-black, acid-scented room, it froze in fear when it returned there, confirming that it had formed a false, context-specific memory, the team reports online today in Science. Tonegawa says that it’s impossible to know just what the mouse experienced as the scientists stimulated its brain with light—whether it felt some or all of those earlier sensations, or even perceived that it was back in the first chamber during the shocks. But it is clear that the rodent recalled a painful experience when it returned to that first environment. It showed no signs of fear when placed in a third, unfamiliar chamber, demonstrating that the fear response was indeed triggered by the first room.

Tonegawa suggests that these results could help explain some of the cases in which humans form false memories. We are constantly imagining, daydreaming, and remembering, and these activities might alter our experience of the events around us, he says. He offers the extreme example of a woman who was watching a TV show at home when someone broke in and assaulted her. She later insisted that the host of the show had been her attacker, apparently transplanting the object of her attention into a memory of the physical experience.

The results are “clear and strong,” and the work is “a very profound finding,” says neuroscientist Mark Mayford of the Scripps Research Institute in San Diego, California, who was not involved in the study. No previous experiment has shown that activating a precise pattern of cells can serve as a substitute for a real-life experience and create a learned behavior, he says. Mayford, whose work also focuses on learning and memory manipulation in mice, says it’s theoretically possible that humans form false memories in a similar way. But more importantly, he says, the research offers clues about where and how a new experience gets encoded in the brain to begin with. With this knowledge, he believes that neuroscientists can start to take a more quantitative approach, someday figuring out how many neurons it takes to give us the perception of what’s around us and what goes on in our neural wiring when we remember—or misremember—the past.

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