Scientists Turn Bad Memories Into Good Inside the Brains of Mice

Neuroscientists have devised a technique for switching the emotional association of a memory from bad to good by directly manipulating the neurons that encode it.
mouse
George Shuklin/Wikimedia

Remember that horrible date you went on a few years ago? The one where you knocked over a candle and doused the flaming tablecloth (and your date) with a bottle of Bordeaux? Horrible! But now the two of you are happily married and the whole thing seems... kind of sweet. Time has a way of shifting the emotions tied to our memories.

Now there's another way. Neuroscientists have devised a technique for switching the emotional association of a memory from bad to good by directly manipulating the neurons that encode it.

If that sounds like a promising therapy for disorders like PTSD, you’ll have to wait. The experiments were done in mice, and the methods, which include genetically altering neurons and inserting an optical fiber into the brain, won’t be used in people anytime soon (if ever). But this study and others like it are illuminating the neural mechanisms of memory in unprecedented detail, and showing that it’s possible to activate, alter, or even create memories just by tweaking the right neurons.

The work was done in the lab of Nobel Prize-winning immunologist-turned-neuroscientist Susumu Tonegawa at MIT. The team, led by postdoctoral fellow Roger Redondo and graduate student Joshua Kim, first created good and bad memories in mice by giving them either a food reward (good!) or a mild shock (bad) when they wandered into a certain part of their enclosure.

Such memories have two components that are encoded by different parts of the brain. The memory of where it happened is encoded by the hippocampus. The emotional component—the memory of whether it was good or bad—is encoded by the amygdala.

To try to switch a memory from bad to good, the researchers reactivated the neurons in the hippocampus that encoded the “where” component of a shock memory in a male mouse while he got a more positive stimulus—in this case, getting to spend some quality time with two female mice. If the business about reactivating the memory sounds simple, it was anything but: It required a slew of clever genetic tricks to mark the relevant neurons, make them responsive to pulses of laser light, and then deliver the light to just the right spot with a surgically-implanted optical fiber.

Prior to the memory altering procedure, when the researchers put the mouse in the enclosure where he'd received the shock and used a pulse of laser light to reactivate the memory in his brain, the mouse avoided the area where he'd gotten zapped. But when they did this after the memory altering procedure, the mouse spent more time in that area and even sniffed around a bit, as if looking for his lady friends. His memory of this place, it seems, had changed from bad to good.

The procedure also worked in reverse: Memories could be altered so that mice would avoid an area where they'd previously received a food reward, the team reports today in Nature.

The work doesn't contain any big surprises for memory researchers, but it represents a very impressive technical feat, says Howard Eichenbaum, a neuroscientist at Boston University. "It's amazing that with this combination of molecular techniques you can label the exact neurons involved in encoding a memory and then reactivate them with light," Eichenbaum said. Such tools are making it possible for researchers to dissect the neural circuits involved in memory and other functions in greater cellular detail than older methods allowed.

The new findings don't have any immediate implications for treating psychiatric conditions, but they do help provide a scientific rationale for certain types of talk therapy used to treat depression and anxiety disorders, Eichenbaum says. "One popular technique in cognitive behavioral therapy is to expose people to a picture of the thing they're afraid of, like a spider, and train them to think of something pleasant," Eichenbaum said.

When Tonegawa's team examined the brains of mice that had undergone their memory-altering procedure, they found microscopic evidence of new connections between the hippocampus and the amygdala. That could explain how positive emotions get attached to previously fearful memories, Eichenbaum says. But they also found anatomical evidence that the original fear memory doesn't completely disappear, he notes, which is consistent with the experience of therapy patients who learn to deal with their anxiety, but never completely overcome it.