Mice may light the way to treating PTSD

Someone who has been mugged in a dark alley will likely never want to return there, having associated that location with a fear of being attacked.

But neuroscientists working with mice say they've discovered the brain circuit that controls how memories are linked with positive and negative emotions. And in rodent tests, they've manipulated brain cells to reverse the emotions attached to a memory.

In essence, they made once-reluctant mice want to return to that dark alley, by replacing their negative emotions with positive ones through stimulation of a key memory region in the brain.

The findings explain what happens inside the brain when psychotherapy helps lift a person out of depression, said senior author Susumu Tonegawa, director of the RIKEN-MIT Center for Neural Circuit Genetics at the Massachusetts Institute of Technology in Cambridge, Mass.

"The psychiatrist will talk with a patient suffering depression and try to make them recall positive memories they have had in the past," Tonegawa said. "Apparently, this will reduce the effect of the bad memories they have had or the very strong stress they have had. But unless you look into the inside of the brain, you can't tell what's going on underneath the behavior."

When people create memories, they store a great deal of context along with the memory itself, he explained. "The memory information stored is not only about what happened, but also about the context in which the event occurred," Tonegawa said. Part of that context includes how a person felt about the event.

Showing that the context of negative memories can be changed is promising, said Dr. Paul Sanberg, professor of neuroscience at the University of South Florida in Tampa. "If we can harness that information and carry it further, we may be able to come up with new clinical insights," he said.

The brain region that creates these emotional links could prove a useful target for new medications and therapies intended to treat disorders such as depression or anxiety, Sanberg said.

But the findings, published in the Aug. 28 issue of Nature, would have to be replicated in humans before they could influence clinical practice.

The investigators set out to discover which brain structures are responsible for linking memories to emotions, using laboratory mice with fiber-optic brain implants. Through a technique called optogenetics, researchers used laser light to stimulate parts of a mouse's brain.

They focused on two parts of the brain -- the amygdala, which processes emotion, and the dentate gyrus of the hippocampus, where much of a memory's context and detail are stored. Context includes information about where an event took place.

Male mice first were conditioned with either fearful memories through small electric shocks or rewarding memories through interaction with a female mouse. The neurons associated with this emotional context were located in the dentate gyrus, researchers found.

Two days later, the mice were placed into a large arena. The researchers recorded which half of the arena the mice naturally preferred, and then began stimulating the dentate gyrus cells with light as the mice wandered around the arena.

Mice conditioned with fear received memory stimulation whenever they were on the side they naturally preferred, and they soon began avoiding that area. On the other hand, mice with happy memories received stimulation when they wandered into the area they preferred less, and they ended up feeling better about that location and spent more time there, the study found.

Researchers then tried to reverse the emotional responses stored in the rodents' brains. For male mice with fear conditioning, the researchers light-activated the memory cells involved in the fear memory while the mice spent pleasant time with female mice. For mice that had initially received the reward conditioning, memory cells were activated while they received mild electric shocks.

The reversal worked, and the mice ended up switching the side of the arena they preferred when their memories were stimulated by light.

Subsequent attempts to alter emotional memories through manipulation of the amygdala didn't work, suggesting that emotions are hard-wired into individual cells inside the amygdala, the study authors noted.

Dr. Scott Turner, a professor of neurology at Georgetown University, said understanding how memory and emotion intersect could be key to treating people with post-traumatic stress disorder (PTSD).

"If you could find ways to reverse the [emotion] associated with a particular memory so it isn't so negative, you could help these people suffering from stressful memories," Turner said. "Obviously, we're a long way from that, since this study was performed in mice."