Optogenetics swaps out negative memories for positive ones in mice

Massachusetts Institute of Technology (MIT; Cambridge, MA) researchers have made mice enjoy spending time in a place they once feared using light-dependent manipulations of the animals' neurons, according to a study. Using optogenetics, the researchers were able to alter connections between hippocampal neurons and amygdala neurons to control memory reversal.

Related: Optogenetics helps clarify brain circuit, aiming for new treatments for psychiatric disorders

Memories are created and stored in multiple areas of the brain. The amygdala, for example, processes information relating to whether something is good or bad and pleasurable or scary, and the hippocampus stores information about particular places and events, explains Richard Morris, a professor of neuroscience at the University of Edinburgh, who did not participate in the study. "But if the amygdala and hippocampus talk to each other through fiber pathways, then you . . . remember a particular place and—because the amygdala neurons are doing their thing—you also remember it's a good place," he says.

Susumu Tonegawa, a professor of biology and neuroscience at MIT, wanted to understand the physiological mechanisms behind changes in emotions. To find out, he and his colleagues used an optogenetic technique that, with a light-activated protein, labels only those neurons that fire during the formation of a specific new memory. The resulting light-inducible, memory-associated cells can then be reactivated with lasers "at will," explains Roger Redondo, a postdoctoral scientist in Tonegawa's laboratory and a lead author of the study.

The team used the technique to label neurons in the amygdala or hippocampus that were activated as male mice learned to fear a particular location, where they received electric shocks to the feet. The researchers then housed each fear-conditioned male mouse with female mice—a pleasant experience—while reactivating their now light-inducible neurons in the hippocampus or amygdala. When the amygdala-reactivated mice were returned to the location they had learned to fear, the animals froze in apparent anticipation of an electric shock, indicating that they still remembered the place was dangerous. When the hippocampus-reactivated mice were returned, however, they were no longer fearful—their memories of the place had become pleasant, thanks to the neurons having been reactivated in the presence of the female mice.

The researchers also performed the reverse experiment, giving male mice access to females in the original location and later reactivating their memory-associated neurons while administering electric shocks. Again, the mice in which amygdala neurons had been reactivated remained happy in the original location, while the mice in which hippocampal neurons had been reactivated became fearful.

The inability of the amygdala circuits to change their valence is thought to be because these neurons either code for "good" or "bad" but not both, says Redondo. Thus, reactivating the labeled amygdala neurons would only have reiterated the original emotion. Indeed, in animals in which hippocampal reactivation had changed their emotions, different cells in the amygdala were activated. "Basically, the [hippocampal] neurons are now plugged to another set of neurons in the amygdala," he explains.

Changing the emotional valence of a memory is a clinical goal for patients who suffer from conditions such as phobias or post-traumatic stress disorder. Indeed, "associations to emotions can be so strong that they impair normal life," says Redondo. The work could someday lead to better treatment strategies for these conditions.

Full details of the work appear in the journal Nature; for more information, please visit http://dx.doi.org/10.1038/nature13725.


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