The mice in the study were subjected to a rewarding experience (socializing with a mouse of the opposite sex), or an unpleasant experience (a mild electric shock).
The researchers explain that memories are made of many different elements, which are housed in different brain regions. The context of a memory - the information about where and when the event took place - is stored in the hippocampus. However, the emotions linked to that memory are stored in the amygdala.
Previous research has suggested that the emotional associations of memory can be altered, which is how psychotherapists are able to help patients with depression or post-traumatic stress disorder. However, the neural mechanism behind this manipulation has been unknown until now.
Last year, the researchers behind the new study reported some success in implanting false memories in mice.
For the new study, they devised a technique to tag neurons that encode a specific memory, or "engram." They did this by labeling hippocampal cells involved in memory formation with a light sensitive protein called channelrhodopsin. This protein allowed the researchers to activate the cells using a laser, which caused their mice subjects to recall the memory encoded by the tagged cells.
Reactivating memories by stimulating dentate gyrus cells with light
The mice in the study were subjected to a rewarding experience (socializing with a mouse of the opposite sex), or an unpleasant experience (a mild electric shock). The researchers then labeled memory cells in the dentate gyrus region of the hippocampus.
After a period of 2 days, the mice were placed into a large area and the researchers made notes on which half of the arena the mice naturally preferred.
The researchers then stimulated the labeled dentate gyrus cells in the mice that experienced the electric shock whenever they went into their preferred side of the arena. The researchers say they knew that the reactivation of the fear memory had worked because these mice soon began avoiding that area.
Similarly, for the mice that received the rewarding experience, the researchers activated the labeled dentate gyrus cells whenever the mice went into the less-preferred side of the arena. Because these mice would then spend more time in that area, the researchers believed that the mice were recalling the pleasant memory.
Reversing the emotional associations of memory
After another gap of 2 days, the researchers attempted to reverse the emotional responses in the mice.
The mice that originally received the fear conditioning had their memory of the electric shock reactivated for 12 minutes while they spent time with mice of the opposite sex. The mice that had initially received the reward conditioning had their reward memory activated while receiving mild electric shocks.
Again, the mice were put into the two-zone arena. Now, the researchers observed that the mice that had originally been conditioned with the fear memory began to spend more time in the area where their fear memory had been reactivated. From this, the researchers deduced that the reward association had replaced the fear memory.
The same reversal was also exhibited by mice that had been originally conditioned with the reward memory.
All of these experiments were then replicated, but this time memory cells in the emotion-processing region of the brain - the basolateral amygdala - were labeled. However, the researchers found that they could not induce the same kind of switch in these mice by reactivating the labeled amygdala cells. The behavior of the mice remained consistent with their original conditioning.
The researchers say these findings demonstrate that emotional associations, or "valences," are encoded in neural circuitry connecting the dentate gyrus to the amygdala. A fear experience strengthens the connections between the memory stored in the hippocampus and the cells in the amygdala that encode fear.
However, the researchers suggest that this connection can be weakened if new connections encoding positive associations are formed between hippocampus and amygdala.
The study concludes that while the hippocampus cells are emotionally neutral, the amygdala cells are active in encoding the emotional associations of a memory.
Next, the team will investigate how to differentiate between the fear-encoding and reward-encoding cells of the amygdala, and examine whether reactivating pleasant memories can diminish depression.