While remembering your telephone number or what time you made dinner reservations for tomorrow night may not flood you with feelings, many memories have emotions attached to them; your first day at school, your wedding day, losing your pet.

It’s been known for some time that these emotional associations, or valences, are malleable. Therapists even take advantage of this intrinsic property of memory in order to treat patients with conditions such as post-traumatic stress disorder. However, the neural mechanisms that enable us to switch emotional associations have long been a mystery. Now, in a new MIT study, neuroscientists have revealed the neuronal circuit that is critical for the association of emotion with memory. Furthermore, they have demonstrated that they can reverse the valence of a memory by activating specific populations of brain cells. The study has been published in Nature.

Two brain structures are known to be critical in the formation of new memories: the hippocampus and the amygdala. The hippocampus is involved in memory formation, organization and storage. The amygdala is involved in emotional processing and memory storage. However, until now, scientists didn’t know at what stage in the brain circuit that valences became assigned to memories, or engrams.

To find out more, the researchers used a technique called optogenetics to manipulate the activity of neurons. This involved using a light-sensitive protein to label a population of cells in either the dorsal dentate gyrus of the hippocampus or the amygdala. The neurons they tagged were those that were activated during a rewarding experience (male mice socializing with females) or during fear (a mild electric shock).

The team then placed the mice in a two-zone arena and observed which side they exhibited a preference for. Next, they used blue light to stimulate the labeled neurons in the fear conditioned mice whenever they entered their preferred side of the arena. The mice quickly started to avoid the area that they had originally preferred, suggesting the fear memory had been reactivated.

They then did the same for the mice that were reward-conditioned, but instead stimulated their neurons when they entered the side they did not prefer. Sure enough, the mice started to enter this side more frequently, suggesting they were recalling the pleasant memory.

Next, the researchers attempted to reverse the valence of a memory by subjecting the conditioned mice to the opposite condition—i.e. they activated the neurons in the mice that originally received reward conditioning while they received electric shocks, and vice versa.

When they placed the mice back in the box, those that were originally fear conditioned and avoiding one side of the arena while their hippocampal neurons were activated now began to prefer this area, suggesting the memory valence had been switched. This switch also took place in mice that were originally reward-conditioned. However, this did not occur in mice that had their amygdala activated as opposed to the hippocampus.

Taken together, this study suggests that valences are encoded in the circuit that connects the dentate gyrus to the amygdala. Furthermore, the neurons carrying memories in the dentate gyrus are plastic, meaning the valence can be reversed by reassociating memories with a stimulus of an opposite valence. Cells of the amygdala, on the other hand, are pre-committed to encode a positive or negative memory and cannot switch.

The researchers are now taking this work forward by examining whether reactivating pleasant memories can positively affect depression.