Memories are often not just flat, purposeless regurgitations of experience. Our memories can be associated with feelings. Discoveries in the lab of Picower Professor Susumu Tonegawa have shown how the emotional associations of memories are formed and can change. In the case of disorders such as depression, anxiety or PTSD fundamental knowledge could help lead to therapies.

In a 2014 study, Tonegawa’s lab revealed key aspects of the emotional association, or “valence” of memories, when the scientists successfully reversed it in lab mice. The team gave a mouse a shock in a location, initially conditioning fear there. The scientists labeled the ensemble of neurons that encoded the memory (called an “engram) and engineered them to be controllable with flashes of light (a technology called “optogenetics”). Then, when they reactivated the engram of that context while presenting a reward, the cells rewired their connection to the amygdala, a region that governs feelings, to produce a more positive association. The researchers also did the opposite, swapping an engram’s positive association for a fearful one.

A year later the lab showed how artificially activating pleasant memories could treat mouse models of depression. After exposing mice to an explicitly pleasant memory and tracking the cells that encoded it (the memory engram), the team then subjected mice to enough stress that they showed signs of depression. But mice in whom they optogenetically re-activated the positive memory during tests for depression performed better than mice in whom they didn’t reactivate the memory.

Above: In the basolateral amygdala of a mouse, positive valence cells are stained green, while the specific cells in a fear extinction memory engram appear red.

Two studies in 2016 and 2017 focused on the cells in the amygdala that produce the valence associated with memories. One study reported that that these emotions are controlled by two distinct populations of neurons in the basolateral amygdala area: one that encodes rewarding (positive) feelings and one that encoded aversive (negative) ones. The populations compete by inhibiting each other via a defined circuit. In the second study they found the populations of cells in the central amygdala that the different valence populations project to.

 The lab followed up in 2020 to show that active competition between these basolateral amygdala populations account for the phenomenon of fear extinction. When a mouse previously made to fear a location was subsequently exposed to the location without new shocks, the reward-encoding neural population took part in a newly acquired fear extinction engram that inhibited the activity of the ensemble encoding a negative valence for the original fear memory. In this way, they showed, the extinction of fear is encoded just like a feeling of reward.