Although our memories may seem all of a piece, they actually consist of two main components—contextual and emotional. What’s more, these components actually reside in different parts of the brain. Contextual details, the where and when of past events, are stored in the hippocampus; emotional associations, so intrinsic to memory—or so we might imagine—reside in the amygdala.
Contextual details and emotional associations within the brain only seem blended because they are connected by neuronal pathways. These pathways, however, are not necessarily fixed. They can be altered, as researchers at MIT demonstrated last year.
These researchers, led by Susumu Tonegawa, were able to color specific memories with false associations. In experiments with mice, the researchers made the cells that stored a memory of a safe environment sensitive to light. By using a laser to “switch on” those cells while subjecting the animal to a mild shock in a new environment, the researchers caused the mouse to fear the original, safe environment.
Following up on this result, which demonstrated it is possible to associate a memory with a neutral setting, Tonegawa and colleagues report that it is also possible to alter a memory that has already been associated with an emotion. This new finding appeared August 27 in Nature, in an article entitled, “Bidirectional switch of the valence associated with a hippocampal contextual memory engram.”
“The neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown,” wrote the authors. “[We] investigated these mechanisms by applying the recently developed memory engram cell-manipulation technique.”
Using this approach, an application of optogenetics, the researchers labeled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. The researchers gained the ability to activate fear memory (of a mild electric shock) or reward memory (for male mice, socializing with a female mouse) by using light to stimulated labeled cells.
With this ability, could the researchers make a mouse’s memory of a feared place pleasurable instead? To find out, the scientists began by placing male mice in a chamber that delivered a mild shock. As the mouse formed of memory of this dangerous place, Tonegawa's team used a method it had previously developed to introduce a light-sensitive protein into the cells that stored the information. By linking the production of the light-sensitive protein to the activation of a gene that is switched on as memories are encoded, they targeted light-sensitivity to the cells that stored the newly formed memory.
The mice were removed from the chamber and a few days later, the scientists artificially reactivated the memory by shining a light into the cells holding the memory of the original place. The animals responded by stopping their explorations and freezing in place, indicating they were afraid.
Now the scientists wanted to see if they could overwrite the fear and give the mice positive associations to the chamber, despite their negative experience there. So they placed the mice in a new environment, where instead of a shock they had the opportunity to interact with female mice. As they did so, the researchers activated their fear memory-storing neurons with light. The scientists activated only one subset of memory-storing neurons at a time—either those in the context-storing hippocampus or those in the emotion-storing amygdala. They then tested the emotional association of the memory of the original chamber by giving mice the opportunity to move away from an environment in which the memory was artificially triggered.
Reactivating the amygdala component of the memory while the male mice had the pleasurable experience of interacting with females failed to change the fear response driven by those amygdala neurons. Consequently, mice retained their fear. When the researchers reactivated the memory-storing cells in the hippocampus while the mice interacted with females, however, the memory cells in the hippocampus acquired a new emotional association. Now the mice sought out environments that triggered the memory.
“So the animal acquired a pleasure memory,” Tonegawa said. “But what happened to the original fear memory? Is it still there or is it gone?” When they put the animals back in the original chamber, where they had experienced the unpleasant shock, the animals showed less fear and more exploratory and reward-seeking behaviors. “The original fear memory was significantly changed,” Tonegawa observed.
The researchers had similar results in experiments where they switched the emotion of a memory in the opposite direction—allowing mice to first develop a pleasurable memory of the chamber, then artificially activating the memory-storing cells in the hippocampus while the animals experienced a shock. In those mice, the pleasurable response linked to the hippocampal memory cells was replaced with a fear response.
The experiments indicate that the cells that store the contextual components of a memory form impermanent or malleable connections to the emotional components of that memory. Tonegawa explained that while a single set of neurons in the hippocampus stores the contextual information about a memory, there are two distinct sets of neurons in the amygdala to which they can connect: one set responsible for positive memory, the other responsible for negative memory. Circuits connect the hippocampal cells to each of the two populations of cells in the amygdala.
“There is a competition between these circuits that dictates the overall emotional value and [positive or negative] direction of a memory,” Tonegawa concluded.