A team of scientists from the Massachusetts Institute of Technology (MIT) has been working on a research consisting of the manipulation of neural circuits in the brain of mice in order to alter their emotional associations with specific memories. The research, published in the journal Nature on August 28^th, was led by Howard Hughes and Sumusu Tonegawa and it revealed that the connections between the sides of the brain that are responsible of storing contextual information about a specific experience and the of the emotional memory of the experience are malleable. By altering the said connections, a negative memory can be transformed into a positive one, as the report in the scientific journal suggests.

While the experiment was a success Tonegawa underlined that this particular scientific discovery will not be able to immediately be used as a form of therapy for patients, since there is no technology to manipulate neurons in people similarly with the way they did during the experiments. What is of scientific relevance, however, is that the findings imply that the neural circuits which connect the hippocampus and the amygdala can be targeted for the development of new drugs treating mental illness. We tend to intimately associate our personal episodes and events with emotion as they become stored as memories in the brain. According to the team of scientists, when remembering them we don’t only recall the objective occurrence but the emotional valences that we attributed to them when they happened as well. Hippocampus is where the contextual information about these events is stored, whereas the emotional part is separately stored in a region of the brain called amygdala.

The image portrays he injection sites and the expression of the viral constructs in the amygdala and hippocampus; Photo Credits: Redondo et al

‘The amygdala can store information with either a positive or negative valence, and associate it with a memory’, Tonegawa explained.

What happened during the experiments is that the team of scientists tried to cause the mice to associate a neutral setting with fear. Once that happened, they wanted to see whether a memory that was already associated with emotions could be altered. In other words, after an animal had already developed fear of a place, could the memory of that place be turned into a pleasurable one?

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“There is some evidence from psychotherapy that positive memory can suppress memories of negative experience. We have shown how the emotional valence of memories can be switched on the cellular level,” said Tonegawa in reference to treatments which are meant to reduce clinical depression by helping patients recall positive memories.

In 2013, Tonegawa and his team of researchers reported that they could create a new, completely false, memory in a mouse as a result of an artificial activation of the small set of cells that stored a specific memory. The cells storing the memory of a safe environment were made sensitive to light in order to be manipulated by the researchers. The mouse proved to fear the original environment after being switched on the cells while it was subjected to a mild shock in a new environment, despite the fact that in the original environment the animal did not suffer any unpleasant experiences. What had scientifically happened was that the mouse associated a neutral setting with fear, and what was left to be seen was whether it was also capable of altering a memory already associated with emotion.

For the next part of the experiment, the male mice were placed in a chamber where they were delivered mild shocks. As the mice formed a memory of he environment being dangerous, the researchers introduced a light-sensitive protein into the cells responsible with storing the information. Light-sensitivity was targeted to the cells sorting the newly formed memory by linking the production of the light-sensitive protein to the activation of a gene which was switched on as the memories are encoded. A few days after removing the mice from the chamber, the scientists artificially reactivated the memory by shining a light into the cells that were responsible with the memory of the original place, which caused the animals to respond by stopping their exploration in a freezing place. This action indicates fear.

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In order to see whether they could overwrite the fear and give the mice positive associations to the chamber in spite of their negative experience, they placed the mice in a new environment. Here, instead of a negative shock the mice were given the chance to interact with female mice. While the mice were socializing, the scientists activated the fear memory-storing neurons with light, one upset at a time – either in the hippocampus or in the amygdala. Turns out that by reactivating the amygdala component of the memory while the male mice had pleasurable experiences failed to change the fear response driven by the amygdala neurons and retained their fear. When the memory-storing cells in the hippocampus were activated while the mice interacted with females, the memory cells acquired a new, positive emotional association.

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In regard to the question whether the original fear memory still existed, when the animals were put back in the original environment where the unpleasant shock happened, they showed less fear and more of an exploratory and reward-seeking behavior, which shows that the original fear memory was significantly changed .

When switching the emotion of a memory in the opposite direction, the scientists had similar results. In those mice, the pleasurable response linked to the hippocampal memory cells was replaced with a fear response.

‘What is so intriguing about this study is that the memory representations associated with a place are dissected into their network components and, rather than re-exposing the animals to the training situation to achieve a change, light is used to selectively reactivate the representation of the ‘where’ component of a memory and then change its ‘what’ association’, declared Tomonori Takeuchi and Richard G.M. Morris of the University of Edinburgh

 

What the experiments indicated was that the cells storing the contextual components of a memory form impermanent or malleable connections to the emotional ones. As the research suggested, while a single set of neurons in the hippocampus is responsible with storing the contextual information about a memory,  there are two distinctive sets of neurons in the amygdala for the connection: one responsible for positive and one for negative memories. The hippocampal cells are connected 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 explained.