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Changing a Negative Feeling About a Memory

This is exciting, but complicated, basic research. Here I simplify the main experiments. Neuroscientists at the Massachusetts Institute of Technology (MIT) have identified a neuronal circuit in mice that associates a positive or negative feeling with a memory. In a tour de force of molecular studies of the brain, the researchers conducted experiments that provide considerable hope for future therapy in humans with syndromes like PTSD (post-traumatic stress disorder), anxiety, and depression. The scientists were able to turn a memory associated with a negative feeling into a memory that has a more positive feeling and vice versa.

(How relevant are studies done in mice? The mouse is an accepted animal model for humans. You might not expect it, but mice and humans are very similar genetically. The DNA sequences of the mouse and human chromosomes are known. Many mouse genes have sequences similar to human genes. They both code for proteins that have similar structures and do the same things. Because mouse and human genes are so similar, much of the underlying biology of mice and humans is also similar. Still there are differences. So until something has been shown to be true in humans, a scientist’s conclusions must be conservative. Most of the time, however, much is learned about humans from the mouse. It has become a convenient initial model for humans.)

The researchers at MIT engineered a virus that infects the mouse brain. They specifically infected either the hippocampus, the part of the brain that contains neurons that store contextual information about a memory (for example, the place), or the amygdala, the part of the brain that contains neurons that put a positive or negative emotional tag onto the memory. The engineered virus is essentially a dead-end. It doesn’t reproduce or harm the cell, but it does have an ability to cause infected neurons to make a light-sensitive protein – but only when the neuron is actively making a new memory. In this way, the researchers were able to make neurons involved in making a new memory sensitive to light. By implanting an optical fiber in the part of the brain that contained the light-sensitive neurons (i.e., in the hippocampus or in the amygdala), the scientists could use light to turn on these memory-making neurons at will. The general technique of using a light-sensitive protein to activate a cell is called “optogenetics.” When the light-sensitive neurons are activated by the researcher, the mice recall that memory with its associated positive or negative feeling. To make a memory with a positive feeling, male mice were allowed to mix with female mice. To make a memory having an associated negative feeling, mice were put into a special cage and given a mild electrical shock. For both kinds of memories, the neurons involved could be turned on by light.

The researchers then took the mice and put them into a cage with two compartments. When a mouse with a negative memory explored a particular compartment, the researchers turned on its bad-memory neurons by shining a laser into the optical fiber to activate those neurons. The mice “remembered” the bad feeling and avoided that compartment. When the experiment was done with the mice having a good memory, the mice preferred that compartment. These results were seen only when neurons of the hippocampus were activated. No change in mouse behavior was seen when amygdala neurons were activated. Whereas the amygdala is needed to add the positive or negative feeling to a memory, the researchers concluded that a memory with its associated feeling is stored in the hippocampus.

The researchers then asked if they could change a negative memory into a positive memory and vice versa. They took the male mice with the negative memory and mixed them with females to make a positive memory. When they used light to activate the bad-memory neurons, the positive feeling from mixing them with females dominated. Unexpectedly, those mice did not suddenly avoid the females when the researchers activated the bad-memory neurons. When the mice were put back into the cage with two compartments, they went randomly into both compartments, even when the researchers activated the bad-memory neurons with light. The bad memory was no longer causing them to avoid one of the compartments. The negative tag had been supplanted by the positive feeling. What happened to the first (negative) tag? Was it removed? Was it changed? This question is being investigated. When the experiment was reversed, the scientists found that the positive feeling became more negative.

This new research gives a molecular explanation for why emotion associated with a memory can be changed – the basis of current therapy. Dr. Susumu Tonegawa, who directed the research, believes that the amygdala has two kinds of neurons: neurons that can tag a memory with a positive feeling and other neurons that can tag a memory with a negative feeling. He wants to identify those two populations of cells and understand how they work at the molecular level. Such information will be valuable for the development of new therapies and drugs. (Full story)

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