How old memories fade away

If you got beat up by a bully on your walk home from school every day, you would probably become very afraid of the spot where you usually met him. However, if the bully moved out of town, you would gradually cease to fear that area.

Neuroscientists call this phenomenon "memory extinction": Conditioned responses fade away as older memories are replaced with new experiences.

A new study from MIT reveals a gene that is critical to the process of memory extinction. Enhancing the activity of this gene, known as Tet1, might benefit people with posttraumatic stress disorder (PTSD) by making it easier to replace fearful memories with more positive associations, says Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory.

The Tet1 gene appears to control a small group of other genes necessary for memory extinction. "If there is a way to significantly boost the expression of these genes, then extinction learning is going to be much more active," says Tsai, the Picower Professor of Neuroscience at MIT and senior author of a paper appearing in the Sept. 18 issue of the journal Neuron.

The paper's lead authors are Andrii Rudenko, a postdoc at the Picower Institute, and Meelad Dawlaty, a postdoc at the Whitehead Institute.

New and old memories

Tsai's team worked with researchers in Rudolf Jaenisch's lab at the Whitehead to study mice with the Tet1 gene knocked out. Tet1 and other Tet proteins help regulate the modifications of DNA that determine whether a particular gene will be expressed or not. Tet proteins are very abundant in the brain, which made scientists suspect they might be involved in learning and memory.

To their surprise, the researchers found that mice without Tet1 were perfectly able to form memories and learn new tasks. However, when the team began to study memory extinction, significant differences emerged.

To measure the mice's ability to extinguish memories, the researchers conditioned the mice to fear a particular cage where they received a mild shock. Once the memory was formed, the researchers then put the mice in the cage but did not deliver the shock. After a while, mice with normal Tet1 levels lost their fear of the cage as new memories replaced the old ones.

"What happens during memory extinction is not erasure of the original memory," Tsai says. "The old trace of memory is telling the mice that this place is dangerous. But the new memory informs the mice that this place is actually safe. There are two choices of memory that are competing with each other."

In normal mice, the new memory wins out. However, mice lacking Tet1 remain fearful. "They don't relearn properly," Rudenko says. "They're kind of getting stuck and cannot extinguish the old memory."

In another set of experiments involving spatial memory, the researchers found that mice lacking the Tet1 gene were able to learn to navigate a water maze, but were unable to extinguish the memory.