Selective memory

Altering a protein in the brain of mice can wipe out specific memories as they are recalled

As much as you might want to wipe Uncle Frank’s tasteless joke out of your mind but still remember the flavor of Aunt Fran’s pie, memory researchers have always said “fuhgedabboudit!” Now, a genetically engineered mouse suggests it may be possible to erase certain unwanted memories.

Scientists from the Medical College of Georgia in Augusta and the EastChinaNormalUniversity in Shanghai selectively removed a shocking memory from a mouse’s brain, the team reports in the Oct. 23 Neuron.

Insight from such experiments may one day lead to therapies that can erase traumatic memories for people suffering from post-traumatic stress disorder, or wipe clean drug-associated cues that lead addicts to relapse.

“We should never think of memories as being fixed,” says Howard Eichenbaum, a neuroscientist at BostonUniversity. “They are constantly being renovated and restructured.”

Careful questioning can alter an eyewitness’s recollection during testimony, Eichenbaum says. The new research, which he calls “terrific” and “interesting,” shows that careful use of molecular tools can also manipulate memories.

Joe Tsien, a neuroscientist at the Medical College of Georgia, and his colleagues genetically engineered a mouse to carry an altered version of a protein called alpha-calcium/calmodulin-dependent protein kinase II, or alpha-CaMKII.

A kinase enzyme, alpha-CaMKII is a type of regulatory protein that governs the activity of other proteins. Previous research showed that alpha-CaMKII is involved in learning and memory. Tsien and his colleagues wanted to find out at which stage of memory the kinase enzyme is important. Stages of memory include learning something new and then processing, retrieving and storing the information.

Scientists are beginning to learn more about how memories are made and stored. Memories are likely formed through interactions of brain chemicals and changing connections between neurons. But exactly how that happens and the physical form memory takes remain a mystery.

Researchers can use chemicals to block an enzyme’s activity, but the business end of most kinase enzymes look alike, so most inhibitory chemicals tend to block all kinase activity in the brain. Tsien got around that problem by building a hidden cavity in alpha-CaMKII. A bulky chemical inhibitor fits into the hidden cavity and blocks alpha-CaMKII from doing its job, but doesn’t interfere with the action of other kinases. By manipulating activity of the engineered protein, the researchers learned that alpha-CaMKII is important for recalling memories.

A mouse might not be able to recall a memory for two reasons, Tsien says. “Either you can’t open the door to get the memory, or you can open the door but there’s no memory there.”

Altering alpha-CaMKII’s activity erases memories as they are being retrieved, the researchers found. And the erasure is specific to the memory being recalled.

The researchers placed mice in a chamber and played a sound, then mildly shocked the mice’s feet. The mice learned to associate both the chamber and the sound with a shock and would freeze in anticipation of getting shocked when they entered the chamber or heard the sound.

Once the mouse learned to associate both the chamber and sound with getting shocked, the researchers replayed one of the conditions while altering activity of alpha-CaMKII. If the researchers placed the mouse in the chamber but didn’t play the sound, only the memory of the chamber was erased when alpha-CaMKII’s activity was altered. When tested again later, the mouse forgot to freeze when placed in the chamber, but the mouse would still freeze when it heard the sound. And if conditions were reversed and alpha-CaMKII activity was altered when the mouse was recalling that the sound signals a shock, the sound memory was erased. But the mice still remembered to freeze when entering the chamber. Those results show that erasure is limited only to the portion of the memory being recalled.

Eichenbaum is not convinced that Tsien and his colleagues have erased the mice’s memories. Altering a memory so that it can’t be recalled under certain circumstances might produce similar results, he says. “We never know for sure that it’s really gone,” he says.

But if chemicals can help someone specifically forget painful or traumatic memories, it may be irrelevant whether the memories are entirely erased or are just altered beyond recognition, Eichenbaum says.

Memory-erasing pills are still science fiction, Tsien stresses. This technique will never be used in people as it involves genetically engineering a protein in the brain, he says. But future studies might reveal other ways to selectively forget.

“We’ve only just put our foot on a very tall mountain,” he says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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