The war veteran who recoils at the sound of a car backfiring and the recovering drug addict who feels a sudden need for their drug of choice when visiting old haunts have one thing in common: Both are victims of their own memories. New research indicates those memories could actually be extinguished.
A new study from the Massachusetts Institute of Technology found a gene called Tet1 can facilitate the process of memory extinction. In the study, mice were put in a cage that delivered an electric shock. Once they learned to fear that cage, they were then put in the same cage but not shocked. Mice with the normal Tet1 levels no longer feared the cage once new memories were formed without the shock. Mice with the Tet1 gene eliminated continued to fear the cage even when there was no shock delivered.
“We learned from this that the animals defective in the Tet1 gene are not capable of weakening the fear memory,” Le-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, told Discovery News. “For more than a half century it has been documented that gene expression and protein synthesis are essential for learning and forming new memories. In this study we speculated that the Tet1 gene regulates chemical modifications to DNA.”
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The MIT researchers found that Tet1 changes levels of DNA methylation, the process of causing a chemical reaction. When methylation is prominent, the process of learning new memories is more efficient. When methylation is weaker, the opposite is true.
“The results support the notion that once a fear memory is formed, to extinguish that memory a new memory has to form,” Tsai said. “The new memory competes with the old memory and eventually supersedes the old memory.”
Experts in the study of memory and anxiety agree.
“This is highly significant research in that it presents a completely new mechanism of memory regulation and behavior regulation,” said Jelena Radulovic, a professor of bipolar disease at Northwestern University. The mechanism of manipulating DNA is likely to affect many other things. Now the question will be whether there will be patterns that emerge, whether there will be side effects on moods and emotions and other aspects. But the findings have real relevance.”
Radulovic, who was not directly involved in the study, says the primary significance of the findings have to do with eliminating fear.
“The results show us a very specific paradigm of learned reduction of fear,” she said. “This could mean that interference with the Tet1 gene and modification of DNA could be an important target to reduce fear in people with anxiety disorders.”
For her part, Tsai is most encouraged at the ability to approach anxiety disorders at the molecular and cellular levels inside the brain. “We can now see the bio-chemical cascade of events in the process of memory formation and memory extinction,” said Tsai. “Hopefully this can lead to new drug discoveries.”
Meanwhile, research in memory extinction is progressing quickly, largely due to new discoveries through traditional experimentation, augmented by advances in technology, Tsai said.
Elsewhere, parallel research is focusing more on physiological processes that cause memories, rather than epigenetics (the study of how genes are turned on or off). At the Scripps Research Institute, researchers are studying what causes a methamphetamine addict to relapse when confronted with familiar triggers that a person associates with drug use.
“Substance users who are trying to stay clean, when exposed to the environment where they used the drug have all kinds of associations and memories in their minds that are strong enough to elicit cravings,” said Courtney Miller, an assistant professor at the Scripps Research Institute, who led the research.
“The idea is to try to selectively disrupt the dangerous memories but not lose other memories.” “We taught rodents to press a lever to get an infusion of meth, and that puts the drug delivery in the animal’s control,” Miller told Discovery News. “They were put in an environment that was unique to them every day for two weeks, where they could press the lever and get meth. They learned to associate that environment with the meth, the place where they could ‘use.’”“The idea is to try to selectively disrupt the dangerous memories but not lose other memories.”
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The animals were then injected with a chemical that inhibited actin polymerization and placed back in their home environment.
“The process of actin polymerization happens when neurons contact each other, and that is how information is passed,” Miller said. “Think of it like a Lego project. There are little pieces that contact each other. The receiving point on a neuron, called a dendritic spine, enlarges when a memory is stored. It gives more surface areas so you can have more neurotransmission.
"Actin controls that, enlarges the spine and keeps it large. In a normal memory, pieces come off the top and circle around and add on to the bottom very slowly. In a meth memory the piece comes off the top, wraps around and comes back much faster. We gave a drug that takes the pieces away and they are not added back on. The point of contact falls apart and the memory is lost.”
The process, called depolymerization, means that memories are no longer stored.
Longtime memory researchers are highly supportive of Miller’s findings.
“The findings here are real game changers,” said Gary S. Lynch, professor of psychiatry and human behavior at University of California School of Medicine. “What this points to is a completely new strategy for treatment of addiction. For the past 10 years there have been many challenges to the notion that memories are cemented in. But this study shows that memory really is still a dynamic, malleable business and that there can be another way of dealing with dependency.”
Lynch is particularly taken with the study’s findings regarding the role of actin.
“Actin is the most prevalent protein in the body,” said Lynch, who has studied memory issues for more than 30 years. “Now to find that it is so critical to dependency is breathtaking in its implications.”
In the future, it's possible the process can be generalized to other addictions, such as nicotine, Miller said.
As for how distant that future may be, Tsai believes we are still many years from applying the current research to human beings with psychiatric disorders.
“I would like to believe that through cognitive behavior therapy or some new medication, eventually — not five or 10 years from now, but eventually — a lot of the mechanisms are going to be solved,” Tsai said. “We’ll know how good memories form, how bad memories form. But the brain is an organ that is not very accessible to manipulation, unlike most other organs. My prediction is that progress on memory research, including memory extinction, will speed up considerably because of the emerging technology.”
That technology, Tsai says, includes a new 3-D, high-resolution brain imaging called CLARITY, developed by a research team at Stanford University. CLARITY essentially makes it possible to view the brain in a transparent way, allowing researchers to see in detail its complex fine wiring and essential features.
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