Scientists may have found the glue that keeps fearful memories stuck in the brain, a discovery that could be useful in new treatments for Alzheimer's disease and post-traumatic stress disorder.
That glue seems to be a protein that is key to maintaining the structure of cells and also is essential to embryonic development, a new study suggests.
The protein, called beta-catenin, transmits early signals in species ranging from flies to frogs to mice that separate an embryo into front and back or top and bottom. It also acts like Velcro, fastening a cell's internal skeleton to proteins on its external membranes that in turn connect them to other cells.
Previous studies have found other factors that govern our feelings of fear:
- One study found a 'fear factor' gene that controls how neurons fire in the brain when mice are faced with impending danger.
- Another found that the brain can learn to fear something, such as a bee's sting, when we view someone else's fear.
- Another recent study detailed how primates and other mammals learned to fear and avoid snakes.
During long-term memory formation, structural changes take place in the connections between neurons in the brain, or synapses, said researcher Kerry Ressler of Emory University's School of Medicine and Yerkes National Primate Research Center.
"We thought beta-catenin could be a hub for the changes that take place in the synapses during memory formation," Ressler said. That turned out to be the case, at least in mice.
Gene deletion
Ressler and his team figured this out by looking at how beta-catenin influenced the formation of fear memories in mice. If mice are electrically shocked just after they hear a certain tone, they gradually learn to fear that tone and show that fear by freezing in place.
Because beta-catenin is important to the development of embryos, Ressler and his team couldn't simply knock out the gene that creates the protein and then breed mice without beta-catenin.
Instead they used two other methods: lithium salts, which appeared to boost beta-catenin, and a virus that deletes the beta-catenin gene in mice whose DNA has been altered around the beta-catenin gene so their cells cannot produce the protein.
The results of the study, funded by the National Institutes of Health, the National Science Foundation, Burroughs Wellcome Fund, the Center for Behavioral Neuroscience and the Yerkes Center, are detailed in the October issue of the journal Nature Neuroscience.
The genetically engineered virus was injected into the amygdala of the mice by Emory graduate student Kimberly Maguschak. The amygdala is a part of the brain thought to be important for forming memories of emotionally charged events.
"We found that after beta-catenin is taken out, the mice can still learn to fear the shocks," Maguschak said. "But two days later, their fear doesn't seem to be retained because they spend half as much time freezing in response to the tone."
So it appears that beta-catenin is turned on in the amygdala to help in signaling during the learning process, Maguschak said.
"However, after the process of moving memories from short-term to long-term is complete, beta-catenin doesn't appear to be necessary anymore," she noted. "Injecting the virus after that point has no effect on the ability of the mice to express their fear memory."
Drug potential
Lithium salts, on the other hand, appeared to boost beta-catenin. When lithium was given to the mice before training, it made them even more afraid of the tone two days later. The researchers think this happens because lithium inhibits an enzyme that usually targets beta-catenin for destruction, causing the protein to become more active.
Maguschak cautions though that lithium affects other enzymes in the brain so it is unclear what exactly it might be doing in the brain. (Lithium is often used to treat mania and bipolar disorder.)
Maguschak and Ressler suggest that medications that inhibit beta-catenin could interfere with memory formation after trauma and help prevent post-traumatic stress disorder. Conversely, drugs that enhance beta-catenin could be a new way to treat memory disorders, such as Alzheimer's disease. Currently though, there are no other drugs besides lithium that target beta-catenin.
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