Scientists know little about how the brain assigns cells to participate in encoding and storing memories. Now a UCLA/University of Toronto team has discovered that a protein called CREB controls the odds of a neuron playing a role in memory formation. The April 20 edition of Science reports the findings, which suggest a new approach for preserving memory in people suffering from Alzheimer's or other brain injury.
"Making a memory is not a conscious act," explained Alcino Silva, principal investigator and a professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA. "Learning triggers a cascade of chemicals in the brain that influence which memories are kept and which are lost.
"Earlier studies have linked the CREB protein to keeping memories stable," added Silva, a member of the UCLA Brain Research Institute. "We suspected it also played a key role in channeling memories to brain cells that are ready to store them."
Silva and his colleagues used a mouse model to evaluate their hypothesis. They implanted CREB into a virus, which they introduced into some of the cells in the animal's amygdala, a brain region critical to emotional memory.
Next they tested the mouse's ability to recall a specific cage it had visited before. The cage was outfitted with patterned walls and a unique smell.
To visualize which brain cells stored the mouse's memories about the cage, the scientists tracked a genetic marker that reveals recent neuron activity. When the team examined the animals' amygdalas after the experiment, they found substantial amounts of CREB and the marker in neurons.
"We discovered that the amount of CREB influences whether or not the brain stores a memory," said Silva. "If a cell is low in CREB, it is less likely to keep a memory. If the cell is high in CREB, it is more likely to store the memory."
Human implications of the new research could prove profound.
"By artificially manipulating CREB levels among groups of cells, we can determine where the brain stores its memories," he explained. "This approach could potentially be used to preserve memory in people suffering from Alzheimer's or other brain injury. We may be able to guide memories into healthy cells and away from sick cells in dying regions of the brain."
Our memories define who we are, so learning how the brain stores memory is fundamental to understanding what it is to be human, Silva observed.
"A memory is not a static snapshot," he said. "Memories serve a purpose. They are about acquiring information that helps us deal with similar situations in the future. What we recall helps us learn from our past experiences and better shape our lives."
The study was funded by the National Institute on Aging and the NARSAD: The Mental Health Research Association. Silva's coauthors included Steven Kushner and Robert Brown of UCLA; Sheena Josselyn, Jin-Hee Han, Adelaide Yiu and Christy Cole of the University of Toronto; Rachel Neve of Harvard University; and John Guzowski of UC Irvine.
Note: This story has been adapted from a news release issued by University of California - Los Angeles.
Scientists Decipher The Formation Of Lasting Memories
Researchers at Karolinska Institutet have discovered a mechanism that controls the brain's ability to create lasting memories. In experiments on genetically manipulated mice, they were able to switch on and off the animals' ability to form lasting memories by adding a substance to their drinking water. The findings, which are published in the scientific journal PNAS, are of potential significance to the future treatment of Alzheimer's and stroke.
"We are constantly being swamped with sensory impression," says Professor Lars Olson, who led the study. "After a while, the brain must decide what's to be stored long term. It's this mechanism for how the connections between nerve fibers are altered so as to store selected memories that we've been able to describe."
The ability to convert new sensory impressions into lasting memories in the brain is the basis for all learning. Much is known about the first steps of this process, those that lead to memories lasting a few hours, whereby altered signalling between neurons causes a series of chemical changes in the connections between nerve fibers, called synapses. However, less is understood about how the chemical changes in the synapses are converted into lasting memories stored in the cerebral cortex.
A research team at Karolinska Institutet has now discovered that signalling via a receptor molecule called nogo receptor 1 (NgR1) in the nerve membrane plays a key part in this process. When nerve cells are activated, the gene for NgR1 is switched off, and the team suspected that this inactivation might be important in the creation of long-term memories. To test this hypothesis they created mice with an extra NgR1 gene that could remain active even when the normal NgR1 was switched off.
"Doing this, we found that the ability to retain something in the memory for the first 24 hours was normal in the genetically modified mice," says Professor Olson. "However, two different memory tests showed that the mice had serious difficulties converting their normal short-term memories to long-term ones, the kind that last for months."
In order to be able to switch the extra NgR1 gene on and off, the group attached a regulatory mechanism to the gene that reacted to a harmless additive in their drinking water. When the extra gene was then switched off, the mice retained their normal ability to form long-term memories. By subsequently switching it off at different times after a memory-forming event, they were able to pinpoint the effect of the NgR1 gene to the first week after such an event.
"We know that concussion can cause someone to forget events that occurred in the week before the injury, what we call retrograde amnesia, even though they can remember events that occurred earlier than about a week before. This we believe tallies with our findings," says Alexandra Karlén, one of the scientists involved in the study.
The scientists hope that their findings will eventually be of use in the development of new treatments for memory impairments, such as those related to Alzheimer's and stroke. Medicines designed to target the NgR1 receptor system would be able to improve the brain's ability to form long-term memories. The studies were conducted in collaboration with American researchers at the National Institute on Drug Abuse.
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