"Scientists have long understood that the hippocampus processes recent memory, but we did not know where the brain housed our oldest memories," explained Dr. Alcino Silva, principal investigator and professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. "We knew that the hippocampus did not store memories permanently.
"Most people define memory as their collective lifetime experiences," added Silva, a member of the UCLA Brain Research Institute. "These memories color who we are, yet until now, we've been mystified by how the brain saves and retrieves them."
Silva and his colleagues tackled this mystery using three strategies. First, the scientists engineered mice with a mutant form of a gene called kinase II, which eliminates the ability to recall old memories. The animals were trained to recognize a cage, then tested for their memory of the cage at one, three, 18 and 36 days after training.
"We found that the mutant mice recognized the cage for up to three days after training, but their memory of the cage disappeared after 18 and 36 days," observed Silva. "While they possessed short-term recall, they never developed a distant memory of the cage."
Earlier research suggested that the cortex - or outer layer of the brain - plays a role in the storage and retrieval of old memories. In their second strategy, the UCLA researchers used imaging methods to visually track which regions of a normal mouse's cortex grew active during memory testing.
No part of the cortex lit up when the animal was exposed to the cage one day after training. When the mouse saw the cage 36 days after training, however, the images highlighted a part of the cortex called the anterior cingulate.
"We were fascinated to see the anterior cingulate switch on when we tested the normal mice for distant memory, but not when we tested them for recent memory," said Silva. "In contrast, the mutant mice's anterior cingulate never switched on during tests for distant memory.
"This result suggests that the kinase II mutation disrupted processes in the anterior cingulate that are required for recalling distant memories," he observed.
Thirdly, the UCLA team injected normal mice with a drug that temporarily turned off the anterior cingulate. The scientists discovered that disabling the anterior cingulate did not disrupt the animals' memory of the cage at one and 3 days after training, but did interrupt the mice's memory of the cage at 18 and 36 days after training.
"When we silenced the anterior cingulate, the mice kept their recent memory of the cage, but lost their distant memory," said Silva. "This was consistent with our two earlier findings.
"We now had several pieces of evidence all pointing to the same conclusion," he noted. "The anterior cingulate plays a special role in keeping our early memories alive. Our work with the mutant mice also suggests that kinase II is critically involved in preserving our oldest memories."
When a person recalls a memory, Silva theorizes, the anterior cingulate rapidly assembles the signals of the memory from different sites in the brain.
"If the anterior cingulate malfunctions, a recalled memory may be too fragmented to make sense to the person," explained Silva. "It's like a puzzle with missing pieces. This could be what occurs during dementia."
Silva believes that the new findings open the door for greater scientific understanding of the molecular mechanisms and biochemistry of cortex storage.
"Now that we know where to look, we're one step closer to developing drugs to target genes or processes of the brain that may be related to memory disorders," he explained.
The National Institute on Aging funded the study. Silva's co-authors included Dr. Paul Frankland, Dr. Bruno Bontempi, Dr. Lynn Talton and Dr. Leszek Kaczmarek.