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How do you recognize a long-lost friend?

You spot a familiar face on the street and rack your brain over where you might have seen him. And then it dawns on you. That is an old high school friend you haven't seen in years.

But how does the brain manage to make this connection from a crowd of strangers walking past?

An international team led by Johns Hopkins University researchers found there is a part of the hippocampus dedicated to creating and processing this type of memory. The work, published Wednesday in the journal Neuron, could help researchers better understand how the mind works and better understand diseases like Alzheimer's.

"You see a familiar face and say to yourself, 'I think I've seen that face.' But is this someone I met five years ago, maybe with thinner hair or different glasses -- or is it someone else entirely," James J. Knierim, a professor of neuroscience at the Zanvyl Krieger Mind/Brain Institute who led the research, said. "That's one of the biggest problems our memory system has to solve."

Researchers have long theorized that two parts of the hippocampus -- the dentate gyrus and CA3 -- competed to determine whether something was new or, like a song you have heard before, more familiar. The dentate gyrus was believed to code things as new, while the CA3 was believe to essentially update each experience -- resulting in the dentate gyrus discounting that old friend while the CA3 recognized him or her.

It turns out that different parts of CA3 take that information from the dentate gyrus and does both, seemingly contradictory jobs. Not only does it serve up the memory of the person but also codes a new memory should that person turn out to be a dead ringer for your college roommate.

"One way of getting around what seems like a contradiction is that your brain has to do both of these things," Knierim said. "Even if you see somebody and you are remembering that person, oh I met this person years ago. You also want to remember this new experience. So, your brain does the two things at the same time ... Maybe this is sort of how the brain has its cake and eats it too."

Knierim said the findings are a crucial step in learning how memory works, acknowledging that "we are still at the early stages in understanding memory."

"Patients with Alzheimer's, stroke or other things who have memory deficits, we certainly want to try and find ways of understanding why memory goes wrong with damage to the hippocampus and hopefully find ways to ameliorate or even cure them one day in the future," he said. "From another point, more of a basic knowledge point of view, it's hard to think of another part of our personality that is more important to us than our memories."

To study CA3, Knierim and Johns Hopkins postdoctoral fellows Heekyung Lee and Cheng Wang, along with Sachin S. Deshmukh, a former assistant research scientist in Knierim's lab now at the Indian Institute of Science, turned to rats.

After implanting electrodes in the hippocampus of the rats, they trained the rats to run around a track, eating chocolate sprinkles. Then they built up memory maps in the rats' brains by offering them different textures on the track floor -- sandpaper, carpet padding, duct tape and a rubber mat -- that each felt and smelled a little different. They also installed a black curtain surrounding the track, attaching various objects such cardboard shapes and colored cloth.

After 10 days, they changed things up. They rotated the track counter-clockwise, while rotating the curtain clockwise, creating a perceptual mismatch in the rats' minds. The effect was similar, Knierim said, to if you opened the door of your home and all of your pictures were hanging on different walls and your furniture had been moved.

"Would you recognize it as your home or think you are lost?" he said. "It's a very disorienting experience and a very uncomfortable feeling."

Even though the changes on the track were small, the researchers found that a part of the CA3 created a new memory for the altered environment. At the same time, the "pattern completing" part of CA3 helped the rats recognize they were in the same place, the old environment but changed up a bit.

Along with better understanding how these types of memories are retrieved, the researchers hope that it could help explain what goes wrong with memory in diseases like Alzheimer's and could help to preserve people's memories as they age.

"We don't want to oversell things but I think there are potential implications," Knierim said of the findings, adding he is doing similar experiments in aging rats with another colleague at Johns Hopkins who is an expert on aging and cognitive changes with aging.

"Can we see evidence to suggest these processes are effected, they are not working normally? We are going to be testing some pharmacological treatment that my colleague has been developing to try to see if we can improve their memories," he said. "As for Alzheimer's, that is much more speculative. But I could imagine, for example, understanding how the hippocampus works and the CA3 region works at the region we are addressing might in the future lead to some neurologist doing experiments to identify patients who are susceptible Alzheimer's before the damage to the brain occurs."

Christine Ann Denny, a neuroscientist at Columbia University Medical Center who did not take part in the study, said the findings "are extremely important because they highlight the need to study the heterogeneity of brain regions rather than to study brain regions as static, homogenous units."

"This and other recent studies show that CA3 is actually much more complicated and diverse that previously thought," Denny said in an email interview, adding that many studies are looking into "the location and function of memory traces in a number of brain regions to include the DG, CA3, and the basolateral amygdala," and that this research suggests they should also look at where within a region those traces are stored.

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