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The Hippocampus’ Remembrance of Things Past

To learn a route, the brain replays the itinerary in reverse.

July, 2010- Some of us have a splendid sense of direction, while others get hopelessly lost even while driving to a place we’ve visited before. Either way, our brains rely—more or less successfully—on a concept called spatial learning.

David Foster says he falls into the latter camp. If he were a rat in a complex maze, he’d fail miserably at finding his way to the wedge of cheese. Yet that hasn’t stopped him from studying spatial learning—how we encode information about our environment and its spatial orientation, information that we can then use to find our way around. 

Foster says that his research, which focuses on the brain’s hippocampus, explores the fundamental question of how neurons absorb, record and process information. But in more practical terms, it may also offer insights into diseases that involve the hippocampus, such as Alzheimer’s, epilepsy and schizophrenia.

For several decades, scientists have known that the hippocampus, the sea horse-shaped structure deep inside the brain, plays an important role in spatial learning. Researchers observed, for example, that rats with damage to the hippocampus are unable to find their way to a platform submerged in a pool of water known as a water maze, a task that normal rats learn with ease. Then scientists using electrodes to monitor the hippocampus in rats discovered special “place cells,” neurons whose activity appears to correspond to different regions in the animal’s environment. When a rat is in a particular location, the place cell representing that area fires rapidly.

But those studies were limited in scope, says Foster. They demonstrated how place cells responded individually but didn’t reveal the system’s gestalt—how groups of neurons worked together to process information about the spatial environment.

So for the past several years, Foster has developed methods for recording the activity of groups of hippocampal neurons at once. First, as a postdoc at MIT, he learned the latest recording techniques from his mentor Matt Wilson, based around a special four-wire electrode—or “tetrode”—that helps to localize signal sources in the brain. “It’s like listening with two ears instead of one,” Foster says. “You hear sounds in stereo and can tell where they come from.”

Since arriving at Hopkins two years ago, he’s continued to refine that technology, making it tinier and tinier. Now in his lab at Hopkins, he’s constructed a device that contains 40 tetrodes, which enables him to listen to 200 to 300 neurons at one time. Such methods enable him to assess the internal dynamics of the hippocampus.

“Until we could record lots of neurons at once, we couldn’t hear neurons speaking to each other,” he says. “Now we can listen in on the conversation.”    

Foster uses the tetrodes to record activity in the rat hippocampus while animals perform various navigational tasks. For these studies he doesn’t use a classic maze with its many twists and turns. Instead, he uses a five-foot-long track, which contains a food well at each end. A rat is placed at one end of the track, runs the length of the track, eats food from the well, pauses (to groom itself, twitch its whiskers, or just sit still) and then runs back to the other end. Throughout the session, the tetrodes measure the electrical activity of hippocampal neurons.

As the animal runs down a track for the first time, place cells corresponding to the rat’s location fire in sequence. So, using the letters of the alphabet to represent a series of place cells, the sequence might go like this: A, B, C, D, E, F, G, H, I, J. But what happens at the end of the track when the rat pauses “is quite amazing,” Foster explains. The same neurons fire again, only in reverse sequence: J, I, H, G, F, E, D, C, B, A.

Foster calls this reverse replay. “These are rapid sequences that recapitulate the behavioral sequence, but in reverse,” says Foster. “It is as though the animal wants to evaluate the path it’s taken to get to its reward, to think back to remember how it got there.”

Foster says it’s likely the human hippocampus works similarly to the rat’s, given that the structure of the hippocampus is highly conserved in rats and people. We may use reverse replay to learn and remember routes.

But the mechanism may also underlie how we learn and remember events, in general. An experience is simply a sequence of events, just as a journey along a path is a series of places encountered. For example, in the morning you wake up, rub your eyes, walk into kitchen, pour cereal into a bowl, eat cereal. As you digest your breakfast, your hippocampus might quickly replay this stream of events as: eat cereal, pour cereal, walk to kitchen, rub eyes.

While continuing this research, Foster is also beginning to explore how activity in the hippocampus may be altered in certain diseases. In one set of studies, conducted in collaboration with investigators at MIT, he’s testing a mouse model of schizophrenia.

The team’s preliminary results show some signs suggesting that the illness may interfere with reverse replay. Instead of firing in a measured way during replay, the neurons are overactive, suggesting a distortion in the information content. It’s possible that an impairment in reverse replay underlies symptoms seen in patients with schizophrenia. But much more research will be required to test that hypothesis, says Foster.

In the meantime, has Foster gleaned anything from his research that might help people in general improve their ability to find their way around the streets and roads that constitute our civilization’s mazes? Unfortunately, no, nothing yet, except this age-old piece of advice: practice.

Melissa Hendricks

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