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Meet This Year's Nobel Laureates in Physiology and Medicine
Finding Cells That Navigate through Space and Memory

ARTICLE IN BRIEF

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Left to right: DRS. EDVARD I. MOSER, JOHN OKEEFE, AND MAY-BRITTER MOSER, winners of the 2014 Nobel Prize for Physiology or Medicine.

Three neuroscientists who were awarded the 2014 Nobel Prize for Physiology or Medicine discuss their research on grid and place cells.

Almost 20 years ago, May-Britt Moser, PhD, and Edvard I. Moser, PhD, spent the summer in the laboratory of John O'Keefe, PhD, who taught the young post-docs how to record from single cells in the brain. Dr. O'Keefe was already well known for his discovery more than two decades earlier of place cells in the hippocampus that provide a cognitive map of spatial memories.

The Mosers would take these lessons back to their laboratory at the Norwegian University of Science and Technology in Trondheim, Norway. There, in 2003, they went on to publish their discovery of another set of cells, grid cells, located in the neighboring entorhinal cortex, that give place cells information about distance as they move around in space. Together, the place cells and grid cells constitute the body's innate, GPS-like navigational system. These discoveries provided detailed insights about how we know where we are and where we've been — and the information required to get us there.

The Mosers and Dr. O'Keefe were awarded the 2014 Nobel Prize for Physiology or Medicine in October for their independent work in understanding how the brain processes and stores spatial memories and uses these internal maps with complex coordinate systems to navigate through ever-changing environments.

“The discovery of the brain's positioning system represents a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions,” the Nobel Prize organization wrote of this year's recipients. “It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning. Their discoveries have solved a problem that has occupied philosophers and scientists for centuries — how does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment.”

The three neuroscientists spoke with Neurology Today about the pathways that inspired their parallel lines of research across two countries and a 25-year time span.

JOHN O'KEEFE

John O'Keefe, PhD, a professor of cognitive neuroscience in the department of cell and developmental biology at University College London and the inaugural director of the Sainsbury Wellcome Centre for Neural Circuits and Behavior, was born in New York City and graduated from City College of New York. But he has spent most of his life as a researcher abroad. He earned his doctoral degree in physiological psychology at McGill University in 1967.

Early on in his doctoral studies, Dr. O'Keefe's research focused on the amygdala. But he soon turned his attention to the hippocampus, as his colleagues at McGill were doing groundbreaking work in unraveling some of the greatest mysteries of memory and learning. Dr. O'Keefe had worked in the laboratory of Ronald Melzack, PhD, a Canadian psychologist, who, together with Patrick David Wall, MD, PhD, was studying pain. But Dr. O'Keefe was also inspired by the work of his colleague, Brenda Milner, PhD, who had published the infamous case of HM (Henry Molaison), the patient whose capacity to form new long-term memories was destroyed at age 27 in a surgery to treat his seizures. Large chunks of HM's entorhinal cortex and hippocampus were removed during the surgery.

In the late 1960s, Dr. O'Keefe was searching for cells in the hippocampus that might be responsible for coding and cataloging spatial memories. He had become an expert at single-cell recordings and began listening to specific cells as an animal made its way around a room. He realized that one nerve cell would become active when a rat was in one part of the room, and another cell would start firing when the rat was somewhere else. He called these “place” cells because he believed that they formed a cognitive map of an animal's environment. These cells were not just registering visual input; they were creating an inner map of the environment, and a memory of this map was being stored in the hippocampus. Together with Jonathan Dostrovsky, PhD, he published this seminal finding in 1971 in the journal Brain Research.

MAY-BRITT AND EDVARD I. MOSER

Drs. May-Britt and Edvard I. Moser are the fifth couple to win the Nobel Prize and only the second husband-and-wife team to do so since Gerty Theresa Cori and Carl Ferdinand Cori shared the Nobel Prize in Physiology or Medicine in 1947. May-Britt spent her college and doctoral years at the University of Oslo, where she earned her doctorate in neurophysiology in 1995.

Edvard finished his doctorate, also in neurophysiology, the same year. They both worked under the supervision of Per Andersen, MD, PhD, who is best known for his study of the hippocampus.

The couple married in 1985 during their undergraduate years and worked in Dr. Andersen's lab studying events that occur in the hippocampus during water maze training. For her doctoral dissertation, May-Britt studied the structural correlates of spatial learning in the hippocampus in the rat. Edvard studied local field potential changes in the dentate gyrus during spatial learning, also in the rat.

In the early 1990s, while attending a scientific meeting, the couple met Richard Morris, PhD, best known for the development of the water maze test a decade earlier. Dr. Morris said that he was so inspired by Dr. O'Keefe's finding of place cells in the hippocampus that he set out to develop a water maze test to study spatial memories. Dr. Morris was also impressed with the Mosers, and invited the couple to work with him at the University of Edinburgh in Scotland after they finished their doctorates.

During their fellowship, Dr. Morris introduced them to Dr. O'Keefe, who extended an invitation to the researchers to visit his lab at University College London for the summer. The couple spent time in the O'Keefe laboratory and when they returned to Trondheim, they started using Dr. O'Keefe's technique for recording cells.

They recorded the rat as it moved around the room (searching for bits of chocolate) and discovered a distinct pattern of activity in the entorhinal cortex. The movements looked random, but in time the scientists realized that the firing of each of the cells activated a beautiful hexagonal pattern.

They called these cells “grid” cells because they created a coordinate system as the animal moved through space. This system allowed for spatial navigation. Like a GPS, the grid cells provided information about the space in the room and the direction the animal was taking, and had a coordinated relationship to the place cells in the hippocampus.

The Mosers published more extensive details of their discovery of grid cells and their role in signaling place, distance, and direction in a paper in Nature in 2005.

Today, the Mosers co-direct the Kavli Institute for Systems Neuroscience and Centre for Neural Computation at the Norwegian University of Science and Technology.

EXPERTS COMMENT

The findings on place cells and grid cells have had major implications for understanding how we move naturally through our environment. The discoveries have also inspired other scientists to study the brain's navigational and spatial memory systems.

Leading scientists told Neurology Today that the work has had major implications for neurological diseases like Alzheimer's. Place cells and grid cells are located in the same regions — the hippocampus and the entorhinal cortex — that are damaged early on in Alzheimer's disease (AD), and some of the earliest cognitive signs of the illness involve getting lost or misplacing things.

Dr. O'Keefe has been involved in studying AD for years. He believes that following the cells in the hippocampus and entorhinal cortex will offer clues about how the disease spreads and how to begin thinking of new ways to target the disease. Earlier this year, Dr. O'Keefe, Dr. Milner, and Washington University School of Medicine's Marcus E. Raichle, PhD, won the Kavli Prize in Neuroscience for their work in identifying brain networks for memory and cognition.

Referring to the work of this year's Nobel laureates, Eric Kandel, MD, the Kavli professor of brain science and director of the Kavli Institute for Brain Science at Columbia University, said, “At the time of these discoveries we knew very little about how spatial memories are represented in the brain. This is the first time a complex representation of thinking has been delineated in such detail. There is a continuity of science in this year's Nobel. These are fantastic findings and could help us understand diseases like Alzheimer's, where people have problems orientating to their environment.”

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PLACE CELLS, discovered by Dr. John OKeefe, reside in the brains hippocampus and become active when a rat is in a certain spot. In the nearby entorhinal cortex, grid cells, discovered by Drs. May-Britt Moser and Edvard I. Moser, fire at regularly spaced intervals as an animal moves through space, forming a hexagonal pattern.

Dr. Kandel was a recipient of the 2000 Nobel Prize in Physiology or Medicine for his research on the physiological basis of memory storage in neurons.

Itzhak Fried, MD, PhD, clinical director of the University of California, Los Angeles department of neurosurgery, said that the work of this year's Nobel laureates inspired his own research on memory. He set out to find place cells and grid cells in humans. His group reported finding place cells in the hippocampus of epilepsy patients undergoing testing for neurosurgery in 2003. Last year, he reported grid-like cells in the entorhinal cortex. [To learn more about Dr. Fried's work, which was funded by the Defense Advanced Research Projects Agency (DARPA), read the Neurology Today article, “DARPA: On the Hunt for Neuroprosthetics to Enhance Memory,” http://bit.ly/NT-DARPA.]

“We are very excited about the Nobel winners. It is great for the scientists but also for our field,” said Dr. Fried.

EXPERTS: ON THE DISCOVERY OF PLACE AND GRID CELLS

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DR. ERIC KANDEL: “At the time of these discoveries we knew very little about how spatial memories are represented in the brain. This is the first time a complex representation of thinking has been delineated in such detail. There is a continuity of science in this years Nobel. These are fantastic findings and could help us understand diseases like Alzheimers, where people have problems orientating to their environment.”

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DR. ITZHAK FRIED said that the work of this years Nobel laureates inspired his own research on memory. He set out to find place cells and grid cells in humans. His group reported finding place cells in the hippocampus of epilepsy patients undergoing testing for neurosurgery in 2003. Last year, he reported grid-like cells in the entorhinal cortex.

LINK UP FOR MORE INFORMATION:

•. O'Keefe J., Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res 1971; 34(1), 171–175
    •. O'Keefe J. Place units in the hippocampus of the freely moving rat. Exper Neurol 1946; 51:78–109.
      •. Fyhn M, Molden S, Witter MP, et al. Spatial representation in the entorhinal cortex. Science 2004; 305:1258–1264.
      •. Hafting T, Fyhn M, Molden S, et al. Microstructure of spatial map in the entorhinal cortex. Nature 2005; 436, 801–806.
      •. Sargolini F, Fyhn M, Hafting T, et al. Conjunctive representation of position, direction, and velocity in the entorhinal cortex. Science 2006; 312:758–762.
      •. A summary of the work of John O'Keefe and Edvard and May-Britt Moser