The Nobel Assembly at Karolinska Institute has awarded the 2014 Nobel Prize in Physiology or Medicine to John O´Keefe and jointly to May-Britt Moser and Edvard I. Moser for their discoveries of cells that constitute a positioning system in the brain.

The Nobel laureates have discovered a positioning system, an “inner GPS” in the brain, that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.

In 1971, John O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O´Keefe concluded that these “place cells” formed a map of the room.

In 2005, the Mosers discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells,” that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.

The discoveries of O´Keefe, Moser and Moser 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?

O´Keefe was fascinated by the problem of how the brain controls behavior and decided, in the late 1960s, to attack this question with neurophysiological methods. When recording signals from individual nerve cells in a part of the brain called the hippocampus, in rats moving freely in a room, O’Keefe discovered that certain nerve cells were activated when the animal assumed a particular place in the environment. He could demonstrate that these “place cells” were not merely registering visual input, but were building up an inner map of the environment.

O’Keefe concluded that the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments. Therefore, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus.

May-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room when they discovered a pattern of activity in a nearby part of the brain called the entorhinal cortex. Here, certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid. Each of these cells was activated in a unique spatial pattern and collectively these “grid cells” constitute a coordinate system that allows for spatial navigation. Together with other cells of the entorhinal cortex that recognize the direction of the head and the border of the room, they form circuits with the place cells in the hippocampus. This circuitry constitutes a comprehensive positioning system, an inner GPS, in the brain.

Recent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer´s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain´s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.

The discovery of the brain’s positioning system represents a paradigm shift in understanding of how ensembles of specialized cells work together to execute higher cognitive functions. It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning.

O’Keefe currently is director of the Sainsbury Wellcome Center in neural circuits and behavior at University College London. May-Britt Moser currently is director of the Center for Neural Computation in Trondheim. Edvard I. Moser currently is director of the Kavli Institute for Systems Neuroscience in Trondheim.