How do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? This year’s 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.

Why grid cells?

In mammals, great insights have been obtained for early stages of sensory systems where signals can be followed through hierarchical networks from receptors to primary sensory cortices. But how the mammalian brain generates its own codes, deep in the association cortices, has remained deeply mysterious. Yet this is where the understanding of subjective experience begins. A path was opened in this terra incognita in 2005 when the Mosers and their students discovered grid cells – the metric of the brain’s map for space.

Grid cells are place-modulated neurons whose firing fields define a triangular array across the entire environment.

These cells are thought to form an essential part of the brain’s coordinate system for metric navigation. Because their matrix-like firing is generated in the brain, far away from specific sensory inputs, grid cells provide unprecedented access to algorithms of neural coding in high-end cortices.

The simplicity and the crystal-like structure of the grid cells offers opportunities for understanding, maybe for the first time, a mammalian behaviour at the level of neuronal network computation.

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.

More than three decades later, in 2005, May-Britt and Edvard Moser 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 John O’Keefe, May-Britt Moser and Edvard 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?

How do we experience our environment?

The sense of place and the ability to navigate are fundamental to our existence. The sense of place gives a perception of position in the environment. During navigation, it is interlinked with a sense of distance that is based on motion and knowledge of previous positions.

Questions about place and navigation have engaged philosophers and scientists for a long time. More than 200 years ago, the German philosopher Immanuel Kant argued that some mental abilities exist as a priori knowledge, independent of experience. He considered the concept of space as an inbuilt principle of the mind, one through which the world is and must be perceived. With the advent of behavioural psychology in the mid-20th century, these questions could be addressed experimentally. When Edward Tolman examined rats moving through labyrinths, he found that they could learn how to navigate, and proposed that a “cognitive map” formed in the brain allowed them to find their way. But questions still lingered – how would such a map be represented in the brain?

John O’Keefe and the place in space

John O’Keefe was fascinated by the problem of how the brain controls behaviour 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 (Figure 1). 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 find the coordinates

May-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room when they discovered an astonishing 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 (Figure 2). 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 (Figure 3).

A place for maps in the human 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 our 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.

How these two scientists discovered the brain GPS

We started recording in this region, and got invaluable help from Menno Witter, a neuroanatomist who was then located at the Free University of Amsterdam, but later moved to become a part of the Kavli Institute in Trondheim. Witter had by that time worked out much of the connectivity between the entorhinal cortex and hippocampus and helped us in the delicate task of guiding electrodes to the right spot. By 2002, the research group had grown  and we now had an outstanding team of students working side by side with us in the lab and on the computer.

The long road to realization
Sometimes scientific discoveries are portrayed as “Eureka” moments, where the researcher suddenly understands the significance of what he or she has found. In our case, it didn’t quite work that way: We didn’t immediately realize that the cells we recorded from were grid cells. At first we noticed that many entorhinal cells spiked every time a rat went to a particular spot, like the place cells in the hippocampus. However, each cell had multiple firing locations and those firing locations formed a peculiarly regular pattern – a hexagonal grid – much like the arrangement of marbles in a Chinese checker board. Every cell did it this way, with actual firing locations differing between cells. The cells were organized topographically in the sense that the size of and distance between grid fields increased from dorsal to ventral. Moreover, cells maintained firing relationships from one environment to the next, suggesting that we were on track of a universal type of spatial map – a map whose activity pattern in many ways disregarded the fine details of the environment. With their strict regularity, the cells had the metrics of the spatial map that had not been found in the hippocampus.

Grid cells and beyond
These discoveries were published in a series of papers that began in 2004, only two years after we published the hippocampal disconnection study. The grid pattern itself was published in 2005. Since then we have continued to explore how grid cells operate, how they are generated, and how they interact with other spatial cell types. There is still a lot to find out. Grid cells have helped us better understand the neural representation of space, but they also provide a window into some of the innermost workings of the brain. Perhaps the most fascinating thing is that the hexagonal pattern is generated by the cortex itself. There is no grid pattern in the outside world – this is made by the brain alone. Because the pattern is so reliable and so regular, it may put us on the track of understanding the fundamental computations of the cortex.