2014 Nobel Prize in Physiology or Medicine: Okif, Moser Couple Discover the Brain's GPS

What You'll Learn in This Article

The 2014 Nobel Prize in Physiology or Medicine was awarded to three individuals for discovering the spatial coordinate system in our brain. John O'Keefe, a British-American neuroscientist, discovered place cells in the hippocampus of rats in 1971 – neurons that fire only when the rat is in a specific location. More than 30 years later, the Norwegian husband-and-wife neuroscientist team, May-Britt Moser and Edvard Moser, who had been O'Keefe's students, discovered grid cells in the entorhinal cortex in 2005 – neurons that fire in a triangular grid pattern. These two types of neurons together form the brain's GPS system. Place cells encode the coordinates of specific landmarks, while grid cells encode a coordinate grid for the entire space. This architecture is the basis for understanding early Alzheimer's pathology, navigation ability, and the spatial basis of memory, and is one of the great achievements of 21st-century cognitive neuroscience.

Something Different Than Common Sense: The Brain Encodes Space with Neuron Firing Patterns

The common sense that "spatial perception is the sum of senses such as vision and touch" is only partially correct. The reason we can map out a city after a while and navigate around a room even with our eyes closed is that the brain integrates sensory information to create an internal representation of spatial coordinates. The three awardees answered the questions of where this coordinate representation is, how it is created, and which neurons are responsible.

Place cells are neurons in the hippocampus, and each neuron has a preferred location. The neuron fires only when the rat passes through that location. For example, one neuron may fire only in the northwest corner of a room, and another may fire only in the southeast center. There are many such neurons in the hippocampus, each of which has a specific location in the room as its "home." By reading the firing patterns of these neurons, we can tell where the rat is.

Grid cells are an even more amazing architecture. Each grid cell in the entorhinal cortex has not one, but multiple preferred locations. And these locations are arranged in a perfectly regular hexagonal grid pattern in the room. Each grid cell has its own grid orientation and grid spacing, and multiple grid cells work together to create a coordinate system that completely covers the space.

If we translate this into a CS framework, it is a combination of a memoized landmark cache and a grid coordinate system. Place cells are a landmark cache that fires when reaching a specific coordinate. Grid cells are the basis vectors of a coordinate system that partitions the entire space into a triangular grid. The two systems work together to enable self-localization and path planning. This is a natural counterpart to the robot SLAM (Simultaneous Localization and Mapping) algorithm, and perhaps an architecture that evolution invented much earlier.

The Zeitgeist: The Year of the Sewol Ferry Tragedy and National Grief

In 2014, South Korea suffered a devastating tragedy with the April 16th Sewol ferry disaster. Of the 304 people who died when the passenger ship sank off the coast of Jindo, most were second-year students from Ansan Danwon High School who were on a school trip. The failure of rescue efforts, the problems with the government's response, and every step of the investigation after the accident became a source of national grief, and yellow ribbons appeared everywhere. This event went beyond a simple disaster and became an opportunity for Korean society to question the fundamental issues of safety, the state's responsibility, and the disaster response system, and its repercussions continued to shape politics and society for years to come.

At the same time, the Asian Games were held in Incheon from September 19 to October 4, and successfully hosting the international sports event confirmed that society was continuing to move forward even amidst the pain of the Sewol tragedy. In November, the Jung Yoon-hoi document scandal was exposed through the leak of internal presidential documents, and in December, the Constitutional Court ruled to dissolve the Unified Progressive Party. Political turmoil continued.

In the world, the Russian annexation of Crimea in March began the Ukraine crisis, and US-Russia relations deteriorated to their worst level since the Cold War. In the summer, ISIS (Islamic State) rapidly expanded in Iraq and Syria, and international response began. An ebola epidemic in West Africa began in March, resulting in more than 10,000 deaths in Liberia, Sierra Leone, and Guinea, and the international health crisis entered a new phase.

On the internet, the Ice Bucket Challenge in the summer created a new form of social media philanthropy. This campaign to raise awareness of ALS (amyotrophic lateral sclerosis) spread around the world, with celebrities, politicians, and ordinary people participating and foreshadowing a new form of social activism in the age of social media.

In the tech world, the release of the iPhone 6 series marked the beginning of the era of large smartphones, and the Apple Watch was announced, foreshadowing the era of wearables. In the field of artificial intelligence, the explosive growth of deep learning was underway, and it was only about two years before the emergence of AlphaGo (2016).

In the scientific community, this award was noteworthy as the second instance of a couple receiving the award together. May-Britt and Edvard Moser met and married while studying at the graduate level and jointly led a laboratory. Previous examples include the Coris (Carl and Gerty Cori, Nobel Prize in Physiology or Medicine) in 1947 and the Curies (Marie and Pierre Curie, Nobel Prize in Physics) in 1903. The fact that a world-class discovery came from a small country and a local university is also part of this story.

Personal Stories: A Boy from Rural New York and a Couple from Trondheim, Norway

John O'Keefe (1939–) was born in New York, USA. He received his bachelor's degree from the City University of New York and his Ph.D. in psychology from McGill University in Montreal. He then settled at University College London (UCL) in the UK, where he spent his entire career. His interest was in the function of the hippocampus.

At the time, the hippocampus was already known to be a brain region associated with memory. The case of the famous patient H.M. – who lost the ability to form new memories after having his hippocampus, including temporal lobe tissue, removed for epilepsy treatment – was published in 1957, making the importance of the hippocampus clear. However, it was not known exactly how the hippocampus was involved in memory.

O'Keefe established a technique of recording the activity of single neurons in the hippocampus of freely moving rats using microelectrodes. With this technique, he made an amazing observation. Some hippocampal neurons fired only when the rat was in a specific location. When the rat was in that location, the neuron fired repeatedly, and when it was in another location, it was silent. O'Keefe named these neurons place cells and published his findings in 1971. His 1978 book, "The Hippocampus as a Cognitive Map," extended these findings into a theory and established the cognitive map theory, which states that the hippocampus represents an internal map of space.

This theory initially caused a great deal of controversy. The psychology community had viewed the hippocampus as a general system for learning and memory, and it was difficult for them to view it as a system for a specific domain (space). It took 20 to 30 years for O'Keefe's theory to become standard, and during that time, he continued his research quietly at UCL.

Edvard Moser (1962–) was born in Ålesund, Norway. May-Britt Moser (1963–) was born in Fosnavåg, Norway. The two met while studying psychology at the University of Oslo, married, and jointly majored in neuroscience. In 1994, the two spent several months as visiting researchers in O'Keefe's UCL laboratory. They directly learned about O'Keefe's place cell experiments and returned to Norway.

They set up their own laboratory at the Norwegian University of Science and Technology (NTNU) Trondheim campus. In a local city in Norway, in a place that was not a major university, they continued to conduct world-class research. Their problem was: "Where does information come from to the place cells? What neurons are upstream?"

The main input to the hippocampus is the entorhinal cortex. The Moser couple began recording neurons in this region. And in 2005, they discovered something amazing. Many of the neurons in the entorhinal cortex fired, and these neurons had not one, but multiple firing locations, and these multiple locations were arranged in a perfectly regular hexagonal grid pattern. There were several firing locations in the room, arranged in a triangular grid pattern. They named these cells grid cells.

The impact of the discovery was immediately understood. Grid cells were encoding the coordinate system of space itself. Multiple grid cells have different grid orientations and grid spacings, and their combination forms a coordinate system that accurately partitions the entire space. This architecture, with place cells overlaying representations of specific landmarks on top of the coordinate system, was complete.

In the years that followed, the Moser couple and other laboratories identified more related neurons. Head direction cells – which fire when looking in a specific direction, border cells – which fire when approaching a wall or boundary, and speed cells – which encode movement speed. All these cells work together to form a complete GPS system in the brain.

The three awardees were recognized 43 years after O'Keefe's discovery and 9 years after the Moser couple's discovery. This was because it was a representative case of cognitive neuroscience explaining the specific cognitive function of the adult brain with the activity of neurons.

Core Achievements: A CS Framework for Understanding the Brain's GPS Architecture

If we represent the brain's spatial coordinate system as a pipeline, it would look like this:

• Sensory Input: Visual, tactile, vestibular, and proprioceptive information are integrated in various brain regions.
• Coordinate System Generation (Grid Layer): Grid cells in the entorhinal cortex integrate this sensory information to create a triangular grid coordinate system. Multiple grid cells have different grid orientations and sizes, and their combination completely partitions the space.
• Landmark Encoding (Place Layer): Place cells in the hippocampus receive information from grid cells and encode specific locations (e.g., a specific corner of a room) in a coordinate system. Each place cell is specialized for a single landmark.
• Self-Localization: By combining the patterns of currently activated place cells and grid cells, the brain can determine its location in real-time.
• Path Planning: The brain calculates a path in the grid coordinate system between the place cell of the destination and the place cell of the current location to plan a route.
• Memory and Replay: During sleep, place cells in the hippocampus reactivate (replay) the routes of the day in a compressed timeframe, reinforcing memories.

The essence of this system is a hierarchical spatial representation with a basis-vector coordinate system. Grid cells act as basis vectors, and their active combination can represent any coordinate. Place cells are a cache of landmarks on this coordinate system. Through the combination of these two layers, the brain achieves spatial cognition far more sophisticated than robot SLAM.

Amazingly, this system works even in the dark. Even when visual information is lost, the brain continues to update grid cell activity based on its own movement information (proprioception and vestibular sense). This path integration is the core computational function of the grid cell system, which corresponds to dead reckoning in robotics.

However, we must also acknowledge the limitations of this analogy. The brain's spatial coordinate system is not a purely Euclidean coordinate system. The grid spacing of grid cells has a hierarchical structure, becoming larger as you go from the dorsal to the ventral side, which represents space at different resolutions depending on the scale. Also, the brain's GPS is recalibrated to fit the specific environment. When entering a new room, the pattern of grid cells is reorganized (remapping), and this flexibility is a characteristic that robot SLAM lacks.

Why It Matters: Alzheimer's, Navigation, and a New Standard for Understanding the Brain

First, it provides insights into the early pathology of Alzheimer's disease. The early pathology of Alzheimer's disease starts in the entorhinal cortex, which is where grid cells are located. The getting lost, confusion in familiar places that appears in the early stages of Alzheimer's reflects the early damage to the grid cell system. Since this observation was established, virtual reality spatial cognition tests have been developed for early diagnosis of Alzheimer's, and these tests have the potential to detect pathology earlier than conventional cognitive tests.

Second, it has become a new standard for understanding cognitive functions of the brain at the cellular level. Previously, there were maps showing which brain regions were involved in specific functions, but there were few cases where the information was encoded in such detail at the level of individual cells. After this discovery, research to find cellular-level codes for other cognitive functions—time perception, social cognition, and language—has become active, and a few years later, time cells that encode time and social cells that encode social relationships were discovered.

Third, it has implications for interaction with artificial intelligence. Several AI research labs, including DeepMind, are using the grid cell architecture as a reference for navigation algorithms in artificial neural networks. In 2018, DeepMind reported that when they trained an artificial neural network on a spatial navigation task, representations similar to grid cells emerged naturally. It was an amazing observation that the coordinate system discovered by evolution and the representations discovered by deep learning converged.

Fourth, it provides evolutionary insights. Grid cells have been found in mice, bats, monkeys, and humans. In bats, grid cells in 3D space have been found, going beyond 2D space, which means that the spatial coordinate system is a very old brain component in evolutionary terms. This system has been necessary since our ancestors, the mammals, began to move on land, and since then, the 3D navigation of birds, the echolocation navigation of bats, and the map-making of humans have all expanded on this foundation.

Fifth, it highlights the intertwining of memory and space. The hippocampus was originally known as a brain region involved in memory, and after O'Keefe's discovery, it became clear that this region is also involved in spatial cognition. This is not a coincidence. Episodic memory—memory for specific events—is strongly linked to when and where the event occurred. The concept that the encoding of "when and where" takes place on the hippocampus's spatial coordinate system has become a major focus of 21st-century memory research. This is why when we recall a specific event, the spatial context of that event also comes to mind.

Sixth, it demonstrates the power of a local university in Norway. The story of how the couple's laboratory created world-class discoveries provides important insights into the geographical distribution of science. This case confirms that even without a large university or a large city, world-class achievements can be made if there is a clear problem setting and intensive research. NTNU Trondheim has grown into an international neuroscience hub since this discovery, and it is also cited as a success story of Norway's basic science support policy.

The brain already had a GPS inside. This sentence summarizes the main point of this award. We are creatures that eventually draw maps and find our way, even in unfamiliar cities, and this ability is a very old part of our evolution. The fourteenth Nobel Prize in Physiology or Medicine of the new century revealed this ancient brain component, and on this story, early diagnosis of Alzheimer's, cognitive map theory, and artificial intelligence navigation research are each following their own trajectories.

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