Inside the Brain’s Navigation System: How Nobel Laureates Revealed Its Mysteries

It seems like ancient history, but there was a time not that long ago when humans had to manage and navigate their surroundings without ubiquitous smartphones equipped with mapping apps and GPS. Furthermore, during more primitive times, humans had to manage without any sort of maps – how ever did we do it?

Believe it or not, humans are really good at navigation. That’s what enabled us, during our history, to navigate the world’s oceans and landmasses; it allowed us to find our way in vast spaces and create compact, navigable areas such as modern cities. You may forget how to get to that one shop or cafe once in a while, but overall, your navigation skill is excellent. But what exactly gives us this innate navigation ability has eluded scientists for the longest time, and was ultimately awarded a Nobel Prize in 2014.

Place Cells

This veil of mystery first started lifting in the early 1970s. British-American scientist John O’Keefe was fascinated by how the brain controls behavior. Before then, for the most part, research in this field was rather general and abstract, but the technology was advancing, enabling the direct study of brain cells. Research methods were also becoming better, and O’Keefe wanted a more quantitative approach.

He wanted to see which neurons do what by isolating groups of neurons responsible for specific tasks. He zoomed in on rats and tried to figure out what goes on in their brain when they orient themselves. Throughout the 1960s, the scientist explored various scenarios, and in 1971, along with his student Jonathan Dostrovsky, they had an important breakthrough.

O’Keefe and Dostrovsky tested individual neurons in rat brains to see how they reacted to environmental stimuli. The two allowed rats to roam freely and noticed that some cells in a part of the brain called the hippocampus would activate when the animals explored some locations. The hippocampus has a major role in learning and memory and when the hippocampus is damaged in humans, orientation is affected — so this evidence seemed to fit very well.

But O’Keefe took things one step further. He proved that these cells in the hippocampus aren’t just responding to stimuli, but they’re building mental maps that include information such as direction and distance. This enables the rats, he showed, to develop a cognitive model of the environment, which is useful in navigation and obtaining rewards, as well as avoiding threats. With these „place cells“, as they were called, the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments.

At first, the discovery wasn’t accepted by everyone in the community.

„I remember how great was the scoffing in the early 1970s when John first described ‚place cells‘,“ said John Stein, emeritus professor of physiology at Oxford University, in a 2014 press release, following the Nobel Prize. „‚Bound to be an artifact‘, ‚He clearly underestimates rats‘ sense of smell‘ were typical reactions. Now, like so many ideas that were at first highly controversial, people say: ‚Well, that’s obvious‘!“

In time, however, further research cemented the find, and the „place cells“ turned out to be a crucial puzzle key when it comes to the brain’s orientation and it seemed that little by little, the shroud was lifted from this enigma. But surprisingly, for a few decades, there were few breakthroughs. That is, until the Mosers came along.

Place and Grid

O’Keefe’s work inspired two up-and-coming neuroscientists: Edvard Moser and his then-wife May-Britt Moser. O’Keefe became their mentor and together, they found another key group of cells.

Yet again, the neuroscientists turned to rats and analysed their brain activity as they were navigating the environment. In 2005, they discovered a new type of cell in an area right next to the hippocampus called the entorhinal cortex.

The entorhinal cortex is the „information gateway“ for the hippocampus, and it showed a striking activity pattern when rats explored multiple locations, enticed by chocolate treats. Some cells in the entorhinal cortex lit up in a unique hexagonal pattern. Edvard and May-Britt Moser called these cells „grid cells“ and found that they work as a coordinate system for navigation.

Together, the grid cells and the place cells do the heavy lifting when it comes to spatial orientation. The realisation marked a paradigm shift in our understanding of cognitive processes, and in particular, of understanding how groups of specialised cells collaborate to perform higher cognitive functions.

This essentially paved the way for a new way to link physical, quantifiable cells to seemingly abstract complex processes. „I think we are entering an era where we are beginning to understand how cognition works in general terms. Space has brought us into this, but that is just the beginning. I think one of the aims can be to understand cognitive functions, like thinking, planning, decision-making, categorising. All these functions that have traditionally been studied in cognitive psychology can now being addressed experimentally in neuroscience,“ said Edvard Moser in an interview with the Lindau Nobel Laureate Meetings.

An Ongoing Area of Research

Oftentimes, it’s surprising to see how research in one field can lead to another. For instance, in 1997, three physicists (Bill Philips, Steven Chu, and Claude Cohen-Tannoudji) were awarded the Nobel Prize in Physics for their work on supercooled lasers, which unexpectedly paved the way for GPS. Similarly, it seems that research into cells linked with orientation may lead to breakthroughs in other fields.

Place and grid cells don’t just exist in rats – they’ve been found in multiple mammals such as bats, monkeys, and humans. They also seem to emerge during infancy, which would suggest that humans develop a sense of orientation (at least a rudimentary one) just one or two months after birth. But grid cell dysfunction was also found to be one of the earliest symptoms of the development of amyloid plaques, one of the earliest markers of Alzheimer’s disease. These groups of cells could also be linked to other conditions, an area that definitely warrants further research.

Of course, place and grid cells aren’t the end of the story. Our brains don’t have direct access to supercooled lasers or GPS, they have to manage navigation using various types of cells.

For instance, O’Keefe (along with Neil Burgess) also demonstrated the existence of boundary cells, which respond to the presence of an environmental boundary at a particular distance and direction from an animal. In 2023, a separate team demonstrated the existence of head direction cells, which can accurately be described what direction the head is facing, with an error of only a few degrees.

Disruptions of these cells were also, tantalisingly, found to be linked with Alzheimer’s, suggesting that we are only scratching the surface of what these cells actually do in the human body. We know that they exist and we know their main function (or one of their main functions), but there is plenty we just don’t know yet.

No doubt, this is not the end of the story. The 2014 Nobel Prize for Physiology rightfully credited the paradigm shift but there are questions that still seek answers. But even as we’re far from answering all the questions in this area, we’re already standing on the shoulders of giants. Armed with findings from the likes of O’Keefe and the Mosers, researchers have been continuously improving our understanding of brain navigation (and the Nobel Laureates themselves have continued work) and how this links to other conditions.

Judging by how complex the human brain is, there will forever be new questions and new answers to look forward to. The journey into the brain has never been more exciting.