Don't Miss
The 2014 Nobel Prize winners in Physiology or Medicine. Photo: Gustav Drevin

Navigating the complexities of the brain

Interview with Edvard Moser – the 2014 Nobel Prize winner in Physiology or Medicine

Story: Iskra Pollak Dorocic   /  Infographics: Jakub Lewicki

nobel_graphics

As Edvard Moser stepped off the plane from Trondheim – blissfully unaware that the 150 emails and 75 text messages on his phone were a sign that this day would be like no other – he was on his way to give yet another guest lecture. As soon as he entered the terminal in Munich, the news came via a congratulating representative. The unsuspecting Dr. Moser finally realized that he had just won the most prestigious prize in science – the Nobel Prize in Physiology or Medicine.

“I’m terribly grateful, it’s absolutely fantastic”, said Dr. Moser to the Nobel spokesperson who contacted him shortly thereafter. “I didn’t even know it was today, I really didn’t even think about it. So even more pleasant when it’s such a surprise.”

Edvard Moser, alongside his lifetime scientific partner and wife May-Britt Moser and their ex-supervisor John O’Keefe, received this year’s prize “for their discoveries of cells that constitute a positioning system in the brain”. The trio described the specific cells in our brains which are responsible for mapping the space around us and giving us a sense of where we are. The research spans several decades, starting with the discovery of the “place cells” in 1971 by O’Keefe, who demonstrated that very specific brain cells are active only when one is in a specific location. The Mosers added to this in 2005 with their discovery of the “grid cells”, which generate the coordinate system used by the brain for exact positioning. Both cell types were initially discovered in rats, but have since also been shown in humans.

LINKING MEMORY AND SPACE

For over two and a half millennia, scientists and philosophers alike have contemplated the ways in which our minds create internal maps of the environment and enable us to navigate through space – tasks crucial for survival. The ancient Greeks were the ones who developed the memory trick still used today, where one imagines walking through a specific space, such as a house, and associates each phrase or number to be remembered with a specific object or location in the house. This trick would allow them to memorize long speeches and recite them effortlessly while mentally walking through the imagined space. Today, participants in memory championships use this strategy to memorize exceptionally long strings of numbers, or the order of cards in multiple decks.

So it was obvious that memory and navigation are somehow linked in the brain. The first person to coin the term “cognitive map” was Edvard Tolman, a mid-20th-century psychologist and adamant anti-behaviouralist. He observed rats navigating through a labyrinth and realized the animals must have been forming an internal representation of the external environmental in their mind and using it to find their way through the maze. But how exactly is this cognitive map represented in the brain? How do the cells in our brains, the neurons, code spatial orientation?

What they found took them completely by surprise.

 

In the late 1960’s the American-British neuroscientist John O’Keefe was just embarking on a promising academic career at University College London (UCL). He was interested in how brain activity directly controls behaviour, and decided to record the activity of single neurons located in the hippocampus of rats while they moved around an enclosed environment. The hippocampus also happens to be the structure where memories are formed in our brains. Neurons communicate with each other via tiny electrical currents, and it is possible to record the electrical activity of a brain cell using small wires, called electrodes, implanted into the brain. O’Keefe discovered that only certain neurons became active when the animal was in a particular spot in its box. So the same neuron was active each time the rat was in the middle of the box, and another specific neuron fired each time the rat moved to the left corner, and so on. O’Keefe coined these special hippocampal cells “place cells” and proposed that the hippocampus generates different cognitive maps which are represented by collections of specific neurons active in different environments. Effectively, the brain forms a memory of a particular place based on the combination of place cells that are active in the hippocampus.

nobel_graphics

nobel_graphics

REVEALING THE HIDDEN PATTERN

May-Britt and Edvard Moser spent some time in O’Keefe’s UCL laboratory in 1996, as part of their post-doctoral research. This is where they learned how to record single-cell activity in rat brains while the animals moved through space. The Mosers took this skill with them and started their own lab in their native Norway. It was there in 2005 that they made the seminal discovery of “grid cells”. Aiming to figure out the control mechanism for O’Keefe’s place cells, the Mosers first looked upstream of the hippocampus, in an area called the entorhinal cortex. This region sends prominent inputs to the hippocampus, and thus also to the place cells. Not much attention had previously been paid to the entorhinal cortex, but the Mosers decided to implant their electrodes into this particular structure and record while the animal moved around its environment. What they found took them completely by surprise.

As the animal moved through particular spots in the box, specific neurons fired, not unlike the place cells in the hippocampus. But in contrast to the place cells, these entorhinal cells fired in other places too. They seemed to form a pattern. “The discovery was a longer process”, says Edvard Moser. The researchers first had to make changes to the recording setup, in order to recognize the pattern produced by the neurons. “We found quite early on that the cells in the entorhinal cortex have a special firing correlate. Each of them have many firing fields that are very regular.” The pattern that emerged was one of many hexagons placed on top of each other as the animal moved through the environment, basically forming a honeycomb pattern. “But then to see that this was really the hexagonal pattern, we had to increase the size of the recording environment so then you could really see how these firing positions were spaced in relation to each other. So I would say that it was a process that took place over maybe half a year, where we became more and more certain that it was a hexagonal pattern. And of course there were those really exciting moments, but it wasn’t really one single moment.”

There is a certain elegance and unusual simplicity with this pattern of grid cell activity. It turns out that the hexagonal geometry is an optimal configuration that allows for maximal spatial resolution and energy conservation of the system. This unexpected simplicity is a scientist’s dream, especially in brain research where the complexity often seems overwhelming. Discovery of patterns starts the journey to understand the computation underlying a complex process, in this case, spatial navigation.

 “What is fascinating about studying the positioning system, is that it is a simple form of cognition that is kind of away from sensory receptors and also far away from the motor neurons. I often say that it is in the middle of the brain”, says Moser. Indeed, since the entorhinal cortex receives no direct sensory input, unlike say, the visual system (which receives information from the retina) the hexagonal pattern is created internally. “Why that is interesting is that unlike most other functions in the brain that are computed in the association cortices, this one has a very clear correlate in the outside world, which is the position of the animal. So it’s very easy to measure and can then be related to the computations that are taking place [inside the brain].”

nobel_graphics

nobel_graphics

TWO MINDS, ONE GOAL

It really takes special minds to unlock the brain the way the Mosers did. Dr. Cori Bargman, distinguished neurobiologist and head of the $100 million BRAIN initiative, tweeted not long after the Nobel Prize announcement, “Lesson from O’Keefe and the Mosers: the brain is stranger than you could imagine. Yet by intelligent observation, you can understand it.”

The Mosers are not your typical Nobel winners. The humble Norwegians defy stereotypes of old, white-haired scientists who made their groundbreaking discoveries many decades ago. Edvard and May-Britt Moser are youthful-looking 50-somethings, who not only hike the mountains surrounding their home in Trondheim, but also volcanoes around the world – in fact, they got engaged on top of Mount Kilimanjaro in Tanzania. Edvard is known to wear his red Converse sneakers at conferences, showing off his laid-back style – both physical but also personality-wise. In fact, he seems a bit overwhelmed with the attention since receiving the Prize. “For sure I enjoy it, as long as it does not become too much, I enjoy it”, he replies when asked how he is handling all the attention. “The days are very chaotic because there’s so many thing that I need to do, many interviews and all these preparations for the things in Stockholm, that’s part of it. I would assume that it comes back to a bit more normal after New Year.”

The Mosers are not your typical Nobel winners.

 

Both Edvard and May-Britt grew up on islands off the coast of Norway in non-academic families. When they met as undergraduates at the University of Oslo, they discovered their mutual interest in brain and behaviour, and through unrelenting motivation ended up in the lab of Per Andersen. At the time he was studying neurons in the hippocampus, and was initially apprehensive about pursuing the project the Mosers really wanted to pursue.

Since the beginning, the Mosers worked as a team. “We share our involvement in all projects, but there are some projects where May-Britt is more involved and some I’m more involved in. But basically we run the group together, we have one common goal, one set of key questions which we want to investigate”, says Edvard Moser about working with his wife. “It’s an advantage in the sense that we are complementary, and that she has strengths that are somewhat different from mine, so if you put those together we become stronger than just the sum of us.”

Despite the advancement in our understanding of the mind, many mysteries still abound. Moser considers, “There are many questions still unanswered, we are just grasping the surface on understanding how higher brain functions come about. Let’s say cognitive functions: how we think, how we plan, how we make decisions, all that. By and large, there is a lot we still don’t know for many of the higher functions.”

“The Human Brain project is somewhat more controversial, there’s a big resistance in Europe.”

 

Indeed, brain research has recently been gaining momentum. Within the last year, both the EU and the US invested substantial amounts of funding in researching the mind and its many disorders. The EU initiated the €1-billion Human Brain Project, while the US followed suit with the BRAIN initiative. When asked how he sees these large initiatives, Moser says, “The BRAIN initiative in the Sates is a very good document, they have formulated key questions that can be addressed with some really new and upcoming techniques and technologies.” For the EU project, Dr. Moser reserves some skepticism, “The Human Brain project is somewhat more controversial, there’s a big resistance in Europe. Not against involvement in neuroscience, because that is what everyone wants. But the way it is done and maybe the focus on the collection of a lot of data, while it’s not always clear how knowledge is going to come out of all this data.”

The Mosers have a common laboratory at the Kavli Institute for Systems Neuroscience, with a large number of PhD students and post-docs. “My advice to young researchers would be try to find a question that really interests you, that hasn’t quite been solved yet, and go for that using new technologies that have come – but don’t forget the question”, says Moser, referring to the many recent technological advances. He continues, “because there are many fancy technologies but it’s even more important to actually find the problems that you really want to solve. Sometimes one has to do more adventurous things if you really want to get far, and that always involves some risk.”

FROM MICE TO MEN

Place and grid cells have more recently also been shown to exist in humans, not just in rats, the model that O’Keefe and the Mosers first investigated. This has potential relevance in Alzheimer’s disease, where both the hippocampus and entorhinal cortex are affected early on. The functional deficits in these regions translate into devastating spatial memory loss, where patients gradually fail to recognize their environment and eventually even family memebers. Understanding the basic mechanisms behind spatial navigation will help shed insight into the cognitive decline seen in such neurodegenerative disorders.

…have shed light on a very fundamental function of our brains.

 

It is still early days in our understanding of the brain. John O’Keefe alongside May-Bitt and Edvard Moser have shed light on a very fundamental function of our brains. Past Nobel Prizes have honoured other essential findings in neuroscience, particularly in the visual, olfactory and memory systems. This year’s winners can rest assured they have added to the progress of understanding one of the greatest mysteries of the universe – our minds.

nobel_graphics

About Medicor Team

Leave a Reply