Eine Landkarte im Gehirn

Edvard Moser fand ihn unter seinen entgangenen Anrufen: den Anruf des Stockholmer Nobelpreiskommitees. Erst als er in München aus dem Flugzeug stieg, erfuhr der norwegische Forscher, dass er einer der Nobelpreisträger 2014 für Physiologie sei. Gemeinsam mit seiner Ehefrau und Ko-Gruppenleiterin May-Britt Moser und dem britisch-amerikanischen Forscher John O’Keefe, bei dem die Mosers eine kurze Zeit lang forschten, erhält er den Nobelpreis für die Entdeckung der “Landkarte im Gehirn”.

Bereits 1971 entdeckte John O’Keefe Nervenzellen, die Ratten als Kompass dienen. Er taufte sie “Platzzellen” (englisch: place cells). Läuft die Ratte durch den Käfig, sendet eine Platzzelle ein Signal, wenn die Ratte beim Futterspender steht, während eine andere Platzzelle sendet, wenn die Ratte in der hinteren Käfigecke hockt. Eine Platzzelle feuert also immer dann ein Signal ab, wenn sich die Ratte an einem bestimmten Punkt befindet. An jedem Ort feuert nur eine geringe Zahl an Platzzellen, die sich in einer speziellen Hirnregion, dem Hippocampus, befinden. So kodieren die Signale von nur wenigen Nervenzellen jeden Punkt in der Umgebung.

Nur eine Schaltstelle zwischen Nervenzellen, Synapse genannt, trennt Platzzellen und “Koordinaten-Zellen”. Zwischen der Entdeckung von Platzzellen durch John O’Keefe und der ersten Beschreibung von Koordinaten-Zellen (englisch: grid cells) durch May-Britt und Edvard Moser verstrichen aber über 30 Jahre. 2005 entdeckten die beiden Norweger ein Koordinatensystem im Gehirn von Ratten. Sie zeichneten dafür, ähnlich wie O’Keefe, die Signale auf, die Nervenzellen senden. Anders als O’Keefe konzentrierten sie sich auf Signale von Nervenzellen im sogenannten entorhinalen Kortex. Das “Feuern” von Nervenzellen klingt beim Aufzeichnen wie das Poppen von Popcorn in der Mikrowelle: jedes Signal ist ein “Pop”. Wenn eine Ratte durch eine experimentelle Umgebung läuft, das ist meistens einfach eine Kiste, hörten die Forscher immer wieder ein Pop. An manchen Orten aber “poppte” es ganz besonders häufig, wie wenn das meiste Popcorn im Sackerl aufspringt.

Zeichnen wir an jedem Ort, an dem sich die Ratte befindet, wenn eine Koordinatenzelle am meisten “poppt”, einen Punkt, entsteht rasch ein faszinierendes Muster: die “Pops” konzentrieren sich auf Sechsecke, die sich in regelmäßigen Abständen wiederholen. Alle Koordinatenzellen feuern in diesem sechseckigen Muster. Bei manchen Koordinatenzellen sind die Sechsecke aber größer oder kleiner, nach links oder rechts verdreht, oder näher oder weiter von einander entfernt. Dieses Koordinatensystem legt sich über den ganzen Raum der Ratte: wie der Längen- und Breitengrad jeden Ort der Welt bestimmen, definieren eine Handvoll Koordinatenzellen jeden Punkt in der Umgebung der Ratte.

Ratten haben noch mehr Nervenzellen, die nur an bestimmten Orten oder Positionen Signale senden: “Kopfrichtungszellen” feuern, wenn die Ratte den Kopf in eine bestimmte Himmelsrichtung hält, “Grenzzellen” senden Signale, wenn die Ratte in einem bestimmten Abstand von einer Wand läuft. Platzzellen und Koordinatenzellen bilden, zusammen mit den Kopfrichtungszellen und Grenzzellen, eine “Landkarte” im Gehirn der Ratte. Mit dieser Landkarte hat die Ratte auch im Dunkeln und in einer neuen Umgebung immer eine Darstellung davon, wo sie ist und wohin sie sich bewegt.

Ein ähnliches GPS befindet sich vermutlich auch in unserem menschlichen Gehirn. Edvard Mosers Platzzellen und Koordinatenzellen, die gerade feuerten, als er von seinem Nobelpreis erfuhr, sind wahrscheinlich untrennbar mit Freude verbunden.

Paper von John O’Keefe und Jonathan Dostrovsky:

Paper von May-Britt Moser und Edvard Moser

Podcast Love

So, John O’Keefe, May-Britt Moser and Edvard Moser got a call from Stockholm yesterday morning. The Nobel Prize in Physiology 2014 is theirs, for the discovery of “the brain’s GPS”, as many like to call it. If you’d like to hear the Mosers themselves talk about their discovery of grid cells, and how they came to study them, this short podcast from the New York Times recorded back in April 2013 is worth listening to. Their enthusiasm is infectious – or how many scientists are likely to describe electrophysiological recordings from the brain as “like popping popcorn in the microwave”?


Science Times Podcast with May-Britt and Edvard Moser

How do we store memories?

If you are a football fan, you probably remember Götze’s title-scoring goal for Germany in Sunday’s world-championship final. If you are not a football fan, you probably remember the pleasant evenings you spent before the football craze set in. The memories are clear before your inner eye, but how do you store them in your brain?

Neuroscientists know that one brain region, called the hippocampus, is our memory storage. However, they have three different theories of how the brain cells, or neurons, in this region can store the memory of Götze’s goal. According to the first theory, one neuron encodes this memory. So this neuron, and only this neuron, sends a signal when you think of Götze scoring – you have a “goal neuron”. The second theory states that many neurons together send signals in a pattern, and this pattern is typical only of your goal memory. But each neuron also contributes to many other memories, like that of the cool beer you drank alongside. Basically, you have a “goal pattern”. The third theory falls in the middle: only a few neurons signal when you think of Götze’s goal, and each neuron also stores a few other memories. But which theory is true?

Psychologists in the US tested this by looking at the brain activity of people recognizing familiar versus new words. The participants in the study were epilepsy patients who wore wire electrodes in preparation for possible surgery, with the aim to find out where in the brain seizures took place. To test how their brains store memory, the researchers gave participants a list of 32 words, which they studied. In the memory test, they were shown 64 words – the 32 from the original list, and 32 new words. The participants were asked to say which ones were “old” words and which ones “new”. Using the electrodes, the research could see the areas of the hippocampus in which neurons sent signals when a new or old word was shown. They found that neurons in some areas signal more often when the participant sees an “old” word rather than a “new” word. For each area, neurons only signal when the participant sees a few “old” words.

This supports the third theory: it is likely that in the hippocampus our memory of Götze’s goal is stored by a group of a few neurons. Each of these neurons, together with a different group of neurons, also stores a few other memories – maybe that of Argentina’s very near misses.

Orginal research paper in PNAS: www.pnas.org/content/early/2014/06/11/1408365111.abstract

Good vibrations?

“Fit in 15 minutes” – just 15 minutes training to get the same results as in a one and a half hours of sweaty workouts – that’s one of the promises of the “vibroplate”, “powerplate” and similar gyms promoting doing exercises on a vibrating plate. “Clever in 15 minutes” might be another claim they are making soon. Researchers in the Netherlands tested whether sitting on a vibrating plate could improve cognition in young, healthy adults. We know that exercise can improve memory, reasoning and problem solving, so-called “executive functions”. However, how can people who are unable to physically exercise reap the same benefits? The researchers tested whether passively sitting on a chair mounted on a vibrating platform – called whole body vibration – could improve executive functions. They found that after two minutes of such whole body vibration, volunteers performed better on a color-word interference test. In this test, participants are shown cards with 20 color names, each printed in one of five colors. However, the ink color of each word is different from the color name. The participants are asked to name the ink color of the word as fast as possible. In the study, participants were quicker in naming the correct ink colors after vibration. But they only improved if they took this test, designed to measure attention and inhibition, immediately after the end of vibrations. They did not improve if another two-minute test, measuring working memory, was done in between. And they also did not score any better on the working memory test.

The researchers suggest that vibrations might stimulate skin receptors that respond to vibrations. They send signals to a region of the brain strongly connected to the prefrontal cortex, which is involved in cognition and the processing of information. However, it is yet to early to add “become Einstein in 15 minutes” to the claims of vibration gyms. The observed improvement only lasts for a short while, less than a minute and only for a specific type of cognition, attention. And the researchers themselves suggest that it is necessary to test how long the vibration sessions have to be, and how often they have to be repeated, to see any strong effects on cognition. But in the long run, whole body vibration might turn out to be clinically relevant, and help people unable to exercise to at least have some of the benefits of going to the gym. For everyone else, the best reason to go to the gym in the meantime probably remains to simply get fit.

Original research paper in PLOS One

Is Alzheimer’s a prion disease?

Alzheimer’s disease affects more than 30 million people worldwide. One cause of this devastating type of dementia are tangles of a protein called tau. Tau usually binds to the cell’s inner skeleton, but in patients it groups together in brain cells and forms tangles, clogging them up. Other neurodegenerative diseases are also caused by tau, together they are called “diseases of tau” or tauopathies. Already 30 years ago, some researchers suggested that the cause for Alzheimer’s and other tauopathies could be a mechanism similar to prions – of mad cow disease fame. Prion-diseases like mad cow, Creuzfeldt-Jakob or scrapie are caused by small prion proteins that clump together. Prions come in different strains, which each cause different forms of clumps. Such clumps are “seeded”: one prion folds into an abnormal structure and causes other, normal, prions to also deform and clump together. Alzheimer’s and other tauopathies spread through networks of brain cells. This suggest that something toxic moves from one brain cell to the next, for example tangles of tau. Also a prion-like process of “seeding” has been suggested, with a tau tangle causing normal tau to deform . But conclusive proof of Alzheimer’s being a prion disease has been missing so far. In a paper in press in Neuron, researchers from the US and the UK show that tau acts like a prion.

Tau in a normal cell, and the formation of bundles in a cell of an Alzheimer's disease patient. Copyright: NIH
Tau in a normal cell, and the formation of bundles in a cell of an Alzheimer’s disease patient. Copyright: NIH

Scientists define prion diseases as “strains” of clumps that transmit into a cell or organism, can be extracted from a cell or organism and then when put back into a new cell or organism cause the same structure of clumps. In their work, the papers’ authors seek to show that a similar process is at work in Alzheimer’s disease. As the brain is a complex organ, scientists often use cells grown in a dish, in so-called cell culture, as a first start in their study. Here, the researchers made cells that produce a tau protein that glows yellow, but otherwise folds normally. When they added small tangles of tau into the cells, the yellow tau protein also joined the tangles. They then isolated colonies of cells with tangles, called clones, and allowed them to grow in single dishes. Different clones had different properties of tau tangles, like the size or position of tangles in the cell. The researchers then burst open clone cells, and put the cell solution into a dish with fresh cells with normal tau. The normal cells then form tau tangles, with the same properties as the clone used to infect them. These tau clones behave similar to prion strains, and the researchers call them tau strains.

The researchers then moved on to look at tau tangles in mouse brains. When they put cell solution into the brain of mice, the different strains cause differing tangle types in different neuron groups. Brain solution from mice infected with one strain caused newly infected mice to get the same tangle structure in the same neuron groups. When the researchers put tau tangles into a brain region called the hippocampus, tangles spread to regions whose brain cells project to or from the hippocampus. This shows that tau tangles spread from one brain region to others that are connected with it by their cells. Finally, when the researchers isolate tau tangles from mice and put them back into cells, they get back the same strain specific tangle structure they started out with.

As a final indicator of whether tau behaves like a prion, the researchers looked at different human tauopathies. For this, they used brain extracts from donated brains of patients who suffered from five different tauopathies, including Alzheimer’s. When extracts from different diseases are put into cells, different and distinct tangle types form. Different tauopathies with their specific disease characteristics are therefore caused by different strains of tau tangles.

For all intents and purposes, from this paper, it looks like tau behaves and is a prion. Strains can be extracted, form distinct clump types, and different strains cause different types of diseases. One important difference that sets Alzheimer’s apart from classic prion diseases like mad cow disease and scrapie is that Alzheimer’s is not infectious , and spreads only within an individual. The paper’s authors posit, however, that limiting the term prion to mean only infectious particles could artificially limit our view of prion diseases, and ignore a mechanism that unites a range of diseases. Also, over 95 percent of human prion disease cases appear to be genetic or spontaneous (sporadic) anyways, and are not linked to an infection, nevertheless they are seen as a prion disease. Does this have any implications for the treatment of Alzheimer’s and other tauopathies? Seen as there is currently no treatment for prion diseases, it might not seem so. But the observation that tau tangles spread from one neuron to the next gives a glimmer of hope. When tau spreads, it is briefly outside of the neuron. In the space outside the neuron, tau is exposed to potential new therapeutics, for example to prevent tangle spread, or to contain the infectious tau tangle in only a limited area of the brain. This paper puts the hypothesis that tau is a prion on firmer ground, and could be a step in the direction of developing a cure for Alzheimer’s – even if only by pointing out one potential angle of attack.

The original research appeared in Neuron: http://www.cell.com/neuron/abstract/S0896-6273%2814%2900362-6