Adrian Wanner aims to map the brain’s architecture. Doing this will allow us to better understand neurodegenerative diseases like Alzheimer’s.
Do you know this situation? You are standing in the kitchen and suddenly don’t remember why you went in there in the first place. Working memory is at fault here. It is supposed to keep information available for us for a period of several minutes. “If it isn’t working properly, it can lead to situations just like this one, where you forget whatever it was you wanted to do,” explains Adrian Wanner, a neurobiologist at the Laboratory of Nanoscale Biology at the PSI Center for Life Sciences (CLS).
In everyday life, situations like this might be unpleasant, but tend to be ultimately harmless. For some people, however, they may indicate a more serious underlying issue, as Adrian Wanner explains: “In the case of Alzheimer’s, working memory is often the first thing to be affected. Long before pathological changes like protein deposits in the brain become clearly visible, patients experience this type of forgetfulness.” Understanding working memory and its structure in detail could thus contribute to better comprehension of the terminal illness Alzheimer’s.
Activity maps and circuit diagrams
In order to reconstruct what exactly happens when the working memory keeps information available, Wanner uses two methods. “First, we create activity maps of brain cells,” the neurobiologist explains. “In these diagrams, the neurons that are activated by a particular action light up in colour.”
The researchers then try to find out how the individual neurons in this area are linked. “It’s like a circuit diagram for a computer,” says Wanner – but with biological synapses instead of electrical connections. Most brain regions and functions have not yet been mapped by way of such a circuit diagram that describes how information is processed: “Does information go directly from point A to point B to point C or are there cross connections or feedback loops in between that move it a step back?”
There are various, often conflicting theories on which paths the brain activates when it processes and then stores information. Adrian Wanner wants to use empirical data to determine which model best reflects reality. He wants to observe which neurons are active during tasks for which working memory is important. He then maps the way in which these neurons are interlinked to create a detailed circuit diagram. “This way, we can track exactly what is happening in the brain at this point in time.”
The working memory at work
For his research, Adrian Wanner works with mice. “In terms of structure and function, their brains are similar to those of humans’,” he explains. “This is why they can also develop forms of dementia and we can analyse how healthy animals differ from sick ones.”
In order to analyse a mouse’s working memory, the neurobiologist sets it a task where the mouse has to remember information for a few seconds. First, the mouse learns how to move around in a virtual environment, similar to a computer game. To do this, the animal watches a screen and runs along a virtual corridor. At the beginning of the corridor, the mouse is shown a specific pattern, for example a checkerboard pattern. It must then remember this pattern.
After a few metres, the corridor forks into a left-hand and a right-hand path. Once the mouse arrives at this point, a pattern is displayed at each path, a line pattern on the right and a checkerboard pattern on the left, for instance. Now, the mouse has to recall: “Aha! There was also a checkerboard pattern at the beginning of the corridor.” If it turns left at the virtual fork, it receives a real reward in the form of food. “It is precisely during this period, when the mouse is no longer looking at the pattern and is running along the corridor, that it must keep the information available – its working memory is active.”
While the mouse is playing this memory game, Wanner and his team are imaging the activity in its brain. By comparing these images to circuit diagrams of the brain, they can determine the rules according to which the neurons are linked in order to keep this piece of information in working memory. “In fact, brain activity differs depending on the pattern that we show the mouse. A checkerboard pattern causes different cells to activate in a different sequence than a line pattern.”
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Image: Tiny section of a mouse brain: a few dozen nerve cells with their synapses are shown, and thus only a fraction of the 100 000 cells that cavort in a cubic millimetre of brain.
Credit: MICrONs Consortium et al.
