Rethinking the brain

Fruit flies

Giving memories context

Science

Enlightening the brain’s circuitry

Created in 1970 by Novartis predecessors Ciba and Geigy to boost basic research and deepen ties between academia and industry, the Friedrich Miescher Institute for Biomedical Research (FMI) – which celebrated its 50th anniversary in 2020 – has since become an investigational powerhouse. One of its key research areas is neurobiology, where FMI researchers shed light on neuronal circuits that program how we behave, learn and remember.

Text by K.E.D. Coan, photos by Bjoern Myhre

Flies can be trained to associate an odor with the presence of an electric shock in a training apparatus called the T-maze. The resulting olfactory memories can be stored and accessed for several days.

Table of contents

Rethinking the brain

Fruit flies

Giving memories context

Published on 29/03/2022

What is memory?

There is still no clear answer to this fundamental question. But the research team at the Friedrich Miescher Institute, or FMI, in Basel has been instrumental in advancing what we know about how the brain works – and in particular memory. Their biggest contribution – and what earned them worldwide recognition – has been their trailblazing approach to study the brain in terms of neuronal circuits.

“One of the biggest challenges in neuroscience – and for neurological and psychiatric treatments – is that we still lack a complete mechanistic understanding of the neuronal circuitry of the human brain,” says Andreas Luethi, senior group leader and a specialist in the circuitry of learning and memory. “During the last 20 years, neuroscience has witnessed enormous progress in understanding how neuronal circuits program memories, movement and behavior, and the FMI has really been at the center of this development.”

The billions of neurons that form the brain have different roles and they interact in groups of tens, thousands, or even larger ensembles. These interactions form the circuitry of the brain – computing all of our senses, actions and memories. The FMI’s neurobiology group was one of the first to focus on this ambitious approach and they have spent the last 20 years deciphering this hidden “language” of the brain.

While such research is far away from the clinic, their findings lay the foundation for future treatments for neurodegenerative diseases like Alzheimer’s, amyotrophic lateral sclerosis (ALS) as well as psychiatric disorders including anxiety, depression and posttraumatic stress disorder.

Fundamental findings

This basic research into hard-to-tackle medical problems is precisely the mission of the FMI. “When the institute was created in 1970 its initial goal was to provide Ciba and Geigy with new ways to drive innovation by tapping into basic research and translate this knowledge into viable products,” says Novartis Chairman Joerg Reinhardt. “The FMI has proven that it is able to bridge the traditional divide between industry and academia.”

Reinhardt goes on that the FMI has done much more than that: “The institute has been successful in setting up new forms of scientific collaboration and has built a unique educational platform, which gives promising scientists the opportunity to deepen their basic research skills while at the same time learning more about the pharmaceutical industry – adding strength to both.”

Collaboration with NIBR is key for the FMI – over 400 collaborations between FMI and Novartis researchers have been put in place since 1998. On the other hand, the FMI is also well established in the academic landscape. The FMI is an affiliated institute of the University of Basel where most of today’s group leaders hold professorships and teach, while they are also engaged in intensive collaboration with faculties around the globe in the realms of neurobiology, epigenetics and quantitative biology.

By seeking collaboration with pan-European science initiatives, such as EU-Life and LifeTime, the FMI has created a strong knowledge network. FMI scientists regularly publish their results in the most renowned scientific journals and they have been extremely successful in attracting competitive third-party funding, such as prestigious ERC grants. All this helps to attract some of the most talented young scientists in the world.

The fact that the institute is home to over 80 postdocs and over 80 Ph.D. students from more than 40 countries speaks impressively of its international attractiveness as a center of excellence for top-notch researchers, including in brain and memory research.

By controlling the intensity of the electric shocks, we can study how flies re-evaluate learned information. In fact, when flies experience the omission of an expected punishment it is coded as a reward, similar to mice and humans.

Rethinking the brain

Becoming experts in memory brain research has been no easy task though. While the field emerged in the 1960s, it made slow progress, even during the boom in molecular and cellular biology in the 1980s and 1990s. At that time, the FMI’s neurobiology group was relatively small. But its contributions were impressive.

One of the FMI’s earliest breakthroughs in neuroscience was thanks to Andrew Matus, a group leader from 1978 to 2007. Matus was an early adopter of new technologies to visualize the different parts of neurons – for example the long conductive axons and the branching dendrites that send information between neurons. Most memorably, in the late 1990s, he captured video showing that small extensions of these dendrites – called spines – even “danced.”

“His discovery made a big splash among neuroscientists partly because it showed that these spines were moving and affecting the cytoskeleton of the neurons,” says Pico Caroni, a senior group leader who joined the FMI in 1989. “At the time, the possibility that neurons could structurally change was just an idea on paper and this was some of the earliest evidence that structural changes might be possible.”

The intriguing idea that neurons could change their structures and connections became one of Caroni’s ongoing specializations. But Caroni and the FMI’s leadership soon realized that the molecular biology approaches of the 1990s were limited to really understand the inner workings of the brain. “Back then, the field believed that molecular biology would basically explain neuroscience, but we realized that wasn’t enough to bring profound insights,” says Caroni. “So we took a risk and, when Matus and several others retired, we rebuilt our neuroscience group – much larger than before and on a completely different focus that we believed would be the future of the field – circuits.”

Attracting talent

Since then, the FMI has published dozens of groundbreaking discoveries, showing the different roles of neurons and how memories are stored in the brain. Caroni’s work, for example, has helped to show how structural changes in neurons are critical to learning and memory. His group discovered networks of neurons that change their connections depending on whether they are switched on or off for learning.

One of the first researchers to join the FMI’s growing brain research group was Andreas Luethi, an expert in the neuronal circuitry of emotions, particularly fear. “Fear learning is a very good model for learning and memory because an animal’s survival depends on fear and remembering potential dangers,” explains Luethi. “But these are also the same systems that make it possible to learn about good things like how to get food and find mates.”

Luethi’s group focuses on a part of the brain called the amygdala, which acts as the central hub in emotional learning. His group has published groundbreaking findings about neuronal circuits in the amygdala, most notably precisely identifying the networks that learn and control fear.

The FMI’s specialization in circuits has helped them recruit some of the best talent in the world, including experts in the circuitry of movement and intelligent behavior. Johannes Felsenberg, who joined in 2019, is also an expert in tracking memories down to specific neurons and studying how they change each time they are used. “We have a broad range of approaches at the FMI and it’s a huge benefit because they each have different strengths and weaknesses,” says Felsenberg. “We constantly benefit not only from the different model systems, but also the knowledge and concepts we gain by looking at our research questions from different perspectives.”

Fly strains with different genetic settings can be easily housed in the lab and allow to manipulate and monitor signaling pathways and activity in identified neurons.

Fruit flies

The FMI’s neurobiology group uses various model systems – such as flies, zebra fish and mice – that range in complexity with respect to the numbers of neurons in the brain. Felsenberg’s work uses the simplest of these, the fruit fly brain, which has only 200 000 neurons. Thanks to this relatively small number of neurons (compared to 90 billion in humans), researchers have identified the roles of nearly every one of these neurons.

“They know every neuron by name,” jokes Luethi about his colleagues. Felsenberg’s group is utilizing tools to study precisely how a single neuron, or a small network, is behaving, allowing them to pinpoint and control individual memories. His group is especially interested in the idea that memories are changed every time they are used; for example, they might be strengthened or they might begin to form new connections with other memories.

“In fruit flies, we know exactly where a simple memory is stored and we can specifically activate or inhibit the process,” adds Felsenberg. “The most fascinating questions for me are about how we can change memory and, consequently, if that can help us change how we think and behave.”

Although fruit flies may seem far from representative of larger animals, the team has been encouraged by the number of times they find similar processes across different organisms. “It’s fascinating to see how often we find overlapping principles,” says Luethi. “Johannes is studying more or less exactly the same questions as we do in mice and, while there are variations in the details, we’re discovering many fundamental aspects that are exactly the same.”

Andreas Luethi, Senior Group Leader at the Friedrich Miescher Institute - “During the last 20 years, neuroscience has witnessed enormous progress in understanding how neuronal circuits program memories, movement and behavior, and the FMI has really been at the center of this development.”

Giving memories context

One of the newest approaches within the FMI has been to add theoretical models and computational neural networks to their methods. Friedemann Zenke, a computational neuroscientist who joined in 2019, has been working together with Felsenberg and Luethi to develop artificial neural networks – similar to those that power artificial intelligence – to pursue questions that simply aren’t feasible to test in the lab.

“The back-and-forth between neuroscience and computational methods are really inspiring each other,” says Felsenberg. “Computationally we can test so many hypotheses, millions and millions, that we would never be able to test in our labs.”

Among these questions, the team is especially interested in understanding the role of context in memory and brain circuitry. Access to memories is highly dependent on context; for example, knowing where to find food is more important when a mouse is hungry than when the mouse is evading a cat. The potential importance of context is also apparent in Alzheimer’s patients when a certain place, song or routine triggers moments of strikingly clear memory.

Observations like these suggest that there are memories that may seem forgotten, but which are actually accessible under the right conditions. With artificial networks, Zenke can add contextual information to look for such patterns in behavior and neuronal circuitry, which may be too complex for researchers to identify otherwise.

Studying memory circuits in human brains is difficult, if not impossible, and so artificial networks may provide insights that can’t currently be measured experimentally. In particular, Luethi’s findings in fear correlate to psychiatric conditions like anxiety and phobias, and future work in this area may help improve behavioral therapies. Also, memory impairments could contribute to mental diseases associated with abnormal social interactions such as autism spectrum disorders. In this context, several FMI groups, including Luethi, Caroni and also the Friedrich group, are engaged in collaborative projects with NIBR that have resulted in fundamental insights.

“It’s not easy to translate the work we do into the clinic, but the implications for disease are enormous and our long-term goal is to find ways to tweak neuronal circuits to steer away from mental health disorders and to promote functional patterns instead,” says Luethi. “Memories define who we are and who we will become, and they guide how we behave and interact with society. So we’re working towards understanding the fundamental building blocks of our everyday behavior and societies.”

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