At PSI in Villigen, a neurobiologist is leading pioneering research to build 3D atlases of neuronal connections and unravel working memory.

In the laboratory of Nanoscale Biology of the Paul Scherrer Institute, a new generation of neuroscientists is trying to design the

“electrical circuit of the mind”.

This is not a metaphor: the neurobiologist Adrian Wanner and his team really want to create brain circuit diagrams, to understand how neurons connect, communicate and keep the working memory, the cognitive function that allows us to remember information for a few seconds or minutes.

“When you walk into the kitchen and forget why you're there, it's your working memory that's betrayed you,”

explains the Swiss scientist, not without a certain dose of irony.

“In everyday life it is a nuisance, but in diseases like Alzheimer's it can be the first sign of a more profound decline.”

Behind this apparent simplicity lies a monumental goal: rebuild the functional network of billions of neurons, capturing its real-time dynamics and three-dimensional structure at the nanoscale. An undertaking that unites biology, physics, artificial intelligence and nanotechnology, and which promises to revolutionize the understanding of brain processes.

The Brain as a Circuit: From Biology to Engineered Models

To reconstruct what happens in the brain during working memory activity, villas The researchers combine two approaches: the neural activity maps and synaptic connection diagramsIn the first case, the cells that are activated during a task are highlighted by fluorescent markers: the brain, literally, lights up at its nerve centers. In the second, scientists try to understand how these neurons are connected to each other, creating a sort of biological electrical diagram.

“It's like drawing a computer circuit board,”

adds the Swiss researcher.

“Except that instead of wires we have synapses and, instead of transistors, living cells.”

Professor Wanner's project is part of a tradition that has made the Switzerland: a global hub for structural and computational neuroscience, thanks to the interaction between PSI, ETH Zurich, Friedrich Miescher Institute Basel and the European network Human Brain Project, of which the Confederation is a founding partner. The goal is shared: to understand not only where neural reactions occur, but how information flows from one cell to another, through direct connections, parallel circuits or return feedback.

This hidden architecture is the heart of the project: if we could translate it into a three-dimensional model, science could finally explain why some areas of the mind deteriorate before others, and pave the way for targeted therapies against neurodegenerative dementias.

A virtual laboratory to observe memory in mouse models

To observe working memory in action, the group at the Paul Scherrer Institute uses mouse models. Mice are trained to move in a immersive virtual environment, similar to a video game. During the experiment, the animal runs along a digital corridor and has to remember a visual pattern shown at the beginning, and then choose the correct direction based on memory.

“It is precisely in that intermediate moment, when the stimulus is no longer seen but must be kept in mind, that working memory comes into play,”

comments Adrian.

While the mouse “plays,” the researchers record brain activity in real time using fluorescence imaging and compare it with the synaptic connection diagrams obtained subsequently. In this way, they can deduce which neural networks are engaged to retain information and how signals propagate between the neurons involved.

The results show that different visual patterns activate specific sequences of neurons, as if the mind used different alphabets for each memory. Each experience, in practice, generates its own microcircuit, which forms, strengthens, and finally fades. A microscopic window into the very act of thinking.

Advanced microscopes and ion beams to map complex brain networks

To create these nanometer-resolution maps, Adrian Wanner and his team have to tackle a almost impossible technical challenge. A single cubic millimeter of brain tissue contains over 100.000 neurons it's about 700 million synapses, distributed along more than four kilometers of nerve fibers.

Representing this complexity in 3D means producing millions of images and then digitally recomposing them into a single coherent architecture. Conventional tools are not enough. PSI researchers have therefore developed a innovative method based on thick-section electron microscopy.

Un automatic microtome cuts the brain tissue into layers of a few tens of nanometers, which are analyzed using a ion beamAfter each step, a layer is removed and photographed, until the entire portion of the brain is reconstructed. The result is a three-dimensional mosaic of the highest precision, where it is possible to follow the path of each individual synapse.

“The hardest part”,

describes the scholar,

"It's about preventing the sections from bending or breaking. Any defect can compromise hours of work and millions of records."

To overcome this limitation, PSI collaborated with an electron microscope manufacturer to create a system capable of handling samples ten times thicker than the traditional method.

The amount of data generated is colossal: several terabytes per single experimentThis is where the synergy with the Swiss National Supercomputing Centre (CSCS) in Lugano, which provides the computing infrastructures to reconstruct 3D images and train artificial intelligence algorithms able to automatically recognize synaptic connections.

SLS 2.0 and next-generation X-rays to explore our minds

The next step of the project aims at an even more ambitious goal: to abandon the sectioning technique altogether and resort to next-generation X-ray tomography developed in Villigen.

With the SLS 2.0 synchrotron light source, currently being updated, it will be possible to reach resolutions up to 4 nanometers thanks to a technique called ptychographyIn theory, this would allow an entire fragment of the brain to be observed without cutting it, reducing time, costs and the risk of damage.

The problem, Wanner explains, is that

"Biological tissues cannot tolerate the intensity of the radiation. At those doses, they are destroyed in a matter of moments."

To overcome this obstacle, the group is experimenting highly resistant industrial epoxy resins, capable of protecting samples up to a thousand times more than normal. The initial results are promising.

“It would be an epochal leap,”

says the scientist.

“Being able to ‘x-ray’ an entire brain in 3D, without worrying about tears or creases, would bring us closer to a true neuronal cartography.”

At the PSI, he underlines, the conditions are ideal:

“The combination of technologies, skills and infrastructure makes this place unique in the world. This is why I came back to Switzerland".

From the lab to society: the new era of neuroinnovation

The impact of this research extends far beyond the academic field. Understanding how the mind constructs and stores memories also means being able to diagnose neurodegenerative diseases early like Alzheimer's or Parkinson's, develop brain-machine interfaces more natural, or create artificial intelligence systems inspired by neural plasticity.

It is no coincidence that Wanner is also the founder of the spin-off ariadne.ai, Based in Buchrain in the Canton of Lucerne, in Lucerne Countryside District, and specialized inautomatic analysis of biomedical images, which collaborates with research institutes in Switzerland and abroad. frontier between neuroscience and technology is dissolving: the mind becomes a model for engineering, and engineering an extension of the mind.

This vision, which intertwines biology, physics and computer science, confirms the Swiss vocation for scientific innovation. From microscope artificial neural networks, from synchrotron ai supercomputer, Switzerland positions itself as global laboratory for the neuroengineering of the future.

Yet, as Adrian himself observes,

"The more we learn to read the brain, the more we realize its complexity. Each map reveals new territories to explore."

The mapping of thought as a frontier of brain science

The "cartography of thought"is no longer a philosophical dream, but a concrete discipline that unites microscopy, mathematics and algorithmsIf today it is possible to visualize a neuron with sub-micrometric precision, tomorrow we could have integral models of the human brain, capable of reproducing dynamics and pathologies.

In the heart of Switzerland, in the laboratory of the Canton of Aargau, this future is already taking shape. The PSI's tools and Adrian Wanner's vision are laying the foundations for a new scientific revolution, in which the knowledge of the mind becomes innovation infrastructure.

From a fragment of a mouse brain to big data of consciousnessThe challenge remains daunting. But each new image, each synapse traced, brings science closer to a deeper understanding of who we are.
And when the first “complete neuronal atlas” will be traced, we could finally read, in terms of pure matter and light, the language with which the brain constructs the the memory, the identity andimagination itself.

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