Researchers at Leiden University have developed a new microscopy technique that makes the connections between brain cells visible in detail and in three dimensions. This innovation marks an important step in unravelling one of the biggest questions in neuroscience: how does information flow through the brain, and what happens when that communication is disrupted in disease?
The research team, led by Professor Sense Jan van der Molen, uses an advanced microscope that can reveal the structure of brain structures down to the level of the synapse. These are the microscopic contact points where neurons exchange signals. This level of detail allows scientists to map functional networks and better understand how abnormalities in these networks contribute to neurological disorders. The research has been published in the Proceedings of the National Academy of Sciences.
PEEM as a new imaging method
In a collaboration between Leiden and Chicago, Photoemission Electron Microscopy (PEEM) has been introduced as an innovative tool for visualising brain tissue. PEEM uses the photoelectric effect to generate extremely detailed images. For this project, the technique was used on ultra-thin, sequential brain sections from the same mouse brain.
The result: razor-sharp images that are produced much faster and more cheaply than with conventional techniques such as transmission electron microscopy (TEM) or scanning electron microscopy (SEM). By analysing these sections in sequence, an accurate 3D model of brain structures can be constructed.
Faster and affordable 3D mapping of the brain
Mapping all neural connections, known as connectomics, is considered a huge technical challenge worldwide. Traditional methods are costly and time-consuming, which often makes large-scale mapping unfeasible. With this proof of concept, PEEM demonstrates that these barriers can be overcome.
At a resolution of 20 nanometres, it is already possible to identify synapses. ‘We have made visible the contact points where electrical and chemical signals are transmitted between neurons,’ says Van der Molen. "PEEM provides rich structural information without the heavy staining or complex preparation required by traditional methods. It opens the door to large-scale, high-throughput brain mapping."
Ready for further optimisation
An important advantage is that the image quality of PEEM can be further improved, both through more optimal sample preparation and through the use of new-generation PEEM microscopes. Together with international partners, the Leiden team is working on even higher resolutions and more accurate reconstructions.
Van der Molen's laboratory is thus building a strong international reputation at the intersection of advanced microscopy and biomedical research. The researchers see great opportunities for combining PEEM with studies of brain diseases, regenerative medicine and even brain models for AI research. This technique brings neuroscience closer to an important ambition: mapping the brain at the synaptic level, faster than ever and at significantly lower costs.
Looking deeper into the brain
A few weeks ago, it was announced that researchers had developed an advanced imaging technology that enables unprecedented deep and broad visualisation of brain activity with single-cell resolution. The innovative microscope is called DEEPscope.
DEEPscope represents a major technological breakthrough in deep brain imaging. Thanks to an adaptive excitation system and a multi-focus polygon scanning scheme, the system can generate efficient fluorescence within a large field of view of 3.23 x 3.23 mm², while still maintaining high resolution. This makes it possible to capture neural activity in both superficial and deep cortical layers of mouse brains.
The system combines simultaneous two-photon and three-photon imaging, enabling detailed exploration of brain areas at different depths. In their study, researchers demonstrated that DEEPscope can visualise entire cortical columns and subcortical structures with single-cell resolution and track more than 4,500 neurons simultaneously.
