Getting a clear look at the intricate connections between cells and structures throughout the brain has been a challenge for researchers exploring neurological conditions, but a Yale team led by Joerg Bewersdorf and Aaron Kuan has now brought the breakthrough power of a new imaging technique to the effort.
The technique known as pan-expansion microscopy, which was developed by Bewersdorf’s lab in 2020, lets scientists look inside tissue to see both where specific molecules are located and what the surrounding cellular structures look like in fine detail. The process involves expanding tissue samples with a special gel, labeling proteins and lipids to reveal tissue structure, and using antibodies to mark specific molecules.
In a new study, published in the journal Nature Biotechnology, researchers updated this technique to work on brain tissue, providing a nanoscale view of both the structure and molecular makeup of brain circuits.
“This gets us closer to understanding cell biological mechanisms in the context of the tissue where the cells are embedded,” said study co-author Bewersdorf, the Harvey and Kate Cushing Professor of Cell Biology at Yale School of Medicine (YSM) who is also a professor of biomedical engineering and of physics, in FAS.
“It’s a big step,” Bewersdorf said. “It allows us to address the big question — namely how is the brain connected?”
The team demonstrated how this new approach can reveal wiring and connectivity in brain circuits, creating comprehensive circuit maps known as “connectomes”. These circuit-mapping efforts were spear-headed by co-lead author Allison Cairns, a GSAS student in the Department of Applied Physics at the Yale School of Engineering & Applied Science.
“Pan-expansion is now making connectomics possible with light microscopy,” said study co-author Kuan, an assistant professor of neuroscience at YSM, assistant professor of biomedical engineering, and a Wu Tsai Institute investigator. “This adds a new molecular dimension and makes it more accessible to researchers.”
Bewersdorf and the study’s co-lead author Ons M’Saad, a former Yale biomedical engineering graduate student, co-founded the New Haven-based startup Panluminate, which is commercializing the use of pan-expansion microscopy.