“The human brain is one of the most complex systems in the universe, containing approximately 200 billion cells and 100 billion neurons. Each neuron forms tens of thousands of unique functional connections with other neurons,” says Kwanghun Chung of the Massachusetts Institute of Technology. “To understand brain function and dysfunction, we need to know how these cells are organized in three dimensions and how they interconnect, but we lack technologies preserving and extracting this 3D information.” Inspired by this challenge, Chung and his research team developed an end-to-end pipeline for preparing, labeling, imaging and ultimately mapping human brain tissue.
The workflow begins with an intact human brain imaged with magnetic resonance imaging to understand the overall structure. Following ex vivo preparation, the brain is sliced using a mechanically enhanced great-size abrasion-free vibratome (MEGAtome) developed for this purpose. Individual slices are then processed, including a clearing and expansion step using a method called magnifiable entangled link-augmented stretchable tissue hydrogel (mELAST) and a labeling step with a rapid staining protocol called system-wide control of interaction time and kinetics of chemicals (SWITCH). The stained slices are imaged at high resolution with mega-scale selective plane illumination microscopy (MegaSPIM) and the tissue computationally reconstructed with high fidelity using bespoke software called unification of neighboring sliced tissues via linkage of interconnected cut fiber endpoints (UNSLICE).
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