Tools for mapping the molecular structure of the brain

Brain circuits are large, 3-D structures. However, the building blocks - proteins, signaling complexes, synapses - are organized with nanoscale precision. This presents a fundamental tension in neuroscience - to understand a neural circuit, you might need to map a large diversity of nanoscale building blocks, across an extended spatial expanse. We are developing a new suite of tools that enable the mapping of the location and identity of the molecular building blocks of the brain, so that comprehensive taxonomies of cells, circuits, and computations might someday become possible, even in entire brains. One of the technologies we are developing enables large 3-D objects to be imaged with nanoscale precision, by physically expanding the sample (in contrast to all previous microscopies, that magnify light from the sample via lenses) - a tool we call expansion microscopy (ExM). We are working to improve expansion microscopy further, and are working, often in interdisciplinary collaborations, on a suite of new labeling and analysis techniques that exploit the biochemical freedom enabled by the expanded state.