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Cortical Column and Whole Brain Imaging of Neural Circuits with Molecular Contrast and Nanoscale Resolution

By Ruixuan Gao, Shoh M Asano, Srigokul Upadhyayula, Pisarev Igor, Daniel E Milkie, Tsung-Li Liu, Singh Ved, Austin Graves, Grace H Huynh, Yongxin Zhao, John Bogovic, Jennifer Colonell, Jennifer Lippincott-Schwartz, Christopher Zugates, Susan Tappan, Alfredo Rodriguez, Kishore R Mosaliganti, Sean G Megason

Posted 23 Jul 2018
bioRxiv DOI: 10.1101/374140 (published DOI: 10.1126/science.aau8302)

Optical and electron microscopy have made tremendous inroads in understanding the complexity of the brain, but the former offers insufficient resolution to reveal subcellular details and the latter lacks the throughput and molecular contrast to visualize specific molecular constituents over mm-scale or larger dimensions. We combined expansion microscopy and lattice light sheet microscopy to image the nanoscale spatial relationships between proteins across the thickness of the mouse cortex or the entire Drosophila brain, including synaptic proteins at dendritic spines, myelination along axons, and presynaptic densities at dopaminergic neurons in every fly neuropil domain. The technology should enable statistically rich, large scale studies of neural development, sexual dimorphism, degree of stereotypy, and structural correlations to behavior or neural activity, all with molecular contrast.

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