NeuroNex Technology Hub: Enhanced resolution for 3DEM analysis of synapses across brain regions and taxa

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As part of the NSF National Research Infrastructure for Neuroscience, this Neurotechnology Hub will develop new approaches to examine the brain in greater detail. Three-dimensional electron microscopy (3DEM) has helped reveal new insights into the role of tiny connections between cells in the brain. However, 3DEM has been limited in impact by the rate of data analysis. This Neurotechnology Hub will improve the 3DEM instrumentation to collect information in greater detail, develop better algorithms to process the information, and link the workflows with high performance computing to greatly increase the rate of knowledge discovery. These innovations and capabilities will be shared with the scientific community through active training on the approach, and through open access to the new software and data. By way of this Neurotechnology Hub, 3DEM will become part of the national infrastructure for neuroscience research. To help address the grand scientific challenge of understanding the brain, this project will apply the improved 3DEM approach across several different mammalian species including humans to identify similarities and differences, and their relationship to behavior, learning, and memory.This Neurotechnology Hub is motivated by challenges in understanding synapses, the tiny points of inter-neuronal communication. The variance in synapse dimensions, connectivity, and subcellular content across species is simply not known, yet required to determine whether model systems represent human brain functions. Current approaches are limited by resolution, inefficient data collection, and analysis bottlenecks. Addressing these challenges, the project will: (1) Develop simultaneous multi-detector and tilt-tomography on the scanning electron microscope operating in the transmission mode. Add-on hardware and software will improve axial resolution from 45 to 10 nm (or less), while maintaining in-plane resolution of 1-2 nm. (2) Integrate automated and interactive tools that speed and improve analysis of synapses in large data volumes. The enhanced resolution will increase data volume but reduce major image processing difficulties by producing more isotropic images. (3) Integrate the enhanced electron microscopy (EM) with high performance computing to increase throughput; to disseminate images, metadata, analyses, and software in a way that facilitates uptake into existing cell type and brain databases; and to provide a venue to develop 3DEM communities. (4) Apply the new technology to image hippocampus and comparable parts of cortex in mice, rats, and humans. This NeuroTechnology Hub award is co-funded by the Division of Emerging Frontiers within the Directorate for Biological Sciences and the Office of Advanced Cyberinfrastructure within the Directorate for Computer and Information Sciences, as part of the BRAIN Initiative and NSF's Understanding the Brain activities.