Toward large-scale connectome reconstructions

•Connectomics provides insights into small stereotypical invertebrate nervous systems.•Applying connectomics to nonstereotypical nervous systems requires the following:•Imaging with good z-resolution and better segmentation algorithms.•Tools for automatic detection, validation, and measurement of synapses.•Uncertainty management, incremental reconstruction, and connectome analysis tools.

Recent results have shown the possibility of both reconstructing connectomes of small but biologically interesting circuits and extracting from these connectomes insights into their function. However, these reconstructions were heroic proof-of-concept experiments, requiring person-months of effort per neuron reconstructed, and will not scale to larger circuits, much less the brains of entire animals. In this paper we examine what will be required to generate and use substantially larger connectomes, finding five areas that need increased attention: firstly, imaging better suited to automatic reconstruction, with excellent z-resolution; secondly, automatic detection, validation, and measurement of synapses; thirdly, reconstruction methods that keep and use uncertainty metrics for every object, from initial images, through segmentation, reconstruction, and connectome queries; fourthly, processes that are fully incremental, so that the connectome may be used before it is fully complete; and finally, better tools for analysis of connectomes, once they are obtained.