Connectomics: The dense reconstruction of neuronal circuits

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The mapping of neuronal connectivity is one of the main challenges in neuroscience. Only with the knowledge of wiring diagrams is it possible to understand the computational capacities of neuronal networks, both in the sensory periphery, and especially in the mammalian cerebral cortex. Our methods for dense circuit mapping are based on 3-dimensional electron microscopy (EM) imaging of tissue, which allows imaging nerve tissue at nanometer-scale resolution across substantial volumes (typically hundreds of micrometers per spatial dimension) using Serial Block-Face Scanning Electron Microscopy (SBEM). The most time-consuming aspect of circuit mapping, however, is image analysis; analysis time far exceeds the time needed to acquire the data. Therefore, we developed methods to make circuit reconstruction feasible by increasing analysis speed and accuracy, using a combination of crowd sourcing and machine learning. We have applied these methods to circuits in the mouse retina, mapping the complete connectivity graph between almost a thousand neurons, and we are currently improving these methods for the application to neuronal circuits in the neocortex using automated image analysis, together with online science games. Helmstaedter M, Briggman KL, Turaga S, Jain V, Seung HS, Denk W (2013) Connectomic reconstruction of the inner plexiform layer in the mouse retina. Nature, in press Helmstaedter M (2013) Cellular-resolution connectomics: challenges of dense neural circuit reconstruction. Nat Methods 10:501-7. Denk W, Briggman KL, Helmstaedter M (2012) Structural Neurobiology: Missing link to a mechanistic understanding of neural computation. Nat. Rev. Neuroscience 13:351-358. Briggman KL, Helmstaedter M, Denk W (2011) Wiring specificity in the direction-selectivity circuit of the retina. Nature 471:183-188. Helmstaedter M, Briggman KL, Denk W (2011) High-accuracy neurite reconstruction for high-throughput neuroanatomy. Nat Neurosci 14:1081-1088.

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