Reconstruction of complete connectivity matrix for connectomics by sampling neural connectivity with fluorescent synaptic markers

Physical organization of the nervous system is a topic of perpetual interest in neuroscience. Despite significant achievements here in the past, many details of the nervous system organization and its role in animals’ behavior remain obscure, while the problem of complete connectivity reconstructions has recently re-emerged as one of the major directions in neuroscience research (i.e. connectomics). We describe a novel paradigm for connectomics reconstructions that can yield connectivity maps with high resolution, high speed of imaging and data analysis, and significant robustness to errors. In essence, we propose that physical connectivity in a neural circuit can be sampled using anatomical fluorescent synaptic markers localized to different parts of the neural circuit with a technique for randomized genetic targeting, and that high-resolution connectivity maps can be extracted from such datasets. We describe how such an approach can be implemented and how neural connectivity matrix can be reconstructed statistically using the methods of Compressive Sensing. Use of Compressive Sensing is the key to allow accurate neural connectivity reconstructions with orders-of-magnitude smaller volumes of experimental data. We test described approach on simulations of neural connectivity reconstruction experiments in C. elegans, where real neural wiring diagram is available from past electron microscopy studies. We show that such wiring diagram can be in principle re-obtained using described approach in 1–7 days of imaging and data analysis. Alternative approaches would require currently at least 1–2 years to produce a single comparable reconstruction. We discuss possible applications of described approach in larger organisms such as Drosophila.

Research highlights
► A novel paradigm for neural connectivity (connectome) reconstructions is described.
► Physical connectivity is sampled with randomly localized fluorescent synaptic markers.
► It is shown that the wiring diagram in C. elegans can be obtained in 1–7 days of imaging and analysis.
► Applications in large organisms such as Drosophila are described using different strategies.