The connectomics challenge.

One of the most fascinating challenges in neuroscience is the reconstruction of the connectivity map of the brain. Recent years have seen a rapid expansion in the field of connectomics, whose aim is to trace this map and understand its relationship with neural computation. Many different approaches, ranging from electron and optical microscopy to magnetic resonance imaging, have been proposed to address the connectomics challenge on various spatial scales and in different species. Here, we review the main technological advances in the microscopy techniques applied to connectomics, highlighting the potential and limitations of the different methods. Finally, we briefly discuss the role of connectomics in the Human Brain Project, the Future and Emerging Technologies (FET) Flagship recently approved by the European Commission.

[1]  K. Harris,et al.  Ultrastructural Analysis of Hippocampal Neuropil from the Connectomics Perspective , 2010, Neuron.

[2]  Enrico Macii,et al.  The Human Brain Project and neuromorphic computing. , 2013, Functional neurology.

[3]  Martin Sarter,et al.  Choline transporters, cholinergic transmission and cognition , 2005, Nature Reviews Neuroscience.

[4]  Jan Huisken,et al.  Selective plane illumination microscopy techniques in developmental biology , 2009, Development.

[5]  E. Marder,et al.  From the connectome to brain function , 2013, Nature Methods.

[6]  Jerome Mertz,et al.  Optical sectioning microscopy with planar or structured illumination , 2011, Nature Methods.

[7]  R. Murray,et al.  The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia , 1997, Schizophrenia Research.

[8]  Shaoqun Zeng,et al.  Continuously tracing brain-wide long-distance axonal projections in mice at a one-micron voxel resolution , 2013, NeuroImage.

[9]  Olaf Ronneberger,et al.  Comprehensive catecholaminergic projectome analysis reveals single-neuron integration of zebrafish ascending and descending dopaminergic systems , 2011, Nature communications.

[10]  R. Weiler,et al.  Chemical Clearing and Dehydration of GFP Expressing Mouse Brains , 2012, PloS one.

[11]  Keith Heberlein,et al.  Imaging human connectomes at the macroscale , 2013, Nature Methods.

[12]  N. K. Popova,et al.  From genes to aggressive behavior: the role of serotonergic system. , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[13]  H. Seung,et al.  Serial two-photon tomography: an automated method for ex-vivo mouse brain imaging , 2011, Nature Methods.

[14]  S. Hell,et al.  Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Rohrbach,et al.  Propagation stability of self-reconstructing Bessel beams enables contrast-enhanced imaging in thick media , 2012, Nature Communications.

[16]  E. Müller-Oehring,et al.  Contribution of Callosal Connections to the Interhemispheric Integration of Visuomotor and Cognitive Processes , 2010, Neuropsychology Review.

[17]  Essa Yacoub,et al.  The WU-Minn Human Connectome Project: An overview , 2013, NeuroImage.

[18]  Jeff W Lichtman,et al.  The rise of the 'projectome' , 2007, Nature Methods.

[19]  Kristina J. Nielsen,et al.  Targeting Single Neuronal Networks for Gene Expression and Cell Labeling In Vivo , 2010, Neuron.

[20]  Kevin L. Briggman,et al.  3D structural imaging of the brain with photons and electrons , 2008, Current Opinion in Neurobiology.

[21]  G. Iannello,et al.  Confocal light sheet microscopy: micron-scale neuroanatomy of the entire mouse brain. , 2012, Optics express.

[22]  Henry Markram,et al.  Seven challenges for neuroscience. , 2013, Functional neurology.

[23]  Karl J. Friston Functional and Effective Connectivity: A Review , 2011, Brain Connect..

[24]  A. Schierloh,et al.  Ultramicroscopy: three-dimensional visualization of neuronal networks in the whole mouse brain , 2007, Nature Methods.

[25]  D. O'Leary,et al.  Labeling Neural Cells Using Adenoviral Gene Transfer of Membrane-Targeted GFP , 1996, Neuron.

[26]  W. Denk,et al.  Deep tissue two-photon microscopy , 2005, Nature Methods.

[27]  G. Palm,et al.  Density of neurons and synapses in the cerebral cortex of the mouse , 1989, The Journal of comparative neurology.

[28]  G. Knott,et al.  Serial Section Scanning Electron Microscopy of Adult Brain Tissue Using Focused Ion Beam Milling , 2008, The Journal of Neuroscience.

[29]  T. Insel,et al.  The NIH BRAIN Initiative , 2013, Science.

[30]  D Mayerich,et al.  Knife‐edge scanning microscopy for imaging and reconstruction of three‐dimensional anatomical structures of the mouse brain , 2008, Journal of microscopy.

[31]  G. Feng,et al.  Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP , 2000, Neuron.

[32]  J. Clayden Imaging connectivity: MRI and the structural networks of the brain. , 2013, Functional neurology.

[33]  Francesco S. Pavone,et al.  ADVANCED OPTICAL TECHNIQUES TO EXPLORE BRAIN STRUCTURE AND FUNCTION , 2013 .

[34]  Javier DeFelipe,et al.  From the Connectome to the Synaptome: An Epic Love Story , 2010, Science.

[35]  Louis K. Scheffer,et al.  Semi-automated reconstruction of neural circuits using electron microscopy , 2010, Current Opinion in Neurobiology.

[36]  W. Denk,et al.  Serial Block-Face Scanning Electron Microscopy to Reconstruct Three-Dimensional Tissue Nanostructure , 2004, PLoS biology.

[37]  Aaron S. Andalman,et al.  Structural and molecular interrogation of intact biological systems , 2013, Nature.

[38]  Francesco S. Pavone,et al.  Light sheet microscopy of cleared mouse brains: aberrations effects caused by refractive index mismatch , 2013, European Conference on Biomedical Optics.

[39]  R. Williams,et al.  Mapping genes that modulate mouse brain development: a quantitative genetic approach. , 2000, Results and problems in cell differentiation.

[40]  Hans-Ulrich Dodt,et al.  Light sheet microscopy of living or cleared specimens , 2012, Current Opinion in Neurobiology.

[41]  J. Lichtman,et al.  Optical sectioning microscopy , 2005, Nature Methods.

[42]  Joav Merrick,et al.  Neurological Disorders: Public Health Challenges , 2007 .

[43]  Egidio D'Angelo,et al.  Realistic modeling of neurons and networks: towards brain simulation. , 2013, Functional neurology.

[44]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[45]  David Manset,et al.  Brain investigation and brain conceptualization. , 2013, Functional neurology.

[46]  U. Frith Mind Blindness and the Brain in Autism , 2001, Neuron.

[47]  J. Rothwell Principles of Neural Science , 1982 .

[48]  T. Wilson,et al.  Aberration correction for confocal imaging in refractive‐index‐mismatched media , 1998 .

[49]  G. By The brain dopaminergic system. Pharmacological, behavioural and electrophysiological studies. , 1995 .

[50]  J. Lippincott-Schwartz,et al.  Imaging Intracellular Fluorescent Proteins at Nanometer Resolution , 2006, Science.

[51]  R. W. Draft,et al.  Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system , 2007, Nature.

[52]  Ullrich Köthe,et al.  3D segmentation of SBFSEM images of neuropil by a graphical model over supervoxel boundaries , 2012, Medical Image Anal..

[53]  Francesco Saverio Pavone,et al.  Correlative two-photon and light sheet microscopy. , 2014, Methods.

[54]  W. Denk,et al.  The Big and the Small: Challenges of Imaging the Brain’s Circuits , 2011, Science.

[55]  N. Kasthuri,et al.  Automating the Collection of Ultrathin Serial Sections for Large Volume TEM Reconstructions , 2006, Microscopy and Microanalysis.

[56]  W. Usrey,et al.  Emerging views of corticothalamic function , 2008, Current Opinion in Neurobiology.

[57]  Moritz Helmstaedter,et al.  High-accuracy neurite reconstruction for high-throughput neuroanatomy , 2011, Nature Neuroscience.

[58]  S. Mori,et al.  Principles of Diffusion Tensor Imaging and Its Applications to Basic Neuroscience Research , 2006, Neuron.

[59]  T. Südhof The synaptic vesicle cycle , 2004 .

[60]  Olaf Sporns,et al.  The Human Connectome: A Structural Description of the Human Brain , 2005, PLoS Comput. Biol..

[61]  Ulrich Kubitscheck,et al.  Scanned light sheet microscopy with confocal slit detection. , 2012, Optics Express.

[62]  G. Palade,et al.  Electron microscope observations of interneuronal and neuromuscular synapses , 1954 .

[63]  Davi D Bock,et al.  Volume electron microscopy for neuronal circuit reconstruction , 2012, Current Opinion in Neurobiology.

[64]  Jeremy D. Schmahmann,et al.  A Proposal for a Coordinated Effort for the Determination of Brainwide Neuroanatomical Connectivity in Model Organisms at a Mesoscopic Scale , 2009, PLoS Comput. Biol..

[65]  C. J. Niedworok,et al.  Charting monosynaptic connectivity maps by two-color light-sheet fluorescence microscopy. , 2012, Cell reports.

[66]  Atsushi Miyawaki,et al.  Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain , 2011, Nature Neuroscience.