Mapping brain circuitry with a light microscope

The beginning of the 21st century has seen a renaissance in light microscopy and anatomical tract tracing that together are rapidly advancing our understanding of the form and function of neuronal circuits. The introduction of instruments for automated imaging of whole mouse brains, new cell type–specific and trans-synaptic tracers, and computational methods for handling the whole-brain data sets has opened the door to neuroanatomical studies at an unprecedented scale. We present an overview of the present state and future opportunities in charting long-range and local connectivity in the entire mouse brain and in linking brain circuits to function.

[1]  S. R. Cajal.  Textura del Sistema Nervioso del Hombre y de los Vertebrados, 1899–1904 , 2019 .

[2]  K. Rockland,et al.  Laminar origins and terminations of cortical connections of the occipital lobe in the rhesus monkey , 1979, Brain Research.

[3]  C. Gerfen,et al.  An anterograde neuroanatomical tracing method that shows the detailed morphology of neurons, their axons and terminals: Immunohistochemical localization of an axonally transported plant lectin,Phaseolus vulgaris leucoagglutinin (PHA-L) , 1984, Brain Research.

[4]  Gudrun Petursdottir,et al.  Fluorescent dextran-amines used as axonal tracers in the nervous system of the chicken embryo , 1986, Journal of Neuroscience Methods.

[5]  P. C. Murphy,et al.  Cerebral Cortex , 2017, Cerebral Cortex.

[6]  F Melsen,et al.  A direct method for fast three‐dimensional serial reconstruction , 1990, Journal of microscopy.

[7]  W. Denk,et al.  Two-photon laser scanning fluorescence microscopy. , 1990, Science.

[8]  D. J. Felleman,et al.  Distributed hierarchical processing in the primate cerebral cortex. , 1991, Cerebral cortex.

[9]  H. Varmus,et al.  Isolation of a chicken gene that confers susceptibility to infection by subgroup A avian leukosis and sarcoma viruses , 1993, Journal of virology.

[10]  H. Varmus,et al.  A system for tissue-specific gene targeting: transgenic mice susceptible to subgroup A avian leukosis virus-based retroviral vectors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Ugolini.  Specificity of rabies virus as a transneuronal tracer of motor networks: Transfer from hypoglossal motoneurons to connected second‐order and higher order central nervous system cell groups , 1995, The Journal of comparative neurology.

[12]  D. G. Herrera,et al.  Activation of c-fos in the brain , 1996, Progress in Neurobiology.

[13]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[14]  M. Frotscher,et al.  Retrograde tracing with Fluoro-Gold: different methods of tracer detection at the ultrastructural level and neurodegenerative changes of back-filled neurons in long-term studies , 2000, Journal of Neuroscience Methods.

[15]  K. Conzelmann,et al.  Spread and pathogenic characteristics of a G-deficient rabies virus recombinant: an in vitro and in vivo study. , 2000, The Journal of general virology.

[16]  I. Llewellyn-Smith,et al.  Tracer-toxins: cholera toxin B-saporin as a model , 2000, Journal of Neuroscience Methods.

[17]  A. Reiner,et al.  Pathway tracing using biotinylated dextran amines , 2000, Journal of Neuroscience Methods.

[18]  Yun Wang,et al.  Synaptic connections and small circuits involving excitatory and inhibitory neurons in layers 2-5 of adult rat and cat neocortex: triple intracellular recordings and biocytin labelling in vitro. , 2002, Cerebral cortex.

[19]  M. Reddington,et al.  Surface imaging microscopy, an automated method for visualizing whole embryo samples in three dimensions at high resolution , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[20]  Winfried Denk,et al.  Targeted Whole-Cell Recordings in the Mammalian Brain In Vivo , 2003, Neuron.

[21]  D. Kleinfeld,et al.  All-Optical Histology Using Ultrashort Laser Pulses , 2003, Neuron.

[22]  T. Harkany,et al.  Pyramidal cell communication within local networks in layer 2/3 of rat neocortex , 2003, The Journal of physiology.

[23]  F. Del Bene,et al.  Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy , 2004, Science.

[24]  Richard C Gerkin,et al.  Alteration of Neuronal Firing Properties after In Vivo Experience in a FosGFP Transgenic Mouse , 2004, The Journal of Neuroscience.

[25]  Sen Song,et al.  Highly Nonrandom Features of Synaptic Connectivity in Local Cortical Circuits , 2005, PLoS biology.

[26]  M. Brecht,et al.  Monosynaptic Pathway from Rat Vibrissa Motor Cortex to Facial Motor Neurons Revealed by Lentivirus-Based Axonal Tracing , 2005, The Journal of Neuroscience.

[27]  Lynn W Enquist,et al.  New developments in tracing neural circuits with herpesviruses. , 2005, Virus research.

[28]  S. Finke,et al.  Replication strategies of rabies virus. , 2005, Virus research.

[29]  Bruce H Smaill,et al.  Automated imaging of extended tissue volumes using confocal microscopy , 2005, Microscopy research and technique.

[30]  Mark Mayford,et al.  Localization of a Stable Neural Correlate of Associative Memory , 2007, Science.

[31]  Ian R. Wickersham,et al.  Monosynaptic Restriction of Transsynaptic Tracing from Single, Genetically Targeted Neurons , 2007, Neuron.

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

[33]  Peter T C So,et al.  High-resolution whole organ imaging using two-photon tissue cytometry. , 2007, Journal of biomedical optics.

[34]  Richard B. Fletcher,et al.  Public thinking about poverty: why it matters and how to measure it , 2007 .

[35]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[36]  Trygve B. Leergaard,et al.  Toward a workbench for rodent brain image data systems architecture and design , 2007, Neuroinformatics.

[37]  Ian R. Wickersham,et al.  Retrograde neuronal tracing with a deletion-mutant rabies virus , 2007, Nature Methods.

[38]  Stephen J. Smith,et al.  Array Tomography: A New Tool for Imaging the Molecular Architecture and Ultrastructure of Neural Circuits , 2007, Neuron.

[39]  K. Fujita.  [Two-photon laser scanning fluorescence microscopy]. , 2007, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[40]  J. Price.  :Allen Reference Atlas: A Digital Color Brain Atlas of the C57BL/6J Male Mouse , 2008 .

[41]  W. Denk,et al.  Targeted patch-clamp recordings and single-cell electroporation of unlabeled neurons in vivo , 2008, Nature Methods.

[42]  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.

[43]  E. P. Gardner,et al.  Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex , 2008, Nature Reviews Neuroscience.

[44]  P. Somogyi,et al.  Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations , 2008, Science.

[45]  A. Borst,et al.  A genetically encoded calcium indicator for chronic in vivo two-photon imaging , 2008, Nature Methods.

[46]  Damian J. Wallace,et al.  Single-spike detection in vitro and in vivo with a genetic Ca2+ sensor , 2008, Nature Methods.

[47]  Hong Wei Dong,et al.  Allen reference atlas : a digital color brain atlas of the C57Black/6J male mouse , 2008 .

[48]  M. Ekstrand,et al.  The alpha-herpesviruses: molecular pathfinders in nervous system circuits. , 2008, Trends in molecular medicine.

[49]  E. Callaway.  Transneuronal circuit tracing with neurotropic viruses , 2008, Current Opinion in Neurobiology.

[50]  S. Sternson,et al.  A FLEX Switch Targets Channelrhodopsin-2 to Multiple Cell Types for Imaging and Long-Range Circuit Mapping , 2008, The Journal of Neuroscience.

[51]  D. Tank,et al.  Intracellular dynamics of hippocampal place cells during virtual navigation , 2009, Nature.

[52]  J. Waters,et al.  Fluorescent Arc/Arg3.1 indicator mice: A versatile tool to study brain activity changes in vitro and in vivo , 2009, Journal of Neuroscience Methods.

[53]  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..

[54]  R. Reep,et al.  Multiple neuroanatomical tract-tracing using fluorescent Alexa Fluor conjugates of cholera toxin subunit B in rats , 2009, Nature Protocols.

[55]  Hans-Ulrich Dodt,et al.  Resolution of Ultramicroscopy and Field of View Analysis , 2009, PloS one.

[56]  D. Kleinfeld,et al.  Correlations of Neuronal and Microvascular Densities in Murine Cortex Revealed by Direct Counting and Colocalization of Nuclei and Vessels , 2009, The Journal of Neuroscience.

[57]  Allan R. Jones,et al.  An anatomic gene expression atlas of the adult mouse brain , 2009, Nature Neuroscience.

[58]  Larry W Swanson,et al.  Hypothesis-driven structural connectivity analysis supports network over hierarchical model of brain architecture , 2010, Proceedings of the National Academy of Sciences.

[59]  Q. Luo,et al.  Micro-Optical Sectioning Tomography to Obtain a High-Resolution Atlas of the Mouse Brain , 2010, Science.

[60]  Ian R. Wickersham,et al.  Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus , 2010, Proceedings of the National Academy of Sciences.

[61]  G. Ugolini,et al.  Advances in viral transneuronal tracing , 2010, Journal of Neuroscience Methods.

[62]  Jerome Mertz,et al.  Scanning light-sheet microscopy in the whole mouse brain with HiLo background rejection. , 2010, Journal of biomedical optics.

[63]  Philipp J. Keller,et al.  Fast, high-contrast imaging of animal development with scanned light sheet–based structured-illumination microscopy , 2010, Nature Methods.

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

[65]  Stephen J. Smith,et al.  Single-Synapse Analysis of a Diverse Synapse Population: Proteomic Imaging Methods and Markers , 2010, Neuron.

[66]  H. S. Meyer,et al.  Number and Laminar Distribution of Neurons in a Thalamocortical Projection Column of Rat Vibrissal Cortex , 2010, Cerebral cortex.

[67]  Hans-Ulrich Dodt,et al.  Image contrast enhancement in confocal ultramicroscopy. , 2010, Optics letters.

[68]  Larry W Swanson,et al.  Foundational model of structural connectivity in the nervous system with a schema for wiring diagrams, connectome, and basic plan architecture , 2010, Proceedings of the National Academy of Sciences.

[69]  Allan R. Jones,et al.  A robust and high-throughput Cre reporting and characterization system for the whole mouse brain , 2009, Nature Neuroscience.

[70]  Kevin L. Briggman,et al.  Wiring specificity in the direction-selectivity circuit of the retina , 2011, Nature.

[71]  P. J. Sjöström,et al.  Functional specificity of local synaptic connections in neocortical networks , 2011, Nature.

[72]  G. Allan Johnson,et al.  Digital Atlasing and Standardization in the Mouse Brain , 2011, PLoS Comput. Biol..

[73]  Arthur W. Wetzel,et al.  Network anatomy and in vivo physiology of visual cortical neurons , 2011, Nature.

[74]  David J. Anderson,et al.  A Cre-Dependent, Anterograde Transsynaptic Viral Tracer for Mapping Output Pathways of Genetically Marked Neurons , 2011, Neuron.

[75]  Andreas T Schaefer,et al.  Transfection via whole-cell recording in vivo: bridging single-cell physiology, genetics and connectomics , 2011, Nature Neuroscience.

[76]  Floris G. Wouterlood,et al.  A half century of experimental neuroanatomical tracing , 2011, Journal of Chemical Neuroanatomy.

[77]  Lief E. Fenno,et al.  The development and application of optogenetics. , 2011, Annual review of neuroscience.

[78]  Fan Wang,et al.  Activity-Induced Remodeling of Olfactory Bulb Microcircuits Revealed by Monosynaptic Tracing , 2011, PloS one.

[79]  Kevin T. Beier,et al.  Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors , 2011, Proceedings of the National Academy of Sciences.

[80]  Ian R. Wickersham,et al.  Cortical representations of olfactory input by trans-synaptic tracing , 2011, Nature.

[81]  S. Nelson,et al.  A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex , 2011, Neuron.

[82]  Arno C. Schmitt,et al.  Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A , 2011, Proceedings of the National Academy of Sciences.

[83]  Harvey J Karten,et al.  High‐resolution digital brain atlases: a Hubble telescope for the brain , 2011, Annals of the New York Academy of Sciences.

[84]  H. S. Meyer,et al.  Cell Type–Specific Three-Dimensional Structure of Thalamocortical Circuits in a Column of Rat Vibrissal Cortex , 2011, Cerebral cortex.

[85]  R Clay Reid,et al.  From Functional Architecture to Functional Connectomics , 2012, Neuron.

[86]  Jasper Akerboom,et al.  Optimization of a GCaMP Calcium Indicator for Neural Activity Imaging , 2012, The Journal of Neuroscience.

[87]  J. Simon Wiegert,et al.  Multiple dynamic representations in the motor cortex during sensorimotor learning , 2012, Nature.

[88]  Christopher D. Harvey,et al.  Choice-specific sequences in parietal cortex during a virtual-navigation decision task , 2012, Nature.

[89]  Ian R. Wickersham,et al.  New technologies for imaging synaptic partners , 2012, Current Opinion in Neurobiology.

[90]  Stephen J. Smith,et al.  Deep molecular diversity of mammalian synapses: why it matters and how to measure it , 2012, Nature Reviews Neuroscience.

[91]  Richard D Emes,et al.  Evolution of synapse complexity and diversity. , 2012, Annual review of neuroscience.

[92]  Troy W. Margrie,et al.  A biophysical signature of network affiliation and sensory processing in mitral cells , 2012, Nature.

[93]  Drew N. Robson,et al.  Brain-wide neuronal dynamics during motor adaptation in zebrafish , 2012, Nature.

[94]  Allan R. Jones,et al.  A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing , 2012, Nature Neuroscience.

[95]  Arthur W. Toga,et al.  Comprehensive connectivity of the mouse main olfactory bulb: analysis and online digital atlas , 2012, Front. Neuroanat..

[96]  Hongkui Zeng,et al.  Adeno‐Associated Viral Vectors for Anterograde Axonal Tracing with Fluorescent Proteins in Nontransgenic and Cre Driver Mice , 2012, Current protocols in neuroscience.

[97]  Christof Koch,et al.  Neuroscience: Observatories of the mind , 2012, Nature.

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

[99]  M. Helmstaedter.  Cellular-resolution connectomics: challenges of dense neural circuit reconstruction , 2013, Nature Methods.

[100]  Philipp J. Keller,et al.  Whole-brain functional imaging at cellular resolution using light-sheet microscopy , 2013, Nature Methods.

[101]  Concha Bielza,et al.  New insights into the classification and nomenclature of cortical GABAergic interneurons , 2013, Nature Reviews Neuroscience.

[102]  Xiang Zhou,et al.  New Modules Are Added to Vibrissal Premotor Circuitry with the Emergence of Exploratory Whisking , 2013, Neuron.

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

[104]  Lydia Ng,et al.  Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system , 2012, Nucleic Acids Res..

[105]  K. Deisseroth,et al.  CLARITY for mapping the nervous system , 2013, Nature Methods.

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

[107]  Paul S. Weiss,et al.  The Brain Activity Map , 2013, Science.

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