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Journal ArticleDOI

Mapping brain circuitry with a light microscope.

TL;DR: 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 is presented.
Abstract: 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.

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Citations
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Journal ArticleDOI
TL;DR: Hydrogel-based structures can be built from within biological tissue to allow subsequent removal of lipids without mechanical disassembly of the tissue, creating a tissue-hydrogel hybrid that is physically stable, that preserves fine structure, proteins and nucleic acids, and that is permeable to both visible-spectrum photons and exogenous macromolecules.
Abstract: With potential relevance for brain-mapping work, hydrogel-based structures can now be built from within biological tissue to allow subsequent removal of lipids without mechanical disassembly of the tissue. This process creates a tissue-hydrogel hybrid that is physically stable, that preserves fine structure, proteins and nucleic acids, and that is permeable to both visible-spectrum photons and exogenous macromolecules. Here we highlight relevant challenges and opportunities of this approach, especially with regard to integration with complementary methodologies for brain-mapping studies.

676 citations

Journal ArticleDOI
27 Feb 2014-Cell
TL;DR: Cortico-cortical connectivity map and connectivity matrices revealed that the entire cortex is organized into four somatic sensorimotor, two medial, and two lateral subnetworks that display unique topologies and can interact through select cortical areas.

630 citations


Cites background from "Mapping brain circuitry with a ligh..."

  • ...As part of the effort to chart long-range connectivity in the mouse brain (Marx, 2012; Osten and Margrie, 2013; Pollock et al., 2014), we launched the Mouse Connectome Project (MCP, www.MouseConnectome.org)....

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  • ...Resource...

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  • ...In conclusion, we and other groups have demonstrated the feasibility of producing and collecting large-scale connectivity data (Osten and Margrie, 2013; Pollock et al., 2014); however, interpretation of this wealth of anatomical data presents an ongoing challenge....

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Journal ArticleDOI
TL;DR: A protocol for advanced CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis) is described in this paper, which enables simple and efficient organ clearing, rapid imaging by light-sheet microscopy and quantitative imaging analysis of multiple samples.
Abstract: Here we describe a protocol for advanced CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis). The CUBIC protocol enables simple and efficient organ clearing, rapid imaging by light-sheet microscopy and quantitative imaging analysis of multiple samples. The organ or body is cleared by immersion for 1-14 d, with the exact time required dependent on the sample type and the experimental purposes. A single imaging set can be completed in 30-60 min. Image processing and analysis can take <1 d, but it is dependent on the number of samples in the data set. The CUBIC clearing protocol can process multiple samples simultaneously. We previously used CUBIC to image whole-brain neural activities at single-cell resolution using Arc-dVenus transgenic (Tg) mice. CUBIC informatics calculated the Venus signal subtraction, comparing different brains at a whole-organ scale. These protocols provide a platform for organism-level systems biology by comprehensively detecting cells in a whole organ or body.

554 citations

PatentDOI
TL;DR: A transparent, flexible neural electrode technology based on graphene is reported, which enables simultaneous optical imaging and electrophysiological recording and may pave the way for high spatio-temporal resolution electro-optic mapping of the dynamic neuronal activity.
Abstract: A flexible, optically transparent electrode array comprises at least one graph electrode. The electrode may be positioned on a substrate. The flexible, optically transparent electrode may be used for simultaneous optical imaging and electrophysiological monitoring.

409 citations

Journal ArticleDOI
06 Aug 2014-Neuron
TL;DR: A comprehensive whole-brain atlas defining the monosynaptic inputs onto forebrain-projecting serotonergic neurons of dorsal versus median raphe based on a genetically restricted transsynaptic retrograde tracing strategy is generated.

349 citations


Cites methods from "Mapping brain circuitry with a ligh..."

  • ...Wholebrain imaging using high-resolution light sheet microscopy or other advanced imaging methods will allow for the classification of cell-type-specific tracing, including integrity of axonal pathways and detailed neuronal morphology (Chung et al., 2013; Osten and Margrie, 2013)....

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References
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Book
31 Jul 2001
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Abstract: "The Mouse Brain in Stereotaxic Coordinates" is the most widely used and cited atlas of the mouse brain in print. It provides researchers and students with both accurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structures for reference. The accompanying DVD provides drawings of brains structures that can be used as templates for making figures for publication. The 3rd edition is both a major revision and an expansion of previous editions. Delineations and photographs in the horizontal plane of section now complement the coronal and sagittal series, and all the tissue sections are now shown in high resolution digital color photography. The photographs of the sections and the intermediate sections are also provided on the accompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised, and naming conventions made consistent with Paxinos and Watson's "Rat Brain in Stereotaxic Coordinates, 6th Edition". The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal and sagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittal figures, for the first time in mammals. Microscopic plates are scanned with a new method in much higher quality.

15,681 citations


"Mapping brain circuitry with a ligh..." refers methods in this paper

  • ...…for standardized digital atlasing (Hawrylycz et al., 2011) allows comparisons of registered mouse brain data using multiple brain atlases, including the Allen Mouse Brain Atlas, the digital Paxinos and Franklin Mouse Brain Atlas (Paxinos and Franklin, 2004), and several MRI reference mouse brains....

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  • ...In addition, the so-called Waxholm space (WHS) for standardized digital atlasing (Hawrylycz et al., 2011) allows comparisons of registered mouse brain data using multiple brain atlases, including the Allen Mouse Brain Atlas, the digital Paxinos and Franklin Mouse Brain Atlas (Paxinos and Franklin, 2004), and several MRI reference mouse brains....

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Journal ArticleDOI
06 Apr 1990-Science
TL;DR: The fluorescence emission increased quadratically with the excitation intensity so that fluorescence and photo-bleaching were confined to the vicinity of the focal plane as expected for cooperative two-photon excitation.
Abstract: Molecular excitation by the simultaneous absorption of two photons provides intrinsic three-dimensional resolution in laser scanning fluorescence microscopy. The excitation of fluorophores having single-photon absorption in the ultraviolet with a stream of strongly focused subpicosecond pulses of red laser light has made possible fluorescence images of living cells and other microscopic objects. The fluorescence emission increased quadratically with the excitation intensity so that fluorescence and photo-bleaching were confined to the vicinity of the focal plane as expected for cooperative two-photon excitation. This technique also provides unprecedented capabilities for three-dimensional, spatially resolved photochemistry, particularly photolytic release of caged effector molecules.

8,905 citations


"Mapping brain circuitry with a ligh..." refers methods in this paper

  • ...…to achieve submicron resolution close to the diffraction limits of LM.1 Three instruments have been designed that combine two-photon microscopy (Denk et al., 1990) followed by tissue sectioning by either ultra-short laser pulses in all-optical histology (Tsai et al., 2003), milling machine in…...

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Journal ArticleDOI
TL;DR: A summary of the layout of cortical areas associated with vision and with other modalities, a computerized database for storing and representing large amounts of information on connectivity patterns, and the application of these data to the analysis of hierarchical organization of the cerebral cortex are reported on.
Abstract: In recent years, many new cortical areas have been identified in the macaque monkey. The number of identified connections between areas has increased even more dramatically. We report here on (1) a summary of the layout of cortical areas associated with vision and with other modalities, (2) a computerized database for storing and representing large amounts of information on connectivity patterns, and (3) the application of these data to the analysis of hierarchical organization of the cerebral cortex. Our analysis concentrates on the visual system, which includes 25 neocortical areas that are predominantly or exclusively visual in function, plus an additional 7 areas that we regard as visual-association areas on the basis of their extensive visual inputs. A total of 305 connections among these 32 visual and visual-association areas have been reported. This represents 31% of the possible number of pathways if each area were connected with all others. The actual degree of connectivity is likely to be closer to 40%. The great majority of pathways involve reciprocal connections between areas. There are also extensive connections with cortical areas outside the visual system proper, including the somatosensory cortex, as well as neocortical, transitional, and archicortical regions in the temporal and frontal lobes. In the somatosensory/motor system, there are 62 identified pathways linking 13 cortical areas, suggesting an overall connectivity of about 40%. Based on the laminar patterns of connections between areas, we propose a hierarchy of visual areas and of somatosensory/motor areas that is more comprehensive than those suggested in other recent studies. The current version of the visual hierarchy includes 10 levels of cortical processing. Altogether, it contains 14 levels if one includes the retina and lateral geniculate nucleus at the bottom as well as the entorhinal cortex and hippocampus at the top. Within this hierarchy, there are multiple, intertwined processing streams, which, at a low level, are related to the compartmental organization of areas V1 and V2 and, at a high level, are related to the distinction between processing centers in the temporal and parietal lobes. However, there are some pathways and relationships (about 10% of the total) whose descriptions do not fit cleanly into this hierarchical scheme for one reason or another. In most instances, though, it is unclear whether these represent genuine exceptions to a strict hierarchy rather than inaccuracies or uncertainities in the reported assignment.

7,796 citations

Journal ArticleDOI
TL;DR: A set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra is generated and enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo.
Abstract: The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universally responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in several Cre-driver lines, including new Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.

5,365 citations


"Mapping brain circuitry with a ligh..." refers background or methods in this paper

  • ..., 2008) can now be generated by imaging cell-typespecific Cre knock-in mouse lines (Madisen et al., 2010; Taniguchi et al., 2011) crossed with Credependent reporter mice expressing nuclear GFP....

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  • ...Brain-region and cell-type specificity for mapping connectivity by the modified RV system can be achieved by using a Cre recombinase–dependent helper virus driving expression of TVA and RV-G and transgenic mouse lines that express Cre in specific cell types or cortical layers (Madisen et al., 2010; Wall et al., 2010; Taniguchi et al., 2011)....

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Journal ArticleDOI
Ed S. Lein1, Michael Hawrylycz1, Nancy Ao2, Mikael Ayres1, Amy Bensinger1, Amy Bernard1, Andrew F. Boe1, Mark S. Boguski1, Mark S. Boguski3, Kevin S. Brockway1, Emi J. Byrnes1, Lin Chen1, Li Chen2, Tsuey-Ming Chen2, Mei Chi Chin1, Jimmy Chong1, Brian E. Crook1, Aneta Czaplinska2, Chinh Dang1, Suvro Datta1, Nick Dee1, Aimee L. Desaki1, Tsega Desta1, Ellen Diep1, Tim A. Dolbeare1, Matthew J. Donelan1, Hong-Wei Dong1, Jennifer G. Dougherty1, Ben J. Duncan1, Amanda Ebbert1, Gregor Eichele4, Lili K. Estin1, Casey Faber1, Benjamin A.C. Facer1, Rick Fields2, Shanna R. Fischer1, Tim P. Fliss1, Cliff Frensley1, Sabrina N. Gates1, Katie J. Glattfelder1, Kevin R. Halverson1, Matthew R. Hart1, John G. Hohmann1, Maureen P. Howell1, Darren P. Jeung1, Rebecca A. Johnson1, Patrick T. Karr1, Reena Kawal1, Jolene Kidney1, Rachel H. Knapik1, Chihchau L. Kuan1, James H. Lake1, Annabel R. Laramee1, Kirk D. Larsen1, Christopher Lau1, Tracy Lemon1, Agnes J. Liang2, Ying Liu2, Lon T. Luong1, Jesse Michaels1, Judith J. Morgan1, Rebecca J. Morgan1, Marty Mortrud1, Nerick Mosqueda1, Lydia Ng1, Randy Ng1, Geralyn J. Orta1, Caroline C. Overly1, Tu H. Pak1, Sheana Parry1, Sayan Dev Pathak1, Owen C. Pearson1, Ralph B. Puchalski1, Zackery L. Riley1, Hannah R. Rockett1, Stephen A. Rowland1, Joshua J. Royall1, Marcos J. Ruiz2, Nadia R. Sarno1, Katherine Schaffnit1, Nadiya V. Shapovalova1, Taz Sivisay1, Clifford R. Slaughterbeck1, Simon Smith1, Kimberly A. Smith1, Bryan I. Smith1, Andy J. Sodt1, Nick N. Stewart1, Kenda-Ruth Stumpf1, Susan M. Sunkin1, Madhavi Sutram1, Angelene Tam2, Carey D. Teemer1, Christina Thaller2, Carol L. Thompson1, Lee R. Varnam1, Axel Visel4, Axel Visel5, Ray M. Whitlock1, Paul Wohnoutka1, Crissa K. Wolkey1, Victoria Y. Wong1, Matthew J.A. Wood2, Murat B. Yaylaoglu2, Rob Young1, Brian L. Youngstrom1, Xu Feng Yuan1, Bin Zhang2, Theresa A. Zwingman1, Allan R. Jones1 
11 Jan 2007-Nature
TL;DR: An anatomically comprehensive digital atlas containing the expression patterns of ∼20,000 genes in the adult mouse brain is described, providing an open, primary data resource for a wide variety of further studies concerning brain organization and function.
Abstract: Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

4,944 citations

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