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8 Publications

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    09/03/20 | A connectome of the adult drosophila central brain.
    Xu CS, Januszewski M, Lu Z, Takemura S, Hayworth KJ, Huang G, Shinomiya K, Maitin-Shepard J, Ackerman D, Berg S, Blakely T, Bogovic J, Clements J, Dolafi T, Hubbard P, Kainmueller D, Katz W, Kawase T, Khairy KA, Leavitt L, Li PH, Lindsey L, Neubarth N, Olbris DJ, Otsuna H, Troutman ET, Umayam L, Zhao T, Ito M, Goldammer J, Wolff T, Svirskas R, Schlegel P, Neace ER, Knecht CJ, Alvarado CX, Bailey DA, Ballinger S, Borycz JA, Canino BS
    eLife. 2020 Sep 03:. doi: https://doi.org/10.1101/2020.01.21.911859

    The neural circuits responsible for behavior remain largely unknown. Previous efforts have reconstructed the complete circuits of small animals, with hundreds of neurons, and selected circuits for larger animals. Here we (the FlyEM project at Janelia and collaborators at Google) summarize new methods and present the complete circuitry of a large fraction of the brain of a much more complex animal, the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses, and proofread such large data sets; new methods that define cell types based on connectivity in addition to morphology; and new methods to simplify access to a large and evolving data set. From the resulting data we derive a better definition of computational compartments and their connections; an exhaustive atlas of cell examples and types, many of them novel; detailed circuits for most of the central brain; and exploration of the statistics and structure of different brain compartments, and the brain as a whole. We make the data public, with a web site and resources specifically designed to make it easy to explore, for all levels of expertise from the expert to the merely curious. The public availability of these data, and the simplified means to access it, dramatically reduces the effort needed to answer typical circuit questions, such as the identity of upstream and downstream neural partners, the circuitry of brain regions, and to link the neurons defined by our analysis with genetic reagents that can be used to study their functions.

    Note: In the next few weeks, we will release a series of papers with more involved discussions. One paper will detail the hemibrain reconstruction with more extensive analysis and interpretation made possible by this dense connectome. Another paper will explore the central complex, a brain region involved in navigation, motor control, and sleep. A final paper will present insights from the mushroom body, a center of multimodal associative learning in the fly brain.

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    01/09/19 | Comparisons between the ON- and OFF-edge motion pathways in the brain.
    Shinomiya K, Huang G, Lu Z, Parag T, Xu CS, Aniceto R, Ansari N, Cheatham N, Lauchie S, Neace E, Ogundeyi O, Ordish C, Peel D, Shinomiya A, Smith C, Takemura S, Talebi I, Rivlin PK, Nern A, Scheffer LK, Plaza SM, Meinertzhagen IA
    eLife. 2019 Jan 09;8:. doi: 10.7554/eLife.40025

    Understanding the circuit mechanisms behind motion detection is a long-standing question in visual neuroscience. In , recent synapse-level connectomes in the optic lobe, particularly in ON-pathway (T4) receptive-field circuits, in concert with physiological studies, suggest an increasingly intricate motion model compared with the ubiquitous Hassenstein-Reichardt model, while our knowledge of OFF-pathway (T5) has been incomplete. Here we present a conclusive and comprehensive connectome that for the first time integrates detailed connectivity information for inputs to both T4 and T5 pathways in a single EM dataset covering the entire optic lobe. With novel reconstruction methods using automated synapse prediction suited to such a large connectome, we successfully corroborate previous findings in the T4 pathway and comprehensively identify inputs and receptive fields for T5. While the two pathways are likely evolutionarily linked and indeed exhibit many similarities, we uncover interesting differences and interactions that may underlie their distinct functional properties.

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    07/18/17 | A connectome of a learning and memory center in the adult Drosophila brain.
    Takemura S, Aso Y, Hige T, Wong AM, Lu Z, Xu CS, Rivlin PK, Hess HF, Zhao T, Parag T, Berg S, Huang G, Katz WT, Olbris DJ, Plaza SM, Umayam LA, Aniceto R, Chang L, Lauchie S, et al
    eLife. 2017 Jul 18;6:e26975. doi: 10.7554/eLife.26975

    Understanding memory formation, storage and retrieval requires knowledge of the underlying neuronal circuits. In Drosophila, the mushroom body (MB) is the major site of associative learning. We reconstructed the morphologies and synaptic connections of all 983 neurons within the three functional units, or compartments, that compose the adult MB’s α lobe, using a dataset of isotropic 8-nm voxels collected by focused ion-beam milling scanning electron microscopy. We found that Kenyon cells (KCs), whose sparse activity encodes sensory information, each make multiple en passant synapses to MB output neurons (MBONs) in each compartment. Some MBONs have inputs from all KCs, while others differentially sample sensory modalities. Only six percent of KC>MBON synapses receive a direct synapse from a dopaminergic neuron (DAN). We identified two unanticipated classes of synapses, KC>DAN and DAN>MBON. DAN activation produces a slow depolarization of the MBON in these DAN>MBON synapses and can weaken memory recall.

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    04/22/17 | The comprehensive connectome of a neural substrate for 'ON' motion detection in Drosophila.
    Takemura S, Nern A, Chklovskii DB, Scheffer LK, Rubin GM, Meinertzhagen IA
    eLife. 2017 Apr 22;6:. doi: 10.7554/eLife.24394

    Analysing computations in neural circuits often uses simplified models because the actual neuronal implementation is not known. For example, a problem in vision, how the eye detects image motion, has long been analysed using Hassenstein-Reichardt (HR) detector or Barlow-Levick (BL) models. These both simulate motion detection well, but the exact neuronal circuits undertaking these tasks remain elusive. We reconstructed a comprehensive connectome of the circuits of Drosophila's motion-sensing T4 cells using a novel EM technique. We uncover complex T4 inputs and reveal that putative excitatory inputs cluster at T4's dendrite shafts, while inhibitory inputs localize to the bases. Consistent with our previous study, we reveal that Mi1 and Tm3 cells provide most synaptic contacts onto T4. We are, however, unable to reproduce the spatial offset between these cells reported previously. Our comprehensive connectome reveals complex circuits that include candidate anatomical substrates for both HR and BL types of motion detectors.

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    12/17/15 | Ig superfamily ligand and receptor pairs expressed in synaptic partners in Drosophila.
    Tan L, Zhang KX, Pecot MY, Nagarkar-Jaiswal S, Lee P, Takemura S, McEwen JM, Nern A, Xu S, Tadros W, Chen Z, Zinn K, Bellen HJ, Morey M, Zipursky SL
    Cell. 2015 Dec 17;163(7):1756-69. doi: 10.1016/j.cell.2015.11.021

    Information processing relies on precise patterns of synapses between neurons. The cellular recognition mechanisms regulating this specificity are poorly understood. In the medulla of the Drosophila visual system, different neurons form synaptic connections in different layers. Here, we sought to identify candidate cell recognition molecules underlying this specificity. Using RNA sequencing (RNA-seq), we show that neurons with different synaptic specificities express unique combinations of mRNAs encoding hundreds of cell surface and secreted proteins. Using RNA-seq and protein tagging, we demonstrate that 21 paralogs of the Dpr family, a subclass of immunoglobulin (Ig)-domain containing proteins, are expressed in unique combinations in homologous neurons with different layer-specific synaptic connections. Dpr interacting proteins (DIPs), comprising nine paralogs of another subclass of Ig-containing proteins, are expressed in a complementary layer-specific fashion in a subset of synaptic partners. We propose that pairs of Dpr/DIP paralogs contribute to layer-specific patterns of synaptic connectivity.

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    08/07/13 | A visual motion detection circuit suggested by Drosophila connectomics.
    Takemura S, Bharioke A, Lu Z, Nern A, Vitaladevuni S, Rivlin PK, Katz WT, Olbris DJ, Plaza SM, Winston P, Zhao T, Horne JA, Fetter RD, Takemura S, Blazek K, Chang L, Ogundeyi O, Saunders MA, Shapiro V, Sigmund C, Rubin GM, Scheffer LK, Meinertzhagen IA, Chklovskii DB
    Nature. 2013 Aug 7;500(7461):175–81. doi: doi:10.1038/nature12450

    Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in the insect visual system remains elusive. Here we develop a semi-automated pipeline using electron microscopy to reconstruct a connectome, containing 379 neurons and 8,637 chemical synaptic contacts, within the Drosophila optic medulla. By matching reconstructed neurons to examples from light microscopy, we assigned neurons to cell types and assembled a connectome of the repeating module of the medulla. Within this module, we identified cell types constituting a motion detection circuit, and showed that the connections onto individual motion-sensitive neurons in this circuit were consistent with their direction selectivity. Our results identify cellular targets for future functional investigations, and demonstrate that connectomes can provide key insights into neuronal computations.

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    10/01/10 | Refinement of tools for targeted gene expression in Drosophila.
    Pfeiffer BD, Ngo TB, Hibbard KL, Murphy C, Jenett A, Truman JW, Rubin GM
    Genetics. 2010 Oct;186(2):735-55. doi: 10.1534/genetics.110.119917

    A wide variety of biological experiments rely on the ability to express an exogenous gene in a transgenic animal at a defined level and in a spatially and temporally controlled pattern. We describe major improvements of the methods available for achieving this objective in Drosophila melanogaster. We have systematically varied core promoters, UTRs, operator sequences, and transcriptional activating domains used to direct gene expression with the GAL4, LexA, and Split GAL4 transcription factors and the GAL80 transcriptional repressor. The use of site-specific integration allowed us to make quantitative comparisons between different constructs inserted at the same genomic location. We also characterized a set of PhiC31 integration sites for their ability to support transgene expression of both drivers and responders in the nervous system. The increased strength and reliability of these optimized reagents overcome many of the previous limitations of these methods and will facilitate genetic manipulations of greater complexity and sophistication.

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    01/01/10 | Anatomic analysis of Gal4 expression patterns of the Rubin line collection: the central complex.
    Jenett A, Wolff T, Nern A, Pfeiffer BD, Ngo T, Murphy C, Long F, Peng H, Rubin GM
    Journal of Neurogenetics. 2010;24:71-2