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10 Janelia Publications

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    09/19/19 | Reconstruction of 1,000 projection neurons reveals new cell types and organization of long-range connectivity in the mouse brain.
    Winnubst J, Bas E, Ferreira TA, Wu Z, Economo MN, Edson P, Arthur BJ, Bruns C, Rokicki K, Schauder D, Olbris DJ, Murphy SD, Ackerman DG, Arshadi C, Baldwin P, Blake R, Elsayed A, Hasan M, Ramirez D, Dos Santos B, Weldon M, Zafar A, Dudman JT, Gerfen CR, Hantman AW, Korff W, Sternson SM, Spruston N, Svoboda K, Chandrashekar J
    Cell. 2019 Sep 19;179(1):268-81. doi: 10.1016/j.cell.2019.07.042

    Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neurons in the mouse brain have been reconstructed in their entirety. Here we present a robust and efficient platform for imaging and reconstructing complete neuronal morphologies, including axonal arbors that span substantial portions of the brain. We used this platform to reconstruct more than 1,000 projection neurons in the motor cortex, thalamus, subiculum, and hypothalamus. Together, the reconstructed neurons constitute more than 85 meters of axonal length and are available in a searchable online database. Axonal shapes revealed previously unknown subtypes of projection neurons and suggest organizational principles of long-range connectivity.

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    09/16/19 | A repeated molecular architecture across thalamic pathways.
    Phillips JW, Schulmann A, Hara E, Winnubst J, Liu C, Valakh V, Wang L, Shields BC, Korff W, Chandrashekar J, Lemire AL, Mensh B, Dudman JT, Nelson SB, Hantman AW
    Nature Neuroscience. 2019 Sep 16;22(11):1925-35. doi: 10.1038/s41593-019-0483-3

    The thalamus is the central communication hub of the forebrain and provides the cerebral cortex with inputs from sensory organs, subcortical systems and the cortex itself. Multiple thalamic regions send convergent information to each cortical region, but the organizational logic of thalamic projections has remained elusive. Through comprehensive transcriptional analyses of retrogradely labeled thalamic neurons in adult mice, we identify three major profiles of thalamic pathways. These profiles exist along a continuum that is repeated across all major projection systems, such as those for vision, motor control and cognition. The largest component of gene expression variation in the mouse thalamus is topographically organized, with features conserved in humans. Transcriptional differences between these thalamic neuronal identities are tied to cellular features that are critical for function, such as axonal morphology and membrane properties. Molecular profiling therefore reveals covariation in the properties of thalamic pathways serving all major input modalities and output targets, thus establishing a molecular framework for understanding the thalamus.

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    04/12/19 | Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain.
    Sugino K, Clark E, Schulmann A, Shima Y, Wang L, Hunt DL, Hooks BM, Traenkner D, Chandrashekar J, Picard S, Lemire AL, Spruston N, Hantman AW, Nelson SB
    Elife. 2019 Apr 12;8:. doi: 10.7554/eLife.38619

    Understanding the principles governing neuronal diversity is a fundamental goal for neuroscience. Here we provide an anatomical and transcriptomic database of nearly 200 genetically identified cell populations. By separately analyzing the robustness and pattern of expression differences across these cell populations, we identify two gene classes contributing distinctly to neuronal diversity. Short homeobox transcription factors distinguish neuronal populations combinatorially, and exhibit extremely low transcriptional noise, enabling highly robust expression differences. Long neuronal effector genes, such as channels and cell adhesion molecules, contribute disproportionately to neuronal diversity, based on their patterns rather than robustness of expression differences. By linking transcriptional identity to genetic strains and anatomical atlases we provide an extensive resource for further investigation of mouse neuronal cell types.

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    03/12/19 | Single-neuron axonal reconstruction: The search for a wiring diagram of the brain.
    Economo MN, Winnubst J, Bas E, Ferreira TA, Chandrashekar J
    The Journal of Comparative Neurology. 2019 Mar 12:. doi: 10.1002/cne.24674

    Reconstruction of the axonal projection patterns of single neurons has been an important tool for understanding both the diversity of cell types in the brain and the logic of information flow between brain regions. Innovative approaches now enable the complete reconstruction of axonal projection patterns of individual neurons with vastly increased throughput. Here we review how advances in genetic, imaging, and computational techniques have been exploited for axonal reconstruction. We also discuss how new innovations could enable the integration of genetic and physiological information with axonal morphology for producing a census of cell types in the mammalian brain at scale. This article is protected by copyright. All rights reserved.

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    10/31/18 | Distinct descending motor cortex pathways and their roles in movement.
    Economo MN, Viswanathan S, Tasic B, Bas E, Winnubst J, Menon V, Graybuck LT, Nguyen TN, Smith KA, Yao Z, Wang L, Gerfen CR, Chandrashekar J, Zeng H, Looger LL, Svoboda K
    Nature. 2018 Nov;563(7729):79-84. doi: 10.1038/s41586-018-0642-9

    Activity in the motor cortex predicts movements, seconds before they are initiated. This preparatory activity has been observed across cortical layers, including in descending pyramidal tract neurons in layer 5. A key question is how preparatory activity is maintained without causing movement, and is ultimately converted to a motor command to trigger appropriate movements. Here, using single-cell transcriptional profiling and axonal reconstructions, we identify two types of pyramidal tract neuron. Both types project to several targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex; populations of these neurons produced early preparatory activity that persisted until the movement was initiated. The second type projects to motor centres in the medulla and mainly produced late preparatory activity and motor commands. These results indicate that two types of motor cortex output neurons have specialized roles in motor control.

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    09/03/18 | Topographic precision in sensory and motor corticostriatal projections varies across cell type and cortical area.
    Hooks BM, Papale AE, Paletzki RF, Feroze MW, Eastwood BS, Couey JJ, Winnubst J, Chandrashekar J, Gerfen CR
    Nature Communications. 2018 Sep 03;9(1):3549. doi: 10.1038/s41467-018-05780-7

    The striatum shows general topographic organization and regional differences in behavioral functions. How corticostriatal topography differs across cortical areas and cell types to support these distinct functions is unclear. This study contrasted corticostriatal projections from two layer 5 cell types, intratelencephalic (IT-type) and pyramidal tract (PT-type) neurons, using viral vectors expressing fluorescent reporters in Cre-driver mice. Corticostriatal projections from sensory and motor cortex are somatotopic, with a decreasing topographic specificity as injection sites move from sensory to motor and frontal areas. Topographic organization differs between IT-type and PT-type neurons, including injections in the same site, with IT-type neurons having higher topographic stereotypy than PT-type neurons. Furthermore, IT-type projections from interconnected cortical areas have stronger correlations in corticostriatal targeting than PT-type projections do. As predicted by a longstanding model, corticostriatal projections of interconnected cortical areas form parallel circuits in the basal ganglia.

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    04/10/18 | Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes.
    Cembrowski MS, Phillips MG, DiLisio SF, Shields BC, Winnubst J, Chandrashekar J, Bas E, Spruston N
    Cell. 2018 Apr 10;173(5):1280-92. doi: 10.1016/j.cell.2018.03.031

    The mammalian hippocampus, comprised of serially connected subfields, participates in diverse behavioral and cognitive functions. It has been postulated that parallel circuitry embedded within hippocampal subfields may underlie such functional diversity. We sought to identify, delineate, and manipulate this putatively parallel architecture in the dorsal subiculum, the primary output subfield of the dorsal hippocampus. Population and single-cell RNA-seq revealed that the subiculum can be divided into two spatially adjacent subregions associated with prominent differences in pyramidal cell gene expression. Pyramidal cells occupying these two regions differed in their long-range inputs, local wiring, projection targets, and electrophysiological properties. Leveraging gene-expression differences across these regions, we use genetically restricted neuronal silencing to show that these regions differentially contribute to spatial working memory. This work provides a coherent molecular-, cellular-, circuit-, and behavioral-level demonstration that the hippocampus embeds structurally and functionally dissociable streams within its serial architecture.

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    02/07/18 | Cell type-specific variation of somatotopic precision across corticostriatal projections.
    Hooks BM, Papale AE, Paletzki R, Feroze M, Eastwood BS, Couey JJ, Winnubst J, Chandrashekar J, Gerfen CR
    bioRxiv. 2018 Feb 7:. doi: 10.1101/261446

    The striatum shows general topographic organization and regional differences in behavioral functions. How corticostriatal topography differs across cortical areas and cell types to support these distinct functions is unclear. This study contrasted corticostriatal projections from two layer 5 cell types, intratelencephalic (IT-type) and pyramidal tract (PT-type) neurons, using viral vectors expressing fluorescent reporters in Cre-driver mice. Long-range corticostriatal projections from sensory and motor cortex are somatotopic, with a decreasing somatotopic specificity as injections move from sensory to motor and frontal areas. Somatotopic organization differs between IT-type and PT-type neurons, including injections in the same site, with IT-type neurons having higher somatotopic stereotypy than PT-type neurons. Furthermore, IT-type projections from interconnected cortical areas have stronger correlations in corticostriatal targeting than PT-type projections do. Thus, as predicted by a long-standing basal ganglia model, corticostriatal projections of interconnected cortical areas form parallel circuits in basal ganglia-thalamus-cortex loops.

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    11/12/16 | Long distance projections of cortical pyramidal neurons.
    Gerfen CR, Economo MN, Chandrashekar J
    Journal of Neuroscience Research. 2016 Nov 12:. doi: 10.1002/jnr.23978

    The neuronal circuits defined by the axonal projections of pyramidal neurons in the cerebral cortex are responsible for processing sensory and other information to plan and execute behavior. Subtypes of cortical pyramidal neurons are organized across layers, with those in different layers distinguished by their patterns of axonal projections and connectivity. For example, those in layers 2 and 3 project between cortical areas to integrate sensory and other information with motor areas; while those in layers 5 and 6 also integrate information between cortical areas, but also project to subcortical structures involved in the generation of behavior. Recent advances in neuroanatomical techniques allow one to target specific subtypes of cortical pyramidal neurons and label both their inputs and projections. Combining these methods with neurophysiological recording techniques and newly introduced atlases of the mouse brain provide the opportunity to achieve a detailed view of the organization of cerebral cortical circuits.

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    01/20/16 | A platform for brain-wide imaging and reconstruction of individual neurons.
    Economo MN, Clack NG, Lavis LD, Gerfen CR, Svoboda K, Myers EW, Chandrashekar J
    eLife. 2016 Jan 20;5:. doi: 10.7554/eLife.10566

    The structure of axonal arbors controls how signals from individual neurons are routed within the mammalian brain. However, the arbors of very few long-range projection neurons have been reconstructed in their entirety, as axons with diameters as small as 100 nm arborize in target regions dispersed over many millimeters of tissue. We introduce a platform for high-resolution, three-dimensional fluorescence imaging of complete tissue volumes that enables the visualization and reconstruction of long-range axonal arbors. This platform relies on a high-speed two-photon microscope integrated with a tissue vibratome and a suite of computational tools for large-scale image data. We demonstrate the power of this approach by reconstructing the axonal arbors of multiple neurons in the motor cortex across a single mouse brain.

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