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177 Janelia Publications

Showing 141-150 of 177 results
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    03/07/19 | Cytoskeletal actin patterns shape mast cell activation.
    Colin-York H, Li D, Korobchevskaya K, Chang VT, Betzig E, Eggeling C, Fritzsche M
    Communications Biology. 2019;2:93. doi: 10.1038/s42003-019-0322-9

    Activation of immune cells relies on a dynamic actin cytoskeleton. Despite detailed knowledge of molecular actin assembly, the exact processes governing actin organization during activation remain elusive. Using advanced microscopy, we here show that Rat Basophilic Leukemia (RBL) cells, a model mast cell line, employ an orchestrated series of reorganization events within the cortical actin network during activation. In response to IgE antigen-stimulation of FCε receptors (FCεR) at the RBL cell surface, we observed symmetry breaking of the F-actin network and subsequent rapid disassembly of the actin cortex. This was followed by a reassembly process that may be driven by the coordinated transformation of distinct nanoscale F-actin architectures, reminiscent of self-organizing actin patterns. Actin patterns co-localized with zones of Arp2/3 nucleation, while network reassembly was accompanied by myosin-II activity. Strikingly, cortical actin disassembly coincided with zones of granule secretion, suggesting that cytoskeletal actin patterns contribute to orchestrate RBL cell activation.

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    03/01/19 | Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder.
    Schulmann A, Ryu E, Goncalves V, Rollins B, Christiansen M, Frye MA, Biernacka J, Vawter MP
    Mol Neuropsychiatry. 2019 Mar 0;5(1):13-27. doi: 10.1159/000495658

    Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ ( = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

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    02/28/19 | GCIB-SEM: A path to 10 nm isotropic imaging of cubic millimeter volumes.
    Hayworth KJ, Peale DR, Januszewski M, Knott G, Lu Z, Xu CS, Hess HF
    bioRxiv. 2019 Feb 28:. doi: 10.1101/563239

    Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) generates 3D datasets optimally suited for segmentation of cell ultrastructure and automated connectome tracing but is limited to small fields of view and is therefore incompatible with the new generation of ultrafast multibeam SEMs. In contrast, section-based techniques are multibeam-compatible but are limited in z-resolution making automatic segmentation of cellular ultrastructure difficult. Here we demonstrate a novel 3D electron microscopy technique, Gas Cluster Ion Beam SEM (GCIB-SEM), in which top-down, wide-area ion milling is performed on a series of thick sections, acquiring < 10 nm isotropic datasets of each which are then stitched together to span the full sectioned volume. Based on our results, incorporating GCIB-SEM into existing single beam and multibeam SEM workflows should be straightforward and should dramatically increase reliability while simultaneously improving z-resolution by a factor of 3 or more.

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    02/28/19 | Neural basis for looming size and velocity encoding in the Drosophila giant fiber escape pathway.
    Ache JM, Polsky J, Alghailani S, Parekh R, Breads P, Peek MY, Bock DD, von Reyn CR, Card GM
    Current Biology : CB. 2019 Feb 28;29(6):1073. doi: 10.1016/j.cub.2019.01.079

    Identified neuron classes in vertebrate cortical [1-4] and subcortical [5-8] areas and invertebrate peripheral [9-11] and central [12-14] brain neuropils encode specific visual features of a panorama. How downstream neurons integrate these features to control vital behaviors, like escape, is unclear [15]. In Drosophila, the timing of a single spike in the giant fiber (GF) descending neuron [16-18] determines whether a fly uses a short or long takeoff when escaping a looming predator [13]. We previously proposed that GF spike timing results from summation of two visual features whose detection is highly conserved across animals [19]: an object's subtended angular size and its angular velocity [5-8, 11, 20, 21]. We attributed velocity encoding to input from lobula columnar type 4 (LC4) visual projection neurons, but the size-encoding source remained unknown. Here, we show that lobula plate/lobula columnar, type 2 (LPLC2) visual projection neurons anatomically specialized to detect looming [22] provide the entire GF size component. We find LPLC2 neurons to be necessary for GF-mediated escape and show that LPLC2 and LC4 synapse directly onto the GF via reconstruction in a fly brain electron microscopy (EM) volume [23]. LPLC2 silencing eliminates the size component of the GF looming response in patch-clamp recordings, leaving only the velocity component. A model summing a linear function of angular velocity (provided by LC4) and a Gaussian function of angular size (provided by LPLC2) replicates GF looming response dynamics and predicts the peak response time. We thus present an identified circuit in which information from looming feature-detecting neurons is combined by a common post-synaptic target to determine behavioral output.

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    02/25/19 | Chronology-based architecture of descending circuits that underlie the development of locomotor repertoire after birth.
    Pujala A, Koyama M
    eLife. 2019 Feb 25;8:. doi: 10.7554/eLife.42135

    The emergence of new and increasingly sophisticated behaviors after birth is accompanied by dramatic increase of newly established synaptic connections in the nervous system. Little is known, however, of how nascent connections are organized to support such new behaviors alongside existing ones. To understand this, in the larval zebrafish we examined the development of spinal pathways from hindbrain V2a neurons and the role of these pathways in the development of locomotion. We found that new projections are continually layered laterally to existing neuropil, and give rise to distinct pathways that function in parallel to existing pathways. Across these chronologically layered pathways, the connectivity patterns and biophysical properties vary systematically to support a behavioral repertoire with a wide range of kinematics and dynamics. Such layering of new parallel circuits equipped with systematically changing properties may be central to the postnatal diversification and increasing sophistication of an animal's behavioral repertoire.

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    Keleman LabFly Functional Connectome
    02/25/19 | Neuronal reactivation during post-learning sleep consolidates long-term memory in .
    Dag U, Lei Z, Le JQ, Wong A, Bushey D, Keleman K
    eLife. 2019 Feb 25;8:. doi: 10.7554/eLife.42786

    Animals consolidate some, but not all, learning experiences into long-term memory. Across the animal kingdom, sleep has been found to have a beneficial effect on the consolidation of recently formed memories into long-term storage. However, the underlying mechanisms of sleep dependent memory consolidation are poorly understood. Here, we show that consolidation of courtship long-term memory in is mediated by reactivation during sleep of dopaminergic neurons that were earlier involved in memory acquisition. We identify specific fan-shaped body neurons that induce sleep after the learning experience and activate dopaminergic neurons for memory consolidation. Thus, we provide a direct link between sleep, neuronal reactivation of dopaminergic neurons, and memory consolidation.

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    02/23/19 | Analysis of phosphatidylinositol transfer at ER-PM junctions in receptor-stimulated live cells.
    Chang C, Liou J
    Methods in Molecular Biology. 2019 Feb 23;1949:1-11. doi: 10.1007/978-1-4939-9136-5_1

    Phosphatidylinositol (PI) is an inositol-containing phospholipid synthesized in the endoplasmic reticulum (ER). PI is a precursor lipid for PI 4,5-bisphosphate (PI(4,5)P) in the plasma membrane (PM) important for Ca signaling in response to extracellular stimuli. Thus, ER-to-PM PI transfer becomes essential for cells to maintain PI(4,5)P homeostasis during receptor stimulation. In this chapter, we discuss two live-cell imaging protocols to analyze ER-to-PM PI transfer at ER-PM junctions, where the two membrane compartments make close appositions accommodating PI transfer. First, we describe how to monitor PI(4,5)P replenishment following receptor stimulation, as a readout of PI transfer, using a PI(4,5)P biosensor and total internal reflection fluorescence microscopy. The second protocol directly visualizes PI transfer proteins that accumulate at ER-PM junctions and mediate PI(4,5)P replenishment with PI in the ER in stimulated cells. These methods provide spatial and temporal analysis of ER-to-PM PI transfer during receptor stimulation and can be adapted to other research questions related to this topic.

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    02/21/19 | Principles governing the dynamics of GABAergic interneurons in the barrel cortex.
    Yu J, Hu H, Agmon A, Svoboda K
    bioRxiv. 2019 Feb 21:. doi: 10.1101/554949

    Information processing in the neocortex is performed by GABAergic interneurons that are integrated with excitatory neurons into precisely structured circuits. To reveal how each neuron type shapes sensory representations, we measured spikes and membrane potential of specific types of neurons in the barrel cortex while mice performed an active, whisker-dependent object localization task. Whiskers were tracked with millisecond precision. Fast-spiking (FS) neurons were activated by touch with short latency and by whisking. FS neurons track thalamic input and provide feedforward inhibition. Somatostatin (SOM)-expressing neurons were also excited by touch, but with a delay (5 ms) compared to excitatory (E) and FS neurons. SOM neurons monitor local excitation and provide feedback inhibition. Vasoactive intestinal polypeptide (VIP)-expressing neurons were not driven by touch but elevated their spike rate during whisking, disinhibiting E and FS neurons. Our data reveal rules of recruitment for specific interneuron types, providing foundations for understanding cortical computations.

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    02/18/19 | Heterogeneity within classical cell types is the rule: lessons from hippocampal pyramidal neurons.
    Cembrowski MS, Spruston N
    Nature Reviews. Neuroscience. 2019 Feb 18;20(4):193-204. doi: 10.1038/s41583-019-0125-5

    The mechanistic operation of brain regions is often interpreted by partitioning constituent neurons into 'cell types'. Historically, such cell types were broadly defined by their correspondence to gross features of the nervous system (such as cytoarchitecture). Modern-day neuroscientific techniques, enabling a more nuanced examination of neuronal properties, have illustrated a wealth of heterogeneity within these classical cell types. Here, we review the extent of this within-cell-type heterogeneity in one of the simplest cortical regions of the mammalian brain, the rodent hippocampus. We focus on the mounting evidence that the classical CA3, CA1 and subiculum pyramidal cell types all exhibit prominent and spatially patterned within-cell-type heterogeneity, and suggest these cell types provide a model system for exploring the organization and function of such heterogeneity. Given that the hippocampus is structurally simple and evolutionarily ancient, within-cell-type heterogeneity is likely to be a general and crucial feature of the mammalian brain.

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    02/13/19 | Dystroglycan is a scaffold for extracellular axon guidance decisions.
    Lindenmaier LB, Parmentier N, Guo C, Tissir F, Wright KM
    eLife. 2019 Feb 13;8:. doi: 10.7554/eLife.42143

    Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events . These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.

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