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1420 Janelia Publications

Showing 61-70 of 1420 results
06/05/18 | Persistent sodium current mediates the steep voltage dependence of spatial coding in hippocampal pyramidal neurons.
Hsu C, Zhao X, Milstein AD, Spruston N
Neuron. 2018 Jun 05:. doi: 10.1016/j.neuron.2018.05.025

The mammalian hippocampus forms a cognitive map using neurons that fire according to an animal's position ("place cells") and many other behavioral and cognitive variables. The responses of these neurons are shaped by their presynaptic inputs and the nature of their postsynaptic integration. In CA1 pyramidal neurons, spatial responses in vivo exhibit a strikingly supralinear dependence on baseline membrane potential. The biophysical mechanisms underlying this nonlinear cellular computation are unknown. Here, through a combination of in vitro, in vivo, and in silico approaches, we show that persistent sodium current mediates the strong membrane potential dependence of place cell activity. This current operates at membrane potentials below the action potential threshold and over seconds-long timescales, mediating a powerful and rapidly reversible amplification of synaptic responses, which drives place cell firing. Thus, we identify a biophysical mechanism that shapes the coding properties of neurons composing the hippocampal cognitive map.

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06/04/18 | Motor control: three-dimensional metric of head movements in the mouse brain.
Finkelstein A
Current Biology : CB. 2018 Jun 04;28(11):R660-R662. doi: 10.1016/j.cub.2018.04.079

Many forms of human and animal behavior involve head movements. A new study reveals the neural code for three-dimensional head movements in the midbrain of freely moving mice.

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06/01/18 | Adaptive optical microscopy for neurobiology.
Rodriguez C, Ji N
Current Opinion in Neurobiology. 2018 Jun;50:83-91. doi: 10.1016/j.conb.2018.01.011


  • Biological specimens introduce wavefront aberrations and deteriorate the image quality of optical microscopy.
  • Adaptive optics is used in optical microscopy to recover ideal imaging performance.
  • Adaptive optical imaging improves structural imaging of neurons, allowing for synaptic-level resolution at depth.
  • Adaptive optical imaging leads to a more accurate characterization of the functional properties of neurons.

With the ability to correct for the aberrations introduced by biological specimens, adaptive optics—a method originally developed for astronomical telescopes—has been applied to optical microscopy to recover diffraction-limited imaging performance deep within living tissue. In particular, this technology has been used to improve image quality and provide a more accurate characterization of both structure and function of neurons in a variety of living organisms. Among its many highlights, adaptive optical microscopy has made it possible to image large volumes with diffraction-limited resolution in zebrafish larval brains, to resolve dendritic spines over 600μm deep in the mouse brain, and to more accurately characterize the orientation tuning properties of thalamic boutons in the primary visual cortex of awake mice.

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Gonen Lab
06/01/18 | Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state.
Lei H, Ma J, Sanchez Martinez S, Gonen T
Nature Structural & Molecular Biology. 2018 Jun;25(6):522-527. doi: 10.1038/s41594-018-0072-2

Recent advances in understanding intracellular amino acid transport and mechanistic target of rapamycin complex 1 (mTORC1) signaling shed light on solute carrier 38, family A member 9 (SLC38A9), a lysosomal transporter responsible for the binding and translocation of several essential amino acids. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by transmembrane helix 1 (TM1) of drSLC38A9, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TM1, and mutations in this motif abolished arginine transport by drSLC38A9. The underlying mechanism of substrate binding is critical for sensitizing the mTORC1 signaling pathway to amino acids and for maintenance of lysosomal amino acid homeostasis. This study offers a first glimpse into a prototypical model for SLC38 transporters.

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06/01/18 | Monitoring the effects of pharmacological reagents on mitochondrial morphology.
Fu D, Lippincott-Schwartz J
Current Protocols in Cell Biology. 2018 Jun;79(1):e45. doi: 10.1002/cpcb.45

This protocol describes how to apply appropriate pharmacological controls to induce mitochondrial fusion or fission in studies of mitochondria morphology for four different mammalian cell types, HepG2 human liver hepatocellular carcinoma cells, MCF7 human breast adenocarcinoma cells, HEK293 human embryonic kidney cells, and collagen sandwich culture of primary rat hepatocytes. The protocol provides methods of treating cells with these pharmacological controls, staining mitochondria with commercially available MitoTracker Green and TMRE dyes, and imaging the mitochondrial morphology in live cells using a confocal fluorescent microscope. It also describes the cell culture methods needed for this protocol. © 2018 by John Wiley & Sons, Inc.

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06/01/18 | Multispectral live-cell imaging.
Cohen S, Valm AM, Lippincott-Schwartz J
Current Protocols in Cell Biology. 2018 Jun;79(1):e46. doi: 10.1002/cpcb.46

Fluorescent proteins and vital dyes are invaluable tools for studying dynamic processes within living cells. However, the ability to distinguish more than a few different fluorescent reporters in a single sample is limited by the spectral overlap of available fluorophores. Here, we present a protocol for imaging live cells labeled with six fluorophores simultaneously. A confocal microscope with a spectral detector is used to acquire images, and linear unmixing algorithms are applied to identify the fluorophores present in each pixel of the image. We describe the application of this method to visualize the dynamics of six different organelles, and to quantify the contacts between organelles. However, this method can be used to image any molecule amenable to tagging with a fluorescent probe. Thus, multispectral live-cell imaging is a powerful tool for systems-level analysis of cellular organization and dynamics. © 2018 by John Wiley & Sons, Inc.

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05/24/18 | Large scale image segmentation with structured loss based deep learning for connectome reconstruction..
Funke J, Tschopp FD, Grisaitis W, Sheridan A, Singh C, Saalfeld S, Turaga SC
IEEE Transactions on Pattern Analysis and Machine Intelligence. 2018 May 24:. doi: 10.1109/TPAMI.2018.2835450

We present a method combining affinity prediction with region agglomeration, which improves significantly upon the state of the art of neuron segmentation from electron microscopy (EM) in accuracy and scalability. Our method consists of a 3D U-net, trained to predict affinities between voxels, followed by iterative region agglomeration. We train using a structured loss based on MALIS, encouraging topologically correct segmentations obtained from affinity thresholding. Our extension consists of two parts: First, we present a quasi-linear method to compute the loss gradient, improving over the original quadratic algorithm. Second, we compute the gradient in two separate passes to avoid spurious gradient contributions in early training stages. Our predictions are accurate enough that simple learning-free percentile-based agglomeration outperforms more involved methods used earlier on inferior predictions. We present results on three diverse EM datasets, achieving relative improvements over previous results of 27%, 15%, and 250%. Our findings suggest that a single method can be applied to both nearly isotropic block-face EM data and anisotropic serial sectioned EM data. The runtime of our method scales linearly with the size of the volume and achieves a throughput of ~2.6 seconds per megavoxel, qualifying our method for the processing of very large datasets.

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05/24/18 | The candidate multi-cut for cell segmentation.
Funke J, Zhang C, Pietzsch T, Gonzalez Ballester MA, Saalfeld S
2018 IEEE 15th International Symposium on Biomedical Imaging (ISBI 2018). 2017 Jul 04:. doi: 10.1109/ISBI.2018.8363658

Two successful approaches for the segmentation of biomedical images are (1) the selection of segment candidates from a merge-tree, and (2) the clustering of small superpixels by solving a Multi-Cut problem. In this paper, we introduce a model that unifies both approaches. Our model, the Candidate Multi-Cut (CMC), allows joint selection and clustering of segment candidates from a merge-tree. This way, we overcome the respective limitations of the individual methods: (1) the space of possible segmentations is not constrained to candidates of a merge-tree, and (2) the decision for clustering can be made on candidates larger than superpixels, using features over larger contexts. We solve the optimization problem of selecting and clustering of candidates using an integer linear program. On datasets of 2D light microscopy of cell populations and 3D electron microscopy of neurons, we show that our method generalizes well and generates more accurate segmentations than merge-tree or Multi-Cut methods alone.

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05/23/18 | Cell-type specific changes in glial morphology and glucocorticoid expression during stress and aging in the medial prefrontal cortex.
Chan TE, Grossman YS, Bloss EB, Janssen WG, Lou W, McEwen BS, Dumitriu D, Morrison JH
Frontiers in Aging Neuroscience. 2018 May 23;10:. doi: 10.3389/fnagi.2018.00146

Repeated exposure to stressors is known to produce large-scale remodeling of neurons within the prefrontal cortex (PFC). Recent work suggests stress-related forms of structural plasticity can interact with aging to drive distinct patterns of pyramidal cell morphological changes. However, little is known about how other cellular components within PFC might be affected by these challenges. Here, we examined the effects of stress exposure and aging on medial prefrontal cortical glial subpopulations. Interestingly, we found no changes in glial morphology with stress exposure but a profound morphological change with aging. Furthermore, we found an upregulation of non-nuclear glucocorticoid receptors (GR) with aging, while nuclear levels remained largely unaffected. Both changes are selective for microglia, with no stress or aging effect found in astrocytes. Lastly, we show that the changes found within microglia inversely correlated with the density of dendritic spines on layer III pyramidal cells. These findings suggest microglia play a selective role in synaptic health within the aging brain.

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05/23/18 | The world of the identified or digital neuron.
Meinertzhagen IA
Journal of Neurogenetics. 2018 May 23:1-6. doi: 10.1080/01677063.2018.1474214

In general, neurons in insects and many other invertebrate groups are individually recognizable, enabling us to assign an index number to specific neurons in a manner which is rarely possible in a vertebrate brain. This endows many studies on insect nervous systems with the opportunity to document neurons with great precision, so that in favourable cases we can return to the same neuron or neuron type repeatedly so as to recognize many separate morphological classes. The visual system of the fly's compound eye particularly provides clear examples of the accuracy of neuron wiring, allowing numerical comparisons between representatives of the same cell type, and estimates of the accuracy of their wiring.

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