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187 Publications

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    11/21/12 | Proprioceptive coupling within motor neurons drives C. elegans forward locomotion.
    Wen Q, Po MD, Hulme E, Chen S, Liu X, Kwok SW, Gershow M, Leifer AM, Butler V, Fang-Yen C, Kawano T, Schafer WR, Whitesides G, Wyart M, Chklovskii DB, Samuel AD
    Neuron. 2012 Nov 21;76(4):750-61. doi: 10.1016/j.neuron.2012.08.039

    Locomotion requires coordinated motor activity throughout an animal's body. In both vertebrates and invertebrates, chains of coupled central pattern generators (CPGs) are commonly evoked to explain local rhythmic behaviors. In C. elegans, we report that proprioception within the motor circuit is responsible for propagating and coordinating rhythmic undulatory waves from head to tail during forward movement. Proprioceptive coupling between adjacent body regions transduces rhythmic movement initiated near the head into bending waves driven along the body by a chain of reflexes. Using optogenetics and calcium imaging to manipulate and monitor motor circuit activity of moving C. elegans held in microfluidic devices, we found that the B-type cholinergic motor neurons transduce the proprioceptive signal. In C. elegans, a sensorimotor feedback loop operating within a specific type of motor neuron both drives and organizes body movement.

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    11/20/12 | Lineage analysis of Drosophila lateral antennal lobe neurons reveals notch-dependent binary temporal fate decisions.
    Lin S, Kao C, Yu H, Huang Y, Lee T
    PLoS Biology. 2012 Nov 20;10(11):e1001425. doi: 10.1371/journal.pbio.1001425

    Binary cell fate decisions allow the production of distinct sister neurons from an intermediate precursor. Neurons are further diversified based on the birth order of intermediate precursors. Here we examined the interplay between binary cell fate and birth-order-dependent temporal fate in the Drosophila lateral antennal lobe (lAL) neuronal lineage. Single-cell mapping of the lAL lineage by twin-spot mosaic analysis with repressible cell markers (ts-MARCM) revealed that projection neurons (PNs) and local interneurons (LNs) are made in pairs through binary fate decisions. Forty-five types of PNs innervating distinct brain regions arise in a stereotyped sequence; however, the PNs with similar morphologies are not necessarily born in a contiguous window. The LNs are morphologically less diverse than the PNs, and the sequential morphogenetic changes in the two pairs occur independently. Sanpodo-dependent Notch activity promotes and patterns the LN fates. By contrast, Notch diversifies PN temporal fates in a Sanpodo-dispensable manner. These pleiotropic Notch actions underlie the differential temporal fate specification of twin neurons produced by common precursors within a lineage, possibly by modulating postmitotic neurons’ responses to Notch-independent transcriptional cascades.

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    Druckmann Lab
    11/20/12 | Neuronal circuits underlying persistent representations despite time varying activity.
    Druckmann S, Chklovskii DB
    Current Biology. 2012 Nov 20;22:2095-103. doi: 10.1016/j.cub.2012.08.058

    Our brains are capable of remarkably stable stimulus representations despite time-varying neural activity. For instance, during delay periods in working memory tasks, while stimuli are represented in working memory, neurons in the prefrontal cortex, thought to support the memory representation, exhibit time-varying neuronal activity. Since neuronal activity encodes the stimulus, its time-varying dynamics appears to be paradoxical and incompatible with stable network stimulus representations. Indeed, this finding raises a fundamental question: can stable representations only be encoded with stable neural activity, or, its corollary, is every change in activity a sign of change in stimulus representation?

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    11/15/12 | ImgLib2--generic image processing in Java.
    Pietzsch T, Preibisch S, Tomancak P, Saalfeld S
    Bioinformatics. 2012 Nov 15;28(22):3009-11. doi: 10.1093/bioinformatics/bts543

    SUMMARY: ImgLib2 is an open-source Java library for n-dimensional data representation and manipulation with focus on image processing. It aims at minimizing code duplication by cleanly separating pixel-algebra, data access and data representation in memory. Algorithms can be implemented for classes of pixel types and generic access patterns by which they become independent of the specific dimensionality, pixel type and data representation. ImgLib2 illustrates that an elegant high-level programming interface can be achieved without sacrificing performance. It provides efficient implementations of common data types, storage layouts and algorithms. It is the data model underlying ImageJ2, the KNIME Image Processing toolbox and an increasing number of Fiji-Plugins.

    AVAILABILITY: ImgLib2 is licensed under BSD. Documentation and source code are available at and in a public repository at

    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Online.


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    11/14/12 | β-secretase cleavage of the fly amyloid precursor protein is required for glial survival.
    Bolkan BJ, Triphan T, Kretzschmar D
    Journal of Neuroscience. 2012 Nov 14;32(46):16181-92. doi: 10.1523/JNEUROSCI.0228-12.2012

    β-secretase (or BACE1) is the key enzyme in the production of β-amyloid (Aβ), which accumulates in the senile plaques characteristic for Alzheimer's disease. Consequently, the lack of BACE1 prevents β-processing of the amyloid precursor protein and Aβ production, which made it a promising target for drug development. However, the loss of BACE1 is also detrimental, leading to myelination defects and altered neuronal activity, functions that have been associated with the cleavage of Neuregulin and a voltage-gated sodium channel subunit. Here we show that the Drosophila ortholog of BACE, dBACE, is required for glial survival. Cell-specific knockdown experiments reveal that this is a non-cell autonomous function, as a knockdown of dBACE in photoreceptor neurons leads to progressive degeneration of glia in their target zone, the lamina. Interestingly, this phenotype is suppressed by the loss of the fly amyloid precursor protein (APPL), whereas a secretion-deficient form of APPL enhances the degeneration. This shows that full-length APPL in neurons promotes the death of neighboring glial cells and that β-processing of APPL is needed to prevent glial death. These results therefore not only demonstrate a novel function for an APP protein in glia, but they also show this function specifically requires regulation by β-cleavage.

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    11/07/12 | DlgS97/SAP97, a neuronal isoform of discs large, regulates ethanol tolerance.
    Maiya R, Lee S, Berger KH, Kong EC, Slawson JB, Griffith LC, Takamiya K, Huganir RL, Margolis B, Heberlein U
    PLoS One. 2012 Nov 7;7(11):e48967. doi: 10.1371/journal.pone.0048967

    From a genetic screen for Drosophila melanogaster mutants with altered ethanol tolerance, we identified intolerant (intol), a novel allele of discs large 1 (dlg1). Dlg1 encodes Discs Large 1, a MAGUK (Membrane Associated Guanylate Kinase) family member that is the highly conserved homolog of mammalian PSD-95 and SAP97. The intol mutation disrupted specifically the expression of DlgS97, a SAP97 homolog, and one of two major protein isoforms encoded by dlg1 via alternative splicing. Expression of the major isoform, DlgA, a PSD-95 homolog, appeared unaffected. Ethanol tolerance in the intol mutant could be partially restored by transgenic expression of DlgS97, but not DlgA, in specific neurons of the fly's brain. Based on co-immunoprecipitation, DlgS97 forms a complex with N-methyl-D-aspartate (NMDA) receptors, a known target of ethanol. Consistent with these observations, flies expressing reduced levels of the essential NMDA receptor subunit dNR1 also showed reduced ethanol tolerance, as did mutants in the gene calcium/calmodulin-dependent protein kinase (caki), encoding the fly homolog of mammalian CASK, a known binding partner of DlgS97. Lastly, mice in which SAP97, the mammalian homolog of DlgS97, was conditionally deleted in adults failed to develop rapid tolerance to ethanol's sedative/hypnotic effects. We propose that DlgS97/SAP97 plays an important and conserved role in the development of tolerance to ethanol via NMDA receptor-mediated synaptic plasticity.

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    11/07/12 | Movies of ice-embedded particles enhance resolution in electron cryo-microscopy.
    Campbell MG, Cheng A, Brilot AF, Moeller A, Lyumkis D, Veesler D, Pan J, Harrison SC, Potter CS, Carragher B, Grigorieff N
    Structure. 2012 Nov 7;20(11):1823-8. doi: 10.1016/j.str.2012.08.026

    Low-dose images obtained by electron cryo-microscopy (cryo-EM) are often affected by blurring caused by sample motion during electron beam exposure, degrading signal especially at high resolution. We show here that we can align frames of movies, recorded with a direct electron detector during beam exposure of rotavirus double-layered particles, thereby greatly reducing image blurring caused by beam-induced motion and sample stage instabilities. This procedure increases the efficiency of cryo-EM imaging and enhances the resolution obtained in three-dimensional reconstructions of the particle. Using movies in this way is generally applicable to all cryo-EM samples and should also improve the performance of midrange electron microscopes that may have limited mechanical stability and beam coherence.

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    11/06/12 | The C-value paradox, junk DNA and ENCODE.
    Eddy SR
    Current Biology. 2012 Nov 6;22(21):R898-9. doi: 10.1016/j.cub.2012.10.002

    paradox? You might expect more complex organisms to have progressively larger genomes, but eukaryotic genome size fails to correlate well with apparent complexity, and instead varies wildly over more than a 100,000-fold range. Single-celled amoebae have some of the largest genomes, up to 100-fold larger than the human genome. This variation suggested that genomes can contain a substantial fraction of DNA other than for genes and their regulatory sequences. C.A. Thomas Jr dubbed it the ‘C-value paradox’ in 1971.

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    11/01/12 | A network of spiking neurons for computing sparse representations in an energy-efficient way.
    Hu T, Genkin A, Chklovskii DB
    Neural computation. 2012 Nov;24:2852-72. doi: 10.1162/NECO_a_00353

    Computing sparse redundant representations is an important problem in both applied mathematics and neuroscience. In many applications, this problem must be solved in an energy-efficient way. Here, we propose a hybrid distributed algorithm (HDA), which solves this problem on a network of simple nodes communicating by low-bandwidth channels. HDA nodes perform both gradient-descent-like steps on analog internal variables and coordinate-descent-like steps via quantized external variables communicated to each other. Interestingly, the operation is equivalent to a network of integrate-and-fire neurons, suggesting that HDA may serve as a model of neural computation. We show that the numerical performance of HDA is on par with existing algorithms. In the asymptotic regime, the representation error of HDA decays with time, t, as 1/t. HDA is stable against time-varying noise; specifically, the representation error decays as 1/√t for gaussian white noise.

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    Singer Lab
    11/01/12 | Imaging translation in single cells using fluorescent microscopy.
    Chao JA, Yoon YJ, Singer RH
    Cold Spring Harbor Perspectives in Biology. 2012 Nov;4(11):. doi: 10.1101/cshperspect.a012310

    The regulation of translation provides a mechanism to control not only the abundance of proteins, but also the precise time and subcellular location that they are synthesized. Much of what is known concerning the molecular basis for translational control has been gleaned from experiments (e.g., luciferase assays and polysome analysis) that measure average changes in the protein synthesis of a population of cells, however, mechanistic insights can be obscured in ensemble measurements. The development of fluorescent microscopy techniques and reagents has allowed translation to be studied within its cellular context. Here we highlight recent methodologies that can be used to study global changes in protein synthesis or regulation of specific mRNAs in single cells. Imaging of translation has provided direct evidence for local translation of mRNAs at synapses in neurons and will become an important tool for studying translational control.

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