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2454 Publications

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    01/01/12 | Design tools for artificial nervous systems.
    Scheffer L
    Design Automation Conference (DAC), 2012 49th ACM/EDAC/IEEE. 2012:

    Electronic and biological systems both perform complex information processing, but they use very different techniques. Though electronics has the advantage in raw speed, biological systems have the edge in many other areas. They can be produced, and indeed self-reproduce, without expensive and finicky factories. They are tolerant of manufacturing defects, and learn and adapt for better performance. In many cases they can self-repair damage. These advantages suggest that biological systems might be useful in a wide variety of tasks involving information processing. So far, all attempts to use the nervous system of a living organism for information processing have involved selective breeding of existing organisms. This approach, largely independent of the details of internal operation, is used since we do not yet understand how neural systems work, nor exactly how they are constructed. However, as our knowledge increases, the day will come when we can envision useful nervous systems and design them based upon what we want them to do, as opposed to variations on what has been already built. We will then need tools, corresponding to our Electronic Design Automation tools, to help with the design. This paper is concerned with what such tools might look like.

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    Baker Lab
    01/01/12 | Doublesex functions early and late in gustatory sense organ development.
    Mellert DJ, Robinett CC, Baker BS
    PLoS One. 2012;7:e51489. doi: 10.1371/journal.pone.0051489

    Somatic sexual dimorphisms outside of the nervous system in Drosophila melanogaster are largely controlled by the male- and female-specific Doublesex transcription factors (DSX(M) and DSX(F), respectively). The DSX proteins must act at the right times and places in development to regulate the diverse array of genes that sculpt male and female characteristics across a variety of tissues. To explore how cellular and developmental contexts integrate with doublesex (dsx) gene function, we focused on the sexually dimorphic number of gustatory sense organs (GSOs) in the foreleg. We show that DSX(M) and DSX(F) promote and repress GSO formation, respectively, and that their relative contribution to this dimorphism varies along the proximodistal axis of the foreleg. Our results suggest that the DSX proteins impact specification of the gustatory sensory organ precursors (SOPs). DSX(F) then acts later in the foreleg to regulate gustatory receptor neuron axon guidance. These results suggest that the foreleg provides a unique opportunity for examining the context-dependent functions of DSX.

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    01/01/12 | Generating neuronal diversity in the Drosophila central nervous system.
    Lin S, Lee T
    Developmental Dynamics: An Official Publication of the American Association of Anatomists. 2012 Jan;241:57-68. doi: 10.1002/dvdy.22739

    Generating diverse neurons in the central nervous system involves three major steps. First, heterogeneous neural progenitors are specified by positional cues at early embryonic stages. Second, neural progenitors sequentially produce neurons or intermediate precursors that acquire different temporal identities based on their birth-order. Third, sister neurons produced during asymmetrical terminal mitoses are given distinct fates. Determining the molecular mechanisms underlying each of these three steps of cellular diversification will unravel brain development and evolution. Drosophila has a relatively simple and tractable CNS, and previous studies on Drosophila CNS development have greatly advanced our understanding of neuron fate specification. Here we review those studies and discuss how the lessons we have learned from fly teach us the process of neuronal diversification in general.

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    01/01/12 | Imaging the post-fusion release and capture of a vesicle membrane protein.
    Sochacki KA, Larson BT, Sengupta DC, Daniels MP, Shtengel G, Hess HF, Taraska JW
    Nature Communications. 2012;3:1154. doi: 10.1038/ncomms2158

    The molecular mechanism responsible for capturing, sorting and retrieving vesicle membrane proteins following triggered exocytosis is not understood. Here we image the post-fusion release and then capture of a vesicle membrane protein, the vesicular acetylcholine transporter, from single vesicles in living neuroendocrine cells. We combine these measurements with super-resolution interferometric photo-activation localization microscopy and electron microscopy, and modelling to map the nanometer-scale topography and architecture of the structures responsible for the transporter’s capture following exocytosis. We show that after exocytosis, the transporter rapidly diffuses into the plasma membrane, but most travels only a short distance before it is locally captured over a dense network of membrane-resident clathrin-coated structures. We propose that the extreme density of these structures acts as a short-range diffusion trap. They quickly sequester diffusing vesicle material and limit its spread across the membrane. This system could provide a means for clathrin-mediated endocytosis to quickly recycle vesicle proteins in highly excitable cells.

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    Magee Lab
    01/01/12 | Ion channel gradients in the apical tuft region of CA1 pyramidal neurons.
    Bittner KC, Andrasfalvy BK, Magee JC
    PLoS one. 2012;7:e46652. doi: 10.1371/journal.pone.0046652

    Dendritic ion channels play a critical role in shaping synaptic input and are fundamentally important for synaptic integration and plasticity. In the hippocampal region CA1, somato-dendritic gradients of AMPA receptors and the hyperpolarization-activated cation conductance (I(h)) counteract the effects of dendritic filtering on the amplitude, time-course, and temporal integration of distal Schaffer collateral (SC) synaptic inputs within stratum radiatum (SR). While ion channel gradients in CA1 distal apical trunk dendrites within SR have been well characterized, little is known about the patterns of ion channel expression in the distal apical tuft dendrites within stratum lacunosum moleculare (SLM) that receive distinct input from the entorhinal cortex via perforant path (PP) axons. Here, we measured local ion channels densities within these distal apical tuft dendrites to determine if the somato-dendritic gradients of I(h) and AMPA receptors extend into distal tuft dendrites. We also determined the densities of voltage-gated sodium channels and NMDA receptors. We found that the densities of AMPA receptors, I(h,) and voltage-gated sodium channels are similar in tuft dendrites in SLM when compared with distal apical dendrites in SR, while the ratio of NMDA receptors to AMPA receptors increases in tuft dendrites relative to distal apical dendrites within SR. These data indicate that the somato-dendritic gradients of I(h) and AMPA receptors in apical dendrites do not extend into the distal tuft, and the relative densities of voltage-gated sodium channels and NMDA receptors are poised to support nonlinear integration of correlated SC and PP input.

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    01/01/12 | Making your database available through Wikipedia: the pros and cons.
    Finn RD, Gardner PP, Bateman A
    Nucleic Acids Research. 2012 Jan;40(Database issue):D9-12. doi: 10.1093/nar/gkr1195

    Wikipedia, the online encyclopedia, is the most famous wiki in use today. It contains over 3.7 million pages of content; with many pages written on scientific subject matters that include peer-reviewed citations, yet are written in an accessible manner and generally reflect the consensus opinion of the community. In this, the 19th Annual Database Issue of Nucleic Acids Research, there are 11 articles that describe the use of a wiki in relation to a biological database. In this commentary, we discuss how biological databases can be integrated with Wikipedia, thereby utilising the pre-existing infrastructure, tools and above all, large community of authors (or Wikipedians). The limitations to the content that can be included in Wikipedia are highlighted, with examples drawn from articles found in this issue and other wiki-based resources, indicating why other wiki solutions are necessary. We discuss the merits of using open wikis, like Wikipedia, versus other models, with particular reference to potential vandalism. Finally, we raise the question about the future role of dedicated database biocurators in context of the thousands of crowdsourced, community annotations that are now being stored in wikis.

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    Magee Lab
    01/01/12 | mGRASP enables mapping mammalian synaptic connectivity with light microscopy.
    Kim J, Zhao T, Petralia RS, Yu Y, Peng H, Myers E, Magee JC
    Nature Methods. 2012 Jan;9:96-102. doi: 10.1038/nmeth.1784

    The GFP reconstitution across synaptic partners (GRASP) technique, based on functional complementation between two nonfluorescent GFP fragments, can be used to detect the location of synapses quickly, accurately and with high spatial resolution. The method has been previously applied in the nematode and the fruit fly but requires substantial modification for use in the mammalian brain. We developed mammalian GRASP (mGRASP) by optimizing transmembrane split-GFP carriers for mammalian synapses. Using in silico protein design, we engineered chimeric synaptic mGRASP fragments that were efficiently delivered to synaptic locations and reconstituted GFP fluorescence in vivo. Furthermore, by integrating molecular and cellular approaches with a computational strategy for the three-dimensional reconstruction of neurons, we applied mGRASP to both long-range circuits and local microcircuits in the mouse hippocampus and thalamocortical regions, analyzing synaptic distribution in single neurons and in dendritic compartments.

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    01/01/12 | Minimizing manual image segmentation turn-around time for neuronal reconstruction by embracing uncertainty.
    Plaza SM, Scheffer LK, Saunders M
    PLoS One. 2012;7:e44448. doi: 10.1371/journal.pone.0044448

    The ability to automatically segment an image into distinct regions is a critical aspect in many visual processing applications. Because inaccuracies often exist in automatic segmentation, manual segmentation is necessary in some application domains to correct mistakes, such as required in the reconstruction of neuronal processes from microscopic images. The goal of the automated segmentation tool is traditionally to produce the highest-quality segmentation, where quality is measured by the similarity to actual ground truth, so as to minimize the volume of manual correction necessary. Manual correction is generally orders-of-magnitude more time consuming than automated segmentation, often making handling large images intractable. Therefore, we propose a more relevant goal: minimizing the turn-around time of automated/manual segmentation while attaining a level of similarity with ground truth. It is not always necessary to inspect every aspect of an image to generate a useful segmentation. As such, we propose a strategy to guide manual segmentation to the most uncertain parts of segmentation. Our contributions include 1) a probabilistic measure that evaluates segmentation without ground truth and 2) a methodology that leverages these probabilistic measures to significantly reduce manual correction while maintaining segmentation quality.

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    01/01/12 | Molecular diversity of Dscam and self-recognition.
    Shi L, Lee T
    Advances in Experimental Medicine and Biology. 2012;739:262-75. doi: 10.1007/978-1-4614-1704-0_17

    Cell recognition requires interactions through molecules located on cell surface. The insect homolog of Down syndrome cell adhesion molecule (Dscam) manifests huge molecular diversity in its extracellular domain. High-affinity Dscam-Dscam interactions only occur between isoforms that carry identical extracellular domains. Homophilic Dscam signaling can, thus, vary in strength depending on the compositions of Dscams present on the opposing cell surfaces. Dscam abundantly exists in the developing nervous system and governs arborization and proper elaboration of neurites. Notably, individual neurons may stochastically and dynamically express a small subset of Dscam isoforms such that any given neurite can be endowed with a unique repertoire of Dscams. This allows individual neurites to recognize their sister branches. Self-recognition leads to self-repulsion, ensuring divergent migration of sister processes. By contrast, weak homophilic Dscam interactions may promote fasciculation of neurites that express analogous, but not identical, Dscams. Differential Dscam binding may provide graded cell recognition that in turn governs complex neuronal morphogenesis.

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    Looger LabSchreiter Lab
    01/01/12 | Neural activity imaging with genetically encoded calcium indicators.
    Tian L, Akerboom J, Schreiter ER, Looger LL
    Progress in Brain Research. 2012;196:79-94. doi: 10.1016/B978-0-444-59426-6.00005-7

    Genetically encoded calcium indicators (GECIs), together with modern microscopy, allow repeated activity measurement, in real time and with cellular resolution, of defined cellular populations. Recent efforts in protein engineering have yielded several high-quality GECIs that facilitate new applications in neuroscience. Here, we summarize recent progress in GECI design, optimization, and characterization, and provide guidelines for selecting the appropriate GECI for a given biological application. We focus on the unique challenges associated with imaging in behaving animals.

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