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192 Publications

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    10/01/13 | Scaling laws of associative memory retrieval.
    Romani S, Pinkoviezky I, Rubin A, Tsodyks M
    Neural Computation. 2013 Oct;25(10):2523-44. doi: 10.1162/NECO_a_00499

    Most people have great difficulty in recalling unrelated items. For example, in free recall experiments, lists of more than a few randomly selected words cannot be accurately repeated. Here we introduce a phenomenological model of memory retrieval inspired by theories of neuronal population coding of information. The model predicts nontrivial scaling behaviors for the mean and standard deviation of the number of recalled words for lists of increasing length. Our results suggest that associative information retrieval is a dominating factor that limits the number of recalled items.

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    10/01/13 | Structure of fully liganded Hb zeta(2)beta(s)(2) trapped in a tense conformation.
    Safo MK, Ko TP, Abdulmalik O, He ZN, Wang AH, Schreiter ER, Russell JE
    Acta Crystallographica Section D:Biological Crystallography. 2013 Oct;69(Pt 10):2061-71. doi: 10.1107/S0907444913019197

    A variant Hb zeta(2)beta(s)(2) that is formed from sickle hemoglobin (Hb S; alpha(2)beta(s)(2)) by exchanging adult alpha-globin with embryonic zeta-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb zeta(2)beta(s)(2) inhibits the polymerization of deoxygenated Hb S in vitro and reverses characteristic features of SCD in vivo in mouse models of the disorder. When compared with either Hb S or with normal human adult Hb A (alpha(2)beta(2)), Hb zeta(2)beta(s)(2) exhibits atypical properties that include a high oxygen affinity, reduced cooperativity, a weak Bohr effect and blunted 2,3-diphosphoglycerate allostery. Here, the 1.95 angstrom resolution crystal structure of human Hb zeta(2)beta(s)(2) that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb zeta(2)beta(s)(2) displays a central water cavity, a zeta 1-beta(s)2 (or zeta 2-beta(s)1) interface, intersubunit salt-bridge/hydrogen-bond interactions, C-terminal beta His146 salt-bridge interactions, and a beta-cleft, that are highly unusual for a relaxed hemoglobin structure and are more typical of a tense conformation. These quaternary tense-like features contrast with the tertiary relaxed-like conformations of the zeta 1-beta(s1) dimer and the CD and FG corners, as well as the overall structures of the heme cavities. This crystallographic study provides insights into the altered oxygen-transport properties of Hb zeta(2)beta(s)(2) and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.

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    10/09/13 | The genetic causes of convergent evolution.
    Stern DL
    Nature Reviews Genetics. 2013 Oct 9;14(11):751-4. doi: 10.1038/nrg3483advance online publication

    The evolution of phenotypic similarities between species, known as convergence, illustrates that populations can respond predictably to ecological challenges. Convergence often results from similar genetic changes, which can emerge in two ways: the evolution of similar or identical mutations in independent lineages, which is termed parallel evolution; and the evolution in independent lineages of alleles that are shared among populations, which I call collateral genetic evolution. Evidence for parallel and collateral evolution has been found in many taxa, and an emerging hypothesis is that they result from the fact that mutations in some genetic targets minimize pleiotropic effects while simultaneously maximizing adaptation. If this proves correct, then the molecular changes underlying adaptation might be more predictable than has been appreciated previously.

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    Egnor Lab
    09/30/13 | Automated multi-day tracking of marked mice for the analysis of social behaviour.
    Ohayon S, Avni O, Taylor AL, Perona P, Roian Egnor SE
    Journal of Neuroscience Methods. 2013 Sep 30;219(1):10-19. doi: 10.1016/j.jneumeth.2013.05.013

    A quantitative description of animal social behaviour is informative for behavioural biologists and clinicians developing drugs to treat social disorders. Social interaction in a group of animals has been difficult to measure because behaviour develops over long periods of time and requires tedious manual scoring, which is subjective and often non-reproducible. Computer-vision systems with the ability to measure complex social behaviour automatically would have a transformative impact on biology. Here, we present a method for tracking group-housed mice individually as they freely interact over multiple days. Each mouse is bleach-marked with a unique fur pattern. The patterns are automatically learned by the tracking software and used to infer identities. Trajectories are analysed to measure behaviour as it develops over days, beyond the range of acute experiments. We demonstrate how our system may be used to study the development of place preferences, associations and social relationships by tracking four mice continuously for five days. Our system enables accurate and reproducible characterisation of wild-type mouse social behaviour and paves the way for high-throughput long-term observation of the effects of genetic, pharmacological and environmental manipulations.

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    09/30/13 | Mice infer probabilistic models for timing.
    Li Y, Dudman JT
    Proceedings of the National Academy of Sciences of the United States of America. 2013 Sep 30;110(42):17154-9. doi: 10.1073/pnas.1310666110

    Animals learn both whether and when a reward will occur. Neural models of timing posit that animals learn the mean time until reward perturbed by a fixed relative uncertainty. Nonetheless, animals can learn to perform actions for reward even in highly variable natural environments. Optimal inference in the presence of variable information requires probabilistic models, yet it is unclear whether animals can infer such models for reward timing. Here, we develop a behavioral paradigm in which optimal performance required knowledge of the distribution from which reward delays were chosen. We found that mice were able to accurately adjust their behavior to the SD of the reward delay distribution. Importantly, mice were able to flexibly adjust the amount of prior information used for inference according to the moment-by-moment demands of the task. The ability to infer probabilistic models for timing may allow mice to adapt to complex and dynamic natural environments.

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    Baker Lab
    09/27/13 | Male-specific fruitless isoforms have different regulatory roles conferred by distinct zinc finger DNA binding domains.
    Dalton JE, Fear JM, Knott S, Baker BS, McIntyre LM, Arbeitman MN
    BMC Genomics. 2013 Sep 27;14:659. doi: 10.1186/1471-2164-14-659

    BACKGROUND: Drosophila melanogaster adult males perform an elaborate courtship ritual to entice females to mate. fruitless (fru), a gene that is one of the key regulators of male courtship behavior, encodes multiple male-specific isoforms (Fru(M)). These isoforms vary in their carboxy-terminal zinc finger domains, which are predicted to facilitate DNA binding. RESULTS: By over-expressing individual Fru(M) isoforms in fru-expressing neurons in either males or females and assaying the global transcriptional response by RNA-sequencing, we show that three Fru(M) isoforms have different regulatory activities that depend on the sex of the fly. We identified several sets of genes regulated downstream of Fru(M) isoforms, including many annotated with neuronal functions. By determining the binding sites of individual Fru(M) isoforms using SELEX we demonstrate that the distinct zinc finger domain of each Fru(M) isoforms confers different DNA binding specificities. A genome-wide search for these binding site sequences finds that the gene sets identified as induced by over-expression of Fru(M) isoforms in males are enriched for genes that contain the binding sites. An analysis of the chromosomal distribution of genes downstream of Fru(M) shows that those that are induced and repressed in males are highly enriched and depleted on the X chromosome, respectively. CONCLUSIONS: This study elucidates the different regulatory and DNA binding activities of three Fru(M) isoforms on a genome-wide scale and identifies genes regulated by these isoforms. These results add to our understanding of sex chromosome biology and further support the hypothesis that in some cell-types genes with male-biased expression are enriched on the X chromosome.

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    Singer Lab
    09/24/13 | Direct observation of frequency modulated transcription in single cells using light activation.
    Larson DR, Fritzsch C, Sun L, Meng X, Lawrence DS, Singer RH
    eLife. 2013 Sep 24;2:e00750. doi: 10.7554/eLife.00750

    Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single steroid-responsive gene and follow dynamic synthesis of RNA from the activated locus. DOI:

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    09/24/13 | Superresolution imaging with standard fluorescent probes.
    Millis BA, Burnette DT, Lippincott-Schwartz J, Kachar B
    Current protocols in cell biology / editorial board, Juan S. Bonifacino ... [et al.]. 2013;60:Unit 21.8.. doi: 10.1002/0471143030.cb2108s60

    For more than 100 years, the ultimate resolution of a light microscope (∼ 200 nm) has been constrained by the fundamental physical phenomenon of diffraction, as described by Ernst Abbe in 1873. While this limitation is just as applicable to today's light microscopes, it is the combination of high-end optics, clever methods of sample illumination, and computational techniques that has enabled researchers to access information at an order of magnitude greater resolution than once thought possible. This combination, broadly termed superresolution microscopy, has been increasingly practical for many labs to implement from both a hardware and software standpoint, but, as with many cutting-edge techniques, it also comes with limitations. One of the current drawbacks to superresolution microscopy is the limited number of probes and conditions that have been suitable for imaging. Here, a technique termed bleaching/blinking-assisted localization microscopy (BaLM) makes use of the inherent blinking and bleaching properties of almost all fluorophores as a means to generate superresolution images.

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    09/22/13 | Multiple perceptible signals from a single olfactory glomerulus.
    Smear M, Resulaj A, Zhang J, Bozza T, Rinberg D
    Nature Neuroscience. 2013 Sep 22;16(11):1687-91. doi: 10.1038/nn.3519

    Glomeruli are functional units in the olfactory system. The mouse olfactory bulb contains roughly 2,000 glomeruli, each receiving inputs from olfactory sensory neurons (OSNs) that express a specific odorant receptor gene. Odors typically activate many glomeruli in complex combinatorial patterns and it is unknown which features of neuronal activity in individual glomeruli contribute to odor perception. To address this, we used optogenetics to selectively activate single, genetically identified glomeruli in behaving mice. We found that mice could perceive the stimulation of a single glomerulus. Single-glomerulus stimulation was also detected on an intense odor background. In addition, different input intensities and the timing of input relative to sniffing were discriminated through one glomerulus. Our data suggest that each glomerulus can transmit odor information using identity, intensity and temporal coding cues. These multiple modes of information transmission may enable the olfactory system to efficiently identify and localize odor sources.

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    09/19/13 | Extremes of lineage plasticity in the Drosophila brain.
    Lin S, Marin EC, Yang C, Kao C, Apenteng BA, Huang Y, O’Connor MB, Truman JW, Lee T
    Current Biology. 2013 Sep 19;23(19):1908-13. doi: 10.1016/j.cub.2013.07.074

    An often-overlooked aspect of neural plasticity is the plasticity of neuronal composition, in which the numbers of neurons of particular classes are altered in response to environment and experience. The Drosophila brain features several well-characterized lineages in which a single neuroblast gives rise to multiple neuronal classes in a stereotyped sequence during development [1]. We find that in the intrinsic mushroom body neuron lineage, the numbers for each class are highly plastic, depending on the timing of temporal fate transitions and the rate of neuroblast proliferation. For example, mushroom body neuroblast cycling can continue under starvation conditions, uncoupled from temporal fate transitions that depend on extrinsic cues reflecting organismal growth and development. In contrast, the proliferation rates of antennal lobe lineages are closely associated with organismal development, and their temporal fate changes appear to be cell cycle-dependent, such that the same numbers and types of uniglomerular projection neurons innervate the antennal lobe following various perturbations. We propose that this surprising difference in plasticity for these brain lineages is adaptive, given their respective roles as parallel processors versus discrete carriers of olfactory information.

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