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14 Publications

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    Pastalkova Lab
    08/25/06 | Storage of spatial information by the maintenance mechanism of LTP.
    Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC
    Science. 2006 Aug 25;313(5790):1141-4. doi: 10.1523/JNEUROSCI.3773-10.2011

    Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not previously possible. Recently however, persistent phosphorylation by the atypical protein kinase C isoform, protein kinase Mzeta (PKMz), has been found to maintain late LTP in hippocampal slices. Here we show that a cell-permeable PKMz inhibitor, injected in the rat hippocampus, both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, the mechanism maintaining LTP sustains spatial memory.

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    Zuker Lab
    08/24/06 | The cells and logic for mammalian sour taste detection.
    Huang AL, Chen X, Hoon MA, Chandrashekar J, Guo W, Tränkner D, Ryba NJ, Zuker CS
    Nature. 2006 Aug 24;442(7105):934-8. doi: 10.1038/nature05084

    Mammals taste many compounds yet use a sensory palette consisting of only five basic taste modalities: sweet, bitter, sour, salty and umami (the taste of monosodium glutamate). Although this repertoire may seem modest, it provides animals with critical information about the nature and quality of food. Sour taste detection functions as an important sensory input to warn against the ingestion of acidic (for example, spoiled or unripe) food sources. We have used a combination of bioinformatics, genetic and functional studies to identify PKD2L1, a polycystic-kidney-disease-like ion channel, as a candidate mammalian sour taste sensor. In the tongue, PKD2L1 is expressed in a subset of taste receptor cells distinct from those responsible for sweet, bitter and umami taste. To examine the role of PKD2L1-expressing taste cells in vivo, we engineered mice with targeted genetic ablations of selected populations of taste receptor cells. Animals lacking PKD2L1-expressing cells are completely devoid of taste responses to sour stimuli. Notably, responses to all other tastants remained unaffected, proving that the segregation of taste qualities even extends to ionic stimuli. Our results now establish independent cellular substrates for four of the five basic taste modalities, and support a comprehensive labelled-line mode of taste coding at the periphery. Notably, PKD2L1 is also expressed in specific neurons surrounding the central canal of the spinal cord. Here we demonstrate that these PKD2L1-expressing neurons send projections to the central canal, and selectively trigger action potentials in response to decreases in extracellular pH. We propose that these cells correspond to the long-sought components of the cerebrospinal fluid chemosensory system. Taken together, our results suggest a common basis for acid sensing in disparate physiological settings.

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    08/23/06 | Nud1p, the yeast homolog of Centriolin, regulates spindle pole body inheritance in meiosis.
    Gordon O, Taxis C, Keller PJ, Benjak A, Stelzer EH, Simchen G, Knop M
    The EMBO Journal. 2006 Aug 23;25(16):3856-68. doi: 10.1038/sj.emboj.7601254

    Nud1p, a protein homologous to the mammalian centrosome and midbody component Centriolin, is a component of the budding yeast spindle pole body (SPB), with roles in anchorage of microtubules and regulation of the mitotic exit network during vegetative growth. Here we analyze the function of Nud1p during yeast meiosis. We find that a nud1-2 temperature-sensitive mutant has two meiosis-related defects that reflect genetically distinct functions of Nud1p. First, the mutation affects spore formation due to its late function during spore maturation. Second, and most important, the mutant loses its ability to distinguish between the ages of the four spindle pole bodies, which normally determine which SPB would be preferentially included in the mature spores. This affects the regulation of genome inheritance in starved meiotic cells and leads to the formation of random dyads instead of non-sister dyads under these conditions. Both functions of Nud1p are connected to the ability of Spc72p to bind to the outer plaque and half-bridge (via Kar1p) of the SPB.

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    08/23/06 | Sparse odor coding in awake behaving mice.
    Rinberg D, Koulakov A, Gelperin A
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2006 Aug 23;26(34):8857-65. doi: 10.1523/JNEUROSCI.3613-08.2008

    Responses of mitral cells represent the results of the first stage of odor processing in the olfactory bulb. Most of our knowledge about mitral cell activity has been obtained from recordings in anesthetized animals. We compared odor-elicited changes in firing rate of mitral cells in awake behaving mice and in anesthetized mice. We show that odor-elicited changes in mitral cell firing rate were larger and more frequently observed in the anesthetized than in the awake condition. Only 27% of mitral cells that showed a response to odors in the anesthetized state were also odor responsive in the awake state. The amplitude of their response in the awake state was smaller, and some of the responses changed sign compared with their responses in the anesthetized state. The odor representation in the olfactory bulb is therefore sparser in awake behaving mice than in anesthetized preparations. A qualitative explanation of the mechanism responsible for this phenomenon is proposed.

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    08/17/06 | Encoding and decoding of overlapping odor sequences.
    Broome BM, Jayaraman V, Laurent G
    Neuron. 2006 Aug 17;51(4):467-82. doi: 10.1016/j.neuron.2006.07.018

    Odors evoke complex responses in locust antennal lobe projection neurons (PNs)-the mitral cell analogs. These patterns evolve over hundreds of milliseconds and contain information about odor identity and concentration. In nature, animals often encounter many odorants in short temporal succession. We explored the effects of such conditions by presenting two different odors with variable intervening delays. PN ensemble representations tracked stimulus changes and, in some delay conditions, reached states that corresponded neither to the representation of either odor alone nor to the static mixture of the two. We then recorded from Kenyon cells (KCs), the PNs’ targets. Their responses were consistent with the PN population’s behavior: in some conditions, KCs were recruited that did not fire during single-odor or mixture stimuli. Thus, PN population dynamics are history dependent, and responses of individual KCs are consistent with piecewise temporal decoding of PN output over large sections of the PN population.

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    08/17/06 | Whole-cell recordings in freely moving rats.
    Lee AK, Manns ID, Sakmann B, Brecht M
    Neuron. 2006 Aug 17;51:399-407. doi: 10.1016/j.neuron.2006.07.004

    Intracellular recording, which allows direct measurement of the membrane potential and currents of individual neurons, requires a very mechanically stable preparation and has thus been limited to in vitro and head-immobilized in vivo experiments. This restriction constitutes a major obstacle for linking cellular and synaptic physiology with animal behavior. To overcome this limitation we have developed a method for performing whole-cell recordings in freely moving rats. We constructed a miniature head-mountable recording device, with mechanical stabilization achieved by anchoring the recording pipette rigidly in place after the whole-cell configuration is established. We obtain long-duration recordings (mean of approximately 20 min, maximum 60 min) in freely moving animals that are remarkably insensitive to mechanical disturbances, then reconstruct the anatomy of the recorded cells. This head-anchored whole-cell recording technique will enable a wide range of new studies involving detailed measurement and manipulation of the physiological properties of identified cells during natural behaviors.

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    Tjian Lab
    08/15/06 | TAF4 nucleates a core subcomplex of TFIID and mediates activated transcription from a TATA-less promoter.
    Wright KJ, Marr MT, Tjian R
    Proceedings of the National Academy of Sciences of the United States of America. 2006 Aug 15;103(33):12347-52. doi: 10.1073/pnas.1100640108

    Activator-dependent recruitment of TFIID initiates formation of the transcriptional preinitiation complex. TFIID binds core promoter DNA elements and directs the assembly of other general transcription factors, leading to binding of RNA polymerase II and activation of RNA synthesis. How TATA box-binding protein (TBP) and the TBP-associated factors (TAFs) are assembled into a functional TFIID complex with promoter recognition and coactivator activities in vivo remains unknown. Here, we use RNAi to knock down specific TFIID subunits in Drosophila tissue culture cells to determine which subunits are most critical for maintaining stability of TFIID in vivo. Contrary to expectations, we find that TAF4 rather than TBP or TAF1 plays the most critical role in maintaining stability of the complex. Our analysis also indicates that TAF5, TAF6, TAF9, and TAF12 play key roles in stability of the complex, whereas TBP, TAF1, TAF2, and TAF11 contribute very little to complex stability. Based on our results, we propose that holo-TFIID comprises a stable core subcomplex containing TAF4, TAF5, TAF6, TAF9, and TAF12 decorated with peripheral subunits TAF1, TAF2, TAF11, and TBP. Our initial functional studies indicate a specific and significant role for TAF1 and TAF4 in mediating transcription from a TATA-less, downstream core promoter element (DPE)-containing promoter, whereas a TATA-containing, DPE-less promoter was far less dependent on these subunits. In contrast to both TAF1 and TAF4, RNAi knockdown of TAF5 had little effect on transcription from either class of promoter. These studies significantly alter previous models for the assembly, structure, and function of TFIID.

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    Tjian Lab
    08/10/06 | An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.
    Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun Z, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Näär AM
    Nature. 2006 Aug 10;442(7103):700-4. doi: 10.1073/pnas.1100640108

    The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis. We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms. Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes. We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15, including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.

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    08/03/06 | Speed-accuracy tradeoff in olfaction.
    Rinberg D, Koulakov A, Gelperin A
    Neuron. 2006 Aug 3;51(3):351-8. doi: 10.1523/JNEUROSCI.3613-08.2008

    The basic psychophysical principle of speed-accuracy tradeoff (SAT) has been used to understand key aspects of neuronal information processing in vision and audition, but the principle of SAT is still debated in olfaction. In this study we present the direct observation of SAT in olfaction. We developed a behavioral paradigm for mice in which both the duration of odorant sampling and the difficulty of the odor discrimination task were controlled by the experimenter. We observed that the accuracy of odor discrimination increases with the duration of imposed odorant sampling, and that the rate of this increase is slower for harder tasks. We also present a unifying picture of two previous, seemingly disparate experiments on timing of odorant sampling in odor discrimination tasks. The presence of SAT in olfaction provides strong evidence for temporal integration in olfaction and puts a constraint on models of olfactory processing.

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    08/03/06 | When good enough is best.
    Kay LM, Beshel J, Martin C
    Neuron. 2006 Aug 3;51:277-8. doi: 10.1523/JNEUROSCI.3613-08.2008

    In this issue of Neuron, Rinberg et al. show that mice use a speed-accuracy tradeoff in odor discrimination. Shorter sampling results in high performance for easy problems, and enforced longer sampling results in higher accuracy for difficult problems, but mice freely choose intermediate sampling durations and accuracy varies with difficulty. Reward value and task requirements may determine sampling time choice and performance levels.

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