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1310 Janelia Publications

Showing 21-30 of 1310 results
01/16/18 | Mutual inhibition of lateral inhibition: a network motif for an elementary computation in the brain.
Koyama M, Pujala A
Current Opinion in Neurobiology. 2018 Jan 16;49:69-74. doi: 10.1016/j.conb.2017.12.019

A series of classical studies in non-human primates has revealed the neuronal activity patterns underlying decision-making. However, the circuit mechanisms for such patterns remain largely unknown. Recent detailed circuit analyses in simpler neural systems have started to reveal the connectivity patterns underlying analogous processes. Here we review a few of these systems that share a particular connectivity pattern, namely mutual inhibition of lateral inhibition. Close examination of these systems suggests that this recurring connectivity pattern ('network motif') is a building block to enforce particular dynamics, which can be used not only for simple behavioral choice but also for more complex choices and other brain functions. Thus, a network motif provides an elementary computation that is not specific to a particular brain function and serves as an elementary building block in the brain.

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01/16/18 | Repetitive aggressive encounters generate a long-lasting internal state in Drosophila melanogaster males.
Kim Y, Saver M, Simon J, Kent CF, Shao L, Eddison M, Agrawal P, Texada M, Truman JW, Heberlein U
Proceedings of the National Academy of Sciences of the United States of America. 2018 Jan 16;115(5):1099-104. doi: 10.1073/pnas.1716612115

Multiple studies have investigated the mechanisms of aggressive behavior in Drosophila; however, little is known about the effects of chronic fighting experience. Here, we investigated if repeated fighting encounters would induce an internal state that could affect the expression of subsequent behavior. We trained wild-type males to become winners or losers by repeatedly pairing them with hypoaggressive or hyperaggressive opponents, respectively. As described previously, we observed that chronic losers tend to lose subsequent fights, while chronic winners tend to win them. Olfactory conditioning experiments showed that winning is perceived as rewarding, while losing is perceived as aversive. Moreover, the effect of chronic fighting experience generalized to other behaviors, such as gap-crossing and courtship. We propose that in response to repeatedly winning or losing aggressive encounters, male flies form an internal state that displays persistence and generalization; fight outcomes can also have positive or negative valence. Furthermore, we show that the activities of the PPL1-γ1pedc dopaminergic neuron and the MBON-γ1pedc>α/β mushroom body output neuron are required for aversion to an olfactory cue associated with losing fights.

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01/15/18 | Sub-ångström cryo-EM structure of a prion protofibril reveals a polar clasp.
Gallagher-Jones M, Glynn C, Boyer DR, Martynowycz MW, Hernandez E, Miao J, Zee C, Novikova IV, Goldschmidt L, McFarlane HT, Helguera GF, Evans JE, Sawaya MR, Cascio D, Eisenberg DS, Gonen T, Rodriguez JA
Nature Structural & Molecular Biology. 2018 Jan 15:. doi: 10.1038/s41594-017-0018-0

The atomic structure of the infectious, protease-resistant, β-sheet-rich and fibrillar mammalian prion remains unknown. Through the cryo-EM method MicroED, we reveal the sub-ångström-resolution structure of a protofibril formed by a wild-type segment from the β2-α2 loop of the bank vole prion protein. The structure of this protofibril reveals a stabilizing network of hydrogen bonds that link polar zippers within a sheet, producing motifs we have named 'polar clasps'.

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01/14/18 | Aberrant calcium signaling in astrocytes inhibits neuronal excitability in a human Down syndrome stem cell model.
Tian L, Or G, Wang Y, Shi G, Wang Y, Sun J, Papadopoulos S, Broussard G, Unger E, Deng W, Weick J, Bhattacharyya A, Chen C, Yu G, Looger LL
bioRxiv. 2018 Jan 14:. doi: 10.1101/247585

Down syndrome (DS) is a devastating genetic disorder causing severe cognitive impairment. The staggering array of effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We developed an in vitro system to examine the interplay of neurons and astrocytes in a fully recapitulated HSA21 trisomy model differentiated from DS patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we utilized this system to investigate the functional defects of DS astroglia and their effects on neuronal excitability. We found that, compared with control isogenic astroglia, DS astroglia exhibited more frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. DS astrocytes exerted this effect on both DS and healthy neurons. Neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated astrocyte-neuron signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100β, a calcium binding protein coded on HSA21. Our results suggest a novel mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability. Furthermore, our study establishes an all optical neurophysiological platform for studying human neuron astrocyte interactions associated with neurological disorders.

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01/11/18 | Persistent activity in a recurrent circuit underlies courtship memory in Drosophila.
Zhao X, Lenek D, Dag U, Dickson B, Keleman K
eLife. 2018 Jan 11;7:. doi: 10.7554/eLife.31425

Recurrent connections are thought to be a common feature of the neural circuits that encode memories, but how memories are laid down in such circuits is not fully understood. Here we present evidence that courtship memory in Drosophila relies on the recurrent circuit between mushroom body gamma (MBg), M6 output, and aSP13 dopaminergic neurons. We demonstrate persistent neuronal activity of aSP13 neurons and show that it transiently potentiates synaptic transmission from MBγ>M6 neurons. M6 neurons in turn provide input to aSP13 neurons, prolonging potentiation of MBγ>M6 synapses over time periods that match short-term memory. These data support a model in which persistent aSP13 activity within a recurrent circuit lays the foundation for a short-term memory.

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01/08/18 | Neural substrates of navigational decision-making in Drosophila larva anemotaxis.
Jovanic T, Truman JW, Gershow M, Zlatic M
bioRxiv. 2018 Jan 08:244608. doi: 10.1101/244608

Small animals navigate in the environment as a function of varying sensory information in order to reach more favorable environmental conditions. To achieve this Drosophila larvae alternate periods of runs and turns in gradients of light, temperature, odors and CO2. While the sensory neurons that mediate the navigation behaviors in the different sensory gradients have been described, where and how are these navigational strategies are implemented in the central nervous system and controlled by neuronal circuit elements is not well known. Here we characterize for the first time the navigational strategies of Drosophila larvae in gradients of air-current speeds using high-throughput behavioral assays and quantitative behavioral analysis. We find that larvae extend runs when facing favorable conditions and increase turn rate when facing unfavorable direction, a strategy they use in other sensory modalities as well. By silencing the activity of individual neurons and very sparse expression patterns (2 or 3 neuron types), we further identify the sensory neurons and circuit elements in the ventral nerve cord and brain of the larva required for navigational decisions during anemotaxis. The phenotypes of these central neurons are consistent with a mechanism where the increase of the turning rate in unfavorable conditions and decrease in turning rate in favorable conditions are independently controlled.

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01/08/18 | Simple integration of fast excitation and offset, delayed inhibition computes directional selectivity in Drosophila.
Gruntman E, Romani S, Reiser MB
Nature Neuroscience. 2018 Jan 08;21(2):250-7. doi: 10.1038/s41593-017-0046-4

A neuron that extracts directionally selective motion information from upstream signals lacking this selectivity must compare visual responses from spatially offset inputs. Distinguishing among prevailing algorithmic models for this computation requires measuring fast neuronal activity and inhibition. In the Drosophila melanogaster visual system, a fourth-order neuron-T4-is the first cell type in the ON pathway to exhibit directionally selective signals. Here we use in vivo whole-cell recordings of T4 to show that directional selectivity originates from simple integration of spatially offset fast excitatory and slow inhibitory inputs, resulting in a suppression of responses to the nonpreferred motion direction. We constructed a passive, conductance-based model of a T4 cell that accurately predicts the neuron's response to moving stimuli. These results connect the known circuit anatomy of the motion pathway to the algorithmic mechanism by which the direction of motion is computed.

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01/04/18 | Robust model-based analysis of single-particle tracking experiments with Spot-On.
Hansen AS, Woringer M, Grimm JB, Lavis LD, Tjian R, Darzacq X
eLife. 2018 Jan 04;7:. doi: 10.7554/eLife.33125

Single-particle tracking (SPT) has become an important method to bridge biochemistry and cell biology since it allows direct observation of protein binding and diffusion dynamics in live cells. However, accurately inferring information from SPT studies is challenging due to biases in both data analysis and experimental design. To address analysis bias, we introduce 'Spot-On', an intuitive web-interface. Spot-On implements a kinetic modeling framework that accounts for known biases, including molecules moving out-of-focus, and robustly infers diffusion constants and subpopulations from pooled single-molecule trajectories. To minimize inherent experimental biases, we implement and validate stroboscopic photo-activation SPT (spaSPT), which minimizes motion-blur bias and tracking errors. We validate Spot-On using experimentally realistic simulations and show that Spot-On outperforms other methods. We then apply Spot-On to spaSPT data from live mammalian cells spanning a wide range of nuclear dynamics and demonstrate that Spot-On consistently and robustly infers subpopulation fractions and diffusion constants.

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12/31/17 | A topographic axis of transcriptional identity in thalamus.
Phillips JW, Schulman A, Hara E, Liu C, Shields BC, Korff W, Lemire A, Dudman JT, Nelson SB, Hantman AW
bioRxiv. 2017 Dec 31:241315. doi: 10.1101/241315

A fundamental goal in neuroscience is to uncover common principles by which different modalities of information are processed. In the mammalian brain, thalamus acts as the essential hub for forebrain circuits handling inputs from sensory, motor, limbic, and cognitive pathways. Whether thalamus imposes common transformations on each of these modalities is unknown. Molecular characterization offers a principled approach to revealing the organization of thalamus. Using near-comprehensive and projection-specific transcriptomic sequencing, we found that almost all thalamic nuclei fit into one of three profiles. These profiles lie on a single axis of genetic variance which is aligned with the mediolateral spatial axis of thalamus. Genes defining this axis of variance include receptors and ion channels, providing a systematic diversification of input/output transformations across the topography of thalamus. Single cell transcriptional profiling revealed graded heterogeneity within individual thalamic nuclei, demonstrating that a spectrum of cell types and potentially diverse input/output transforms exist within a given thalamic nucleus. Together, our data argue for an archetypal organization of pathways serving diverse input modalities, and provides a comprehensive organizational scheme for thalamus.

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12/27/17 | Common fibrillar spines of amyloid-β and human Islet Amyloid Polypeptide revealed by Micro Electron Diffraction and inhibitors developed using structure-based design.
Krotee P, Griner SL, Sawaya MR, Cascio D, Rodriguez JA, Shi D, Philipp S, Murray K, Saelices L, Lee J, Seidler P, Glabe CG, Jiang L, Gonen T, Eisenberg DS
The Journal of Biological Chemistry. 2017 Dec 27:. doi: 10.1074/jbc.M117.806109

Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues, and are associated with Alzheimer's disease (AD) and Type-II Diabetes (T2D), respectively. Individuals with T2D have an increased risk of developing AD, and conversely, AD patients have an increased risk of developing T2D. Evidence suggests that this link between AD and T2D might originate from a structural similarity between aggregates of Aβ and hIAPP. Using the cryoEM method Micro-Electron Diffraction (MicroED) we determined the atomic structures of 11-residue segments from both Aβ and hIAPP, termed Aβ 24-34 WT and hIAPP 19-29 S20G, with 64% sequence similarity. We observe a high degree of structural similarity between their backbone atoms (0.96 Å RMSD). Moreover, fibrils of these segments induce amyloid formation through self- and cross-seeding. Furthermore, inhibitors designed for one segment show cross-efficacy for full-length Aβ and hIAPP and reduce cytotoxicity of both proteins, though by apparently blocking different cytotoxic mechanisms. The similarity of the atomic structures of Aβ 24-34 WT and hIAPP 19-29 S20G offers a molecular model for cross-seeding between Aβ and hIAPP.

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