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14 Janelia Publications

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    10/29/20 | The Statistical Structure of the Hippocampal Code for Space as a Function of Time, Context, and Value.
    Lee JS, Briguglio JJ, Cohen JD, Romani S, Lee AK
    Cell. 2020 Oct 29;183(3):620-35. doi: 10.1016/j.cell.2020.09.024

    Hippocampal activity represents many behaviorally important variables, including context, an animal's location within a given environmental context, time, and reward. Using longitudinal calcium imaging in mice, multiple large virtual environments, and differing reward contingencies, we derived a unified probabilistic model of CA1 representations centered on a single feature-the field propensity. Each cell's propensity governs how many place fields it has per unit space, predicts its reward-related activity, and is preserved across distinct environments and over months. Propensity is broadly distributed-with many low, and some very high, propensity cells-and thus strongly shapes hippocampal representations. This results in a range of spatial codes, from sparse to dense. Propensity varied ∼10-fold between adjacent cells in salt-and-pepper fashion, indicating substantial functional differences within a presumed cell type. Intracellular recordings linked propensity to cell excitability. The stability of each cell's propensity across conditions suggests this fundamental property has anatomical, transcriptional, and/or developmental origins.

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    10/23/20 | A post-invasion role for type III effector TarP in modulating the dynamics and organization of host cell focal adhesions.
    Pedrosa AT, Murphy KN, Nogueira AT, Brinkworth AJ, Thwaites TR, Aaron J, Chew T, Carabeo RA
    Journal of Biological Chemistry. 2020 Oct 23;295(43):14763-14779. doi: 10.1074/jbc.RA120.015219

    The human pathogen targets epithelial cells lining the genital mucosa. We observed that infection of various cell types, including fibroblasts and epithelial cells resulted in the formation of unusually stable and mature focal adhesions that resisted disassembly induced by the myosin II inhibitor, blebbistatin. Super-resolution microscopy revealed in infected cells the vertical displacement of paxillin and FAK from the signaling layer of focal adhesions; while vinculin remained in its normal position within the force transduction layer. The candidate type III effector TarP which localized to focal adhesions during infection and when expressed ectopically, was sufficient to mimic both the reorganization and blebbistatin-resistant phenotypes. These effects of TarP, including its localization to focal adhesions, required a post-invasion interaction with the host protein vinculin through a specific domain at the C-terminus of TarP. This interaction is repurposed from an actin-recruiting and -remodeling complex to one that mediates nano-architectural and dynamic changes of focal adhesions. The consequence of -stabilized focal adhesions was restricted cell motility and enhanced attachment to the extracellular matrix. Thus, via a novel mechanism, inserts TarP within focal adhesions to alter their organization and stability.

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    10/19/20 | A geometric framework to predict structure from function in neural networks
    Biswas T, Fitzgerald JE
    arXiv. 2020 Oct 19:

    Neural computation in biological and artificial networks relies on nonlinear synaptic integration. The structural connectivity matrix of synaptic weights between neurons is a critical determinant of overall network function. However, quantitative links between neural network structure and function are complex and subtle. For example, many networks can give rise to similar functional responses, and the same network can function differently depending on context. Whether certain patterns of synaptic connectivity are required to generate specific network-level computations is largely unknown. Here we introduce a geometric framework for identifying synaptic connections required by steady-state responses in recurrent networks of rectified-linear neurons. Assuming that the number of specified response patterns does not exceed the number of input synapses, we analytically calculate all feedforward and recurrent connectivity matrices that can generate the specified responses from the network inputs. We then use this analytical characterization to rigorously analyze the solution space geometry and derive certainty conditions guaranteeing a non-zero synapse between neurons. Numerical simulations of feedforward and recurrent networks verify our analytical results. Our theoretical framework could be applied to neural activity data to make anatomical predictions that follow generally from the model architecture. It thus provides novel opportunities for discerning what model features are required to accurately relate neural network structure and function.

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    10/23/20 | Brain-wide, scale-wide physiology underlying behavioral flexibility in zebrafish.
    Mu Y, Narayan S, Mensh BD, Ahrens MB
    Current Opinion in Neurobiology. 2020 Oct 19;64:151-160. doi: 10.1016/j.conb.2020.08.013

    The brain is tasked with choosing actions that maximize an animal's chances of survival and reproduction. These choices must be flexible and informed by the current state of the environment, the needs of the body, and the outcomes of past actions. This information is physiologically encoded and processed across different brain regions on a wide range of spatial scales, from molecules in single synapses to networks of brain areas. Uncovering these spatially distributed neural interactions underlying behavior requires investigations that span a similar range of spatial scales. Larval zebrafish, given their small size, transparency, and ease of genetic access, are a good model organism for such investigations, allowing the use of modern microscopy, molecular biology, and computational techniques. These approaches are yielding new insights into the mechanistic basis of behavioral states, which we review here and compare to related studies in mammalian species.

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    10/16/20 | Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles.
    Xu S, Yang H, Menon V, Lemire AL, Wang L, Henry FE, Turaga SC, Sternson SM
    Science. 2020 Oct 16;370(6514):. doi: 10.1126/science.abb2494

    Brains encode behaviors using neurons amenable to systematic classification by gene expression. The contribution of molecular identity to neural coding is not understood because of the challenges involved with measuring neural dynamics and molecular information from the same cells. We developed CaRMA (calcium and RNA multiplexed activity) imaging based on recording in vivo single-neuron calcium dynamics followed by gene expression analysis. We simultaneously monitored activity in hundreds of neurons in mouse paraventricular hypothalamus (PVH). Combinations of cell-type marker genes had predictive power for neuronal responses across 11 behavioral states. The PVH uses combinatorial assemblies of molecularly defined neuron populations for grouped-ensemble coding of survival behaviors. The neuropeptide receptor neuropeptide Y receptor type 1 (Npy1r) amalgamated multiple cell types with similar responses. Our results show that molecularly defined neurons are important processing units for brain function.

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    10/16/20 | Robotic Multi-Probe-Single-Actuator Inchworm Neural Microdrive
    Smith R, Kolb I, Tanaka S, Lee A, Harris T, Barbic M
    bioRxiv. 2020 Oct 16:

    Electrophysiology is one of the major experimental techniques used in neuroscience. The favorable spatial and temporal resolution as well as the increasingly larger site counts of brain recording electrodes contribute to the popularity and importance of electrophysiology in neuroscience. Such electrodes are typically mechanically placed in the brain to perform acute or chronic freely moving animal measurements. The micro positioners currently used for such tasks employ a single translator per independent probe being placed into the targeted brain region, leading to significant size and weight restrictions. To overcome this limitation, we have developed a miniature robotic multi-probe neural microdrive that utilizes novel phase-change-material-filled resistive heater micro-grippers. The microscopic dimensions, gentle gripping action, independent electronic actuation control, and high packing density of the grippers allow for micrometer-precision independent positioning of multiple arbitrarily shaped parallel neural electrodes with only a single piezo actuator in an inchworm motor configuration. This multi-probe-single-actuator design allows for significant size and weight reduction, as well as remote control and potential automation of the microdrive. We demonstrate accurate placement of multiple independent recording electrodes into the CA1 region of the rat hippocampus in vivo in acute and chronic settings. Thus, our robotic neural microdrive technology is applicable towards basic neuroscience and clinical studies, as well as other multi-probe or multi-sensor micro-positioning applications.

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    10/14/20 | The neuroanatomical ultrastructure and function of a biological ring attractor.
    Turner-Evans DB, Jensen KT, Ali S, Paterson T, Sheridan A, Ray RP, Wolff T, Lauritzen JS, Rubin GM, Bock DD, Jayaraman V
    Neuron. 2020 Oct 14;108(1):145-63. doi: 10.1016/j.neuron.2020.08.006

    Neural representations of head direction (HD) have been discovered in many species. Theoretical work has proposed that the dynamics associated with these representations are generated, maintained, and updated by recurrent network structures called ring attractors. We evaluated this theorized structure-function relationship by performing electron-microscopy-based circuit reconstruction and RNA profiling of identified cell types in the HD system of Drosophila melanogaster. We identified motifs that have been hypothesized to maintain the HD representation in darkness, update it when the animal turns, and tether it to visual cues. Functional studies provided support for the proposed roles of individual excitatory or inhibitory circuit elements in shaping activity. We also discovered recurrent connections between neuronal arbors with mixed pre- and postsynaptic specializations. Our results confirm that the Drosophila HD network contains the core components of a ring attractor while also revealing unpredicted structural features that might enhance the network's computational power.

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    10/06/20 | Nuclear crowding and nonlinear diffusion during interkinetic nuclear migration in the zebrafish retina.
    Azizi A, Herrmann A, Wan Y, Buse SJ, Keller PJ, Goldstein RE, Harris WA
    eLife. 2020 Oct 06;9:. doi: 10.7554/eLife.58635

    An important question in early neural development is the origin of stochastic nuclear movement between apical and basal surfaces of neuroepithelia during interkinetic nuclear migration. Tracking of nuclear subpopulations has shown evidence of diffusion - mean squared displacements growing linearly in time - and suggested crowding from cell division at the apical surface drives basalward motion. Yet, this hypothesis has not yet been tested, and the forces involved not quantified. We employ long-term, rapid light-sheet and two-photon imaging of early zebrafish retinogenesis to track entire populations of nuclei within the tissue. The time-varying concentration profiles show clear evidence of crowding as nuclei reach close-packing and are quantitatively described by a nonlinear diffusion model. Considerations of nuclear motion constrained inside the enveloping cell membrane show that concentration-dependent stochastic forces inside cells, compatible in magnitude to those found in cytoskeletal transport, can explain the observed magnitude of the diffusion constant.

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    10/06/20 | Simultaneous computation of dynamical and equilibrium information using a weighted ensemble of trajectories
    Suarez E, Lettieri S, Stringer CA, Zwier MC, Subramanian SR, Chong LT, Zuckerman DM
    Journal of chemical theory and computation;10:2658–2667
    10/06/20 | Simultaneous computation of dynamical and equilibrium information using a weighted ensemble of trajectories
    Suarez E, Lettieri S, Stringer CA, Zwier MC, Subramanian SR, Chong LT, Zuckerman DM
    Journal of chemical theory and computation;10:2658–2667