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1404 Publications

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    06/21/19 | High precision coding in visual cortex
    Stringer C, Michaelos M, Pachitariu M
    BioRxiv. 06/2019:679324. doi: https://doi.org/10.1101/679324

    Single neurons in visual cortex provide unreliable measurements of visual features due to their high trial-to-trial variability. It is not known if this “noise” extends its effects over large neural populations to impair the global encoding of sensory stimuli. We recorded simultaneously from ∼20,000 neurons in mouse visual cortex and found that the neural population had discrimination thresholds of 0.3° in an orientation decoding task. These thresholds are ∼100 times smaller than those reported behaviorally in mice. The discrepancy between neural and behavioral discrimination could not be explained by the types of stimuli we used, by behavioral states or by the sequential nature of trial-by-trial perceptual learning tasks. These results imply that the limits of sensory perception in mice are not set by neural noise in sensory cortex, but by the limitations of downstream decoders.

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    06/10/19 | Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis
    Yamada KM, Collins JW, Cruz Walma DA, Doyle AD, Morales SG, Lu J, Matsumoto K, Nazari SS, Sekiguchi R, Shinsato Y, Wang S
    International Journal of Experimental Pathology. 06/2019;100:144-152. doi: https://doi.org/10.1111/iep.12329

    Summary This review describes how direct visualization of the dynamic interactions of cells with different extracellular matrix microenvironments can provide novel insights into complex biological processes. Recent studies have moved characterization of cell migration and invasion from classical 2D culture systems into 1D and 3D model systems, revealing multiple differences in mechanisms of cell adhesion, migration and signalling—even though cells in 3D can still display prominent focal adhesions. Myosin II restrains cell migration speed in 2D culture but is often essential for effective 3D migration. 3D cell migration modes can switch between lamellipodial, lobopodial and/or amoeboid depending on the local matrix environment. For example, “nuclear piston” migration can be switched off by local proteolysis, and proteolytic invadopodia can be induced by a high density of fibrillar matrix. Particularly, complex remodelling of both extracellular matrix and tissues occurs during morphogenesis. Extracellular matrix supports self-assembly of embryonic tissues, but it must also be locally actively remodelled. For example, surprisingly focal remodelling of the basement membrane occurs during branching morphogenesis—numerous tiny perforations generated by proteolysis and actomyosin contractility produce a microscopically porous, flexible basement membrane meshwork for tissue expansion. Cells extend highly active blebs or protrusions towards the surrounding mesenchyme through these perforations. Concurrently, the entire basement membrane undergoes translocation in a direction opposite to bud expansion. Underlying this slowly moving 2D basement membrane translocation are highly dynamic individual cell movements. We conclude this review by describing a variety of exciting research opportunities for discovering novel insights into cell-matrix interactions.

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    05/29/19 | Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons
    Engelhard B, Finkelstein J, Cox J, Fleming W, Jang HJ, Ornelas S, Koay SA, Thiberge SY, Daw ND, Tank DW, Witten IB
    Nature. 05/2019;570(7762):509 - 513. doi: 10.1038/s41586-019-1261-9

    There is increased appreciation that dopamine neurons in the midbrain respond not only to reward1 and reward-predicting cues1,2, but also to other variables such as the distance to reward3, movements4,5,6,7,8,9 and behavioural choices10,11. An important question is how the responses to these diverse variables are organized across the population of dopamine neurons. Whether individual dopamine neurons multiplex several variables, or whether there are subsets of neurons that are specialized in encoding specific behavioural variables remains unclear. This fundamental question has been difficult to resolve because recordings from large populations of individual dopamine neurons have not been performed in a behavioural task with sufficient complexity to examine these diverse variables simultaneously. Here, to address this gap, we used two-photon calcium imaging through an implanted lens to record the activity of more than 300 dopamine neurons from the ventral tegmental area of the mouse midbrain during a complex decision-making task. As mice navigated in a virtual-reality environment, dopamine neurons encoded an array of sensory, motor and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioural variables, in addition to encoding reward. These functional clusters were spatially organized, with neighbouring neurons more likely to be part of the same cluster. Together with the topography between dopamine neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by dopamine neurons.

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    04/11/19 | A high-content imaging approach to profile C. elegans embryonic development
    Wang S, Ochoa SD, Khaliullin RN, Gerson-Gurwitz A, Hendel JM, Zhao Z, Biggs R, Chisholm AD, Desai A, Oegema K, Green RA
    Development. 04-2019;146:. doi: 10.1242/dev.174029

    The Caenorhabditis elegans embryo is an important model for analyzing mechanisms of cell fate specification and tissue morphogenesis. Sophisticated lineage-tracing approaches for analyzing embryogenesis have been developed but are labor intensive and do not naturally integrate morphogenetic readouts. To enable the rapid classification of developmental phenotypes, we developed a high-content method that employs two custom strains: a Germ Layer strain that expresses nuclear markers in the ectoderm, mesoderm and endoderm/pharynx; and a Morphogenesis strain that expresses markers labeling epidermal cell junctions and the neuronal cell surface. We describe a procedure that allows simultaneous live imaging of development in 80-100 embryos and provide a custom program that generates cropped, oriented image stacks of individual embryos to facilitate analysis. We demonstrate the utility of our method by perturbing 40 previously characterized developmental genes in variants of the two strains containing RNAi-sensitizing mutations. The resulting datasets yielded distinct, reproducible signature phenotypes for a broad spectrum of genes that are involved in cell fate specification and morphogenesis. In addition, our analysis provides new in vivo evidence for MBK-2 function in mesoderm fate specification and LET-381 function in elongation.

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    04/01/19 | Neuronal Transdifferentiation Potential of Human Mesenchymal Stem Cells from Neonatal and Adult Sources by a Small Molecule Cocktail.
    Cortés-Medina LV, Pasantes-Morales H, Aguilera-Castrejon A, Picones A, Lara-Figueroa CO, Luis E, Montesinos JJ, Cortés-Morales VA, De la Rosa Ruiz MP, Hernández-Estévez E, Bonifaz LC, Alvarez-Perez MA, Ramos-Mandujano G
    Stem Cells Int. 04/2019;2019:7627148. doi: 10.1155/2019/7627148

    Human mesenchymal stem cells (MSCs) are good candidates for brain cell replacement strategies and have already been used as adjuvant treatments in neurological disorders. MSCs can be obtained from many different sources, and the present study compares the potential of neuronal transdifferentiation in MSCs from adult and neonatal sources (Wharton's jelly (WhJ), dental pulp (DP), periodontal ligament (PDL), gingival tissue (GT), dermis (SK), placenta (PLAC), and umbilical cord blood (UCB)) with a protocol previously tested in bone marrow- (BM-) MSCs consisting of a cocktail of six small molecules: I-BET151, CHIR99021, forskolin, RepSox, Y-27632, and dbcAMP (ICFRYA). Neuronal morphology and the presence of cells positive for neuronal markers (TUJ1 and MAP2) were considered attributes of neuronal induction. The ICFRYA cocktail did not induce neuronal features in WhJ-MSCs, and these features were only partial in the MSCs from dental tissues, SK-MSCs, and PLAC-MSCs. The best response was found in UCB-MSCs, which was comparable to the response of BM-MSCs. The addition of neurotrophic factors to the ICFRYA cocktail significantly increased the number of cells with complex neuron-like morphology and increased the number of cells positive for mature neuronal markers in BM- and UCB-MSCs. The neuronal cells generated from UCB-MSCs and BM-MSCs showed increased reactivity of the neuronal genes TUJ1, MAP2, NF-H, NCAM, ND1, TAU, ENO2, GABA, and NeuN as well as down- and upregulation of MSC and neuronal genes, respectively. The present study showed marked differences between the MSCs from different sources in response to the transdifferentiation protocol used here. These results may contribute to identifying the best source of MSCs for potential cell replacement therapies.

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    03/25/19 | The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis
    Dhanya K. Cheerambathur , Bram Prevo , Tiffany-Lynn Chow , Neil Hattersley , Shaohe Wang , Zhiling Zhao , Taekyung Kim , Adina Gerson-Gurwitz , Karen Oegema , Rebecca Green , Arshad Desai
    Developmental Cell. 03/2019;48:864-872.e7. doi: https://doi.org/10.1016/j.devcel.2019.02.002

    Summary Dynamic coupling of microtubule ends to kinetochores, built on the centromeres of chromosomes, directs chromosome segregation during cell division. Here, we report that the evolutionarily ancient kinetochore-microtubule coupling machine, the KMN (Knl1/Mis12/Ndc80-complex) network, plays a critical role in neuronal morphogenesis. We show that the KMN network concentrates in microtubule-rich dendrites of developing sensory neurons that collectively extend in a multicellular morphogenetic event that occurs during C. elegans embryogenesis. Post-mitotic degradation of KMN components in sensory neurons disrupts dendritic extension, leading to patterning and functional defects in the sensory nervous system. Structure-guided mutations revealed that the molecular interface that couples kinetochores to spindle microtubules also functions in neuronal development. These results identify a cell-division-independent function for the chromosome-segregation machinery and define a microtubule-coupling-dependent event in sensory nervous system morphogenesis.

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    03/25/19 | The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins
    Malaker SA, Pedram K, Ferracane MJ, Bensing BA, Krishnan V, Pett C, Yu J, Woods EC, Kramer JR, Westerlind U, Dorigo O, Bertozzi CR
    Proceedings of the National Academy of Sciences. Sep-04-2019;116(15):7278 - 7287. doi: 10.1073/pnas.1813020116

    Mucin domains are densely O-glycosylated modular protein domains that are found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins are known to be key players in a host of human diseases, especially cancer, wherein mucin expression and glycosylation patterns are altered. Mucin biology has been difficult to study at the molecular level, in part, because methods to manipulate and structurally characterize mucin domains are lacking. Here, we demonstrate that secreted protease of C1 esterase inhibitor (StcE), a bacterial protease from Escherichia coli, cleaves mucin domains by recognizing a discrete peptide- and glycan-based motif. We exploited StcE's unique properties to improve sequence coverage, glycosite mapping, and glycoform analysis of recombinant human mucins by mass spectrometry. We also found that StcE digests cancer-associated mucins from cultured cells and from ascites fluid derived from patients with ovarian cancer. Finally, using StcE, we discovered that sialic acid-binding Ig-type lectin-7 (Siglec-7), a glycoimmune checkpoint receptor, selectively binds sialomucins as biological ligands, whereas the related receptor Siglec-9 does not. Mucin-selective proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of mucin domain structure and function.

     

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    Studies of perceptual decision-making have often assumed that the main role of sensory cortices is to provide sensory input to downstream processes that accumulate and drive behavioral decisions. We performed a systematic comparison of neural activity in primary visual (V1) to secondary visual and retrosplenial cortices, as mice performed a task where they should accumulate pulsatile visual cues through time to inform a navigational decision. Even in V1, only a small fraction of neurons had sensory-like responses to cues. Instead, in all areas neurons were sequentially active, and contained information ranging from sensory to cognitive, including cue timings, evidence, place/time, decision and reward outcome. Per-cue sensory responses were amplitude-modulated by various cognitive quantities, notably accumulated evidence. This inspired a multiplicative feedback-loop circuit hypothesis that proposes a more intricate role of sensory areas in the accumulation process, and furthermore explains a surprising observation that perceptual discrimination deviates from Weber-Fechner Law.Highlights / eTOC BlurbMice made navigational decisions based on accumulating pulsatile visual cuesThe bulk of neural activity in visual cortices was sequential and beyond-sensoryAccumulated pulse-counts modulated sensory (cue) responses, suggesting feedbackA feedback-loop neural circuit explains behavioral deviations from Weber’s LawHighlights / eTOC BlurbIn a task where navigation was informed by accumulated pulsatile visual evidence, neural activity in visual cortices predominantly coded for cognitive variables across multiple timescales, including outside of a visual processing context. Even sensory responses to visual pulses were amplitude-modulated by accumulated pulse counts and other variables, inspiring a multiplicative feedback-loop circuit hypothesis that in turn explained behavioral deviations from Weber-Fechner Law.

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    02/07/19 | Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules.
    Zviran A, Mor N, Rais Y, Gingold H, Peles S, Chomsky E, Viukov S, Buenrostro JD, Scognamiglio R, Weinberger L, Manor YS, Krupalnik V, Zerbib M, Hezroni H, Jaitin DA, Larastiaso D, Gilad S, Benjamin S, Gafni O, Mousa A, Ayyash M, Sheban D, Bayerl J, Aguilera-Castrejon A, Massarwa R, Maza I, Hanna S, Stelzer Y, Ulitsky I, Greenleaf WJ, Tanay A, Trumpp A, Amit I, Pilpel Y, Novershtern N, Hanna JH
    Cell Stem Cell. 02/2019;24(2):328-341.e9. doi: 10.1016/j.stem.2018.11.014

    The epigenetic dynamics of induced pluripotent stem cell (iPSC) reprogramming in correctly reprogrammed cells at high resolution and throughout the entire process remain largely undefined. Here, we characterize conversion of mouse fibroblasts into iPSCs using Gatad2a-Mbd3/NuRD-depleted and highly efficient reprogramming systems. Unbiased high-resolution profiling of dynamic changes in levels of gene expression, chromatin engagement, DNA accessibility, and DNA methylation were obtained. We identified two distinct and synergistic transcriptional modules that dominate successful reprogramming, which are associated with cell identity and biosynthetic genes. The pluripotency module is governed by dynamic alterations in epigenetic modifications to promoters and binding by Oct4, Sox2, and Klf4, but not Myc. Early DNA demethylation at certain enhancers prospectively marks cells fated to reprogram. Myc activity drives expression of the essential biosynthetic module and is associated with optimized changes in tRNA codon usage. Our functional validations highlight interweaved epigenetic- and Myc-governed essential reconfigurations that rapidly commission and propel deterministic reprogramming toward naive pluripotency.

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    Darshan Lab
    02/01/19 | Neuronal activity and learning in local cortical networks are modulated by the action-perception state
    Ben Engelhard , Ran Darshan , Nofar Ozeri-Engelhard , Zvi Israel , Uri Werner-Reiss , David Hansel , Hagai Bergman , Eilon Vaadia
    bioRxiv. 2019 Feb 01:. doi: 10.1101/537613

    During sensorimotor learning, neuronal networks change to optimize the associations between action and perception. In this study, we examine how the brain harnesses neuronal patterns that correspond to the current action-perception state during learning. To this end, we recorded activity from motor cortex while monkeys either performed a familiar motor task (movement-state) or learned to control the firing rate of a target neuron using a brain-machine interface (BMI-state). Before learning, monkeys were placed in an observation-state, where no action was required. We found that neuronal patterns during the BMI-state were markedly different from the movement-state patterns. BMI-state patterns were initially similar to those in the observation-state and evolved to produce an increase in the firing rate of the target neuron. The overall activity of the non-target neurons remained similar after learning, suggesting that excitatory-inhibitory balance was maintained. Indeed, a novel neural-level reinforcement-learning network model operating in a chaotic regime of balanced excitation and inhibition predicts our results in detail. We conclude that during BMI learning, the brain can adapt patterns corresponding to the current action-perception state to gain rewards. Moreover, our results show that we can predict activity changes that occur during learning based on the pre-learning activity. This new finding may serve as a key step toward clinical brain-machine interface applications to modify impaired brain activity.

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