Coordinated optimization of visual cortical maps : 2. Numerical studies

In the juvenile brain, the synaptic architecture of the visual cortex remains in a state of flux for months after the natural onset of vision and the initial emergence of feature selectivity in visual cortical neurons. It is an attractive hypothesis that visual cortical architecture is shaped during this extended period of juvenile plasticity by the coordinated optimization of multiple visual cortical maps such as orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we introduced a class of analytically tractable coordinated optimization models and solved representative examples, in which a spatially complex organization of the OP map is induced by interactions between the maps. We found that these solutions near symmetry breaking threshold predict a highly ordered map layout. Here we examine the time course of the convergence towards attractor states and optima of these models. In particular, we determine the timescales on which map optimization takes place and how these timescales can be compared to those of visual cortical development and plasticity. We also assess whether our models exhibit biologically more realistic, spatially irregular solutions at a finite distance from threshold, when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. We show that, although maps typically undergo substantial rearrangement, no other solutions than pinwheel crystals and stripes dominate in the emerging layouts. Pinwheel crystallization takes place on a rather short timescale and can also occur for detuned wavelengths of different maps. Our numerical results thus support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the architecture of the visual cortex. We discuss several alternative scenarios that may improve the agreement between model solutions and biological observations

Coordinated optimization of visual cortical maps : 1. Symmetry-based analysis

In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of orientation columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about a hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference. From basic symmetry assumptions we obtain a comprehensive phenomenological classification of possible inter-map coupling energies and examine representative examples. We show that each individual coupling energy leads to a different class of OP solutions with different correlations among the maps such that inferences about the optimization principle from map layout appear viable. We systematically assess whether quantitative laws resembling experimental observations can result from the coordinated optimization of orientation columns with other feature maps

Pinwheel stabilization by ocular dominance segregation

We present an analytical approach for studying the coupled development of ocular dominance and orientation preference columns. Using this approach we demonstrate that ocular dominance segregation can induce the stabilization and even the production of pinwheels by their crystallization in two types of periodic lattices. Pinwheel crystallization depends on the overall dominance of one eye over the other, a condition that is fulfilled during early cortical development. Increasing the strength of inter-map coupling induces a transition from pinwheel-free stripe solutions to intermediate and high pinwheel density states.Comment: 10 pages, 4 figure

Scale-down of an orbital shaken bioreactor: High cell density cultivation in perfusion mode and virus production

Application of single-use bioreactors has been commonly shown for several cell culture-based production systems including commercial vaccine production. Compared to stainless steel bioreactors, competitive cell growth characteristics as well as virus yields can be reached [1]. In addition to conventional stirred tank reactors (STR), wave bioreactors or orbital shaken bioreactors (OSBs) are available that rely on alternative mixing regimes. For small-scale screening of clones and media, cell maintenance and process optimization, OSBs are the most widely used system. Besides their simple design and ease of handling, OSBs allow for robust processes due to reduced mechanical stress caused by stirring and aeration [2]. Furthermore, scale-up (£ 2500 L) is simplified as larger OSBs rely on the same basic principles for mixing and aeration (e.g. bubble-free surface gassing). Particularly for high cell density (HCD) processes, high oxygen transfer rates, short mixing times, and low shear stress are beneficial. Until now, the step from spin tubes or shake flasks into larger OSBs was rather large, as only the OSB SB10-X (Kühner AG, Switzerland) with a minimum working volume (wv) of 4-5 L was available. In this study, a novel scale-down 3 L vessel module (wv = 1-3 L) for the OSB SB10-X was evaluated for cultivation of suspension BHK-21 cells (CEVA, Germany) in perfusion mode to HCD. Cultivation was carried out in serum-free medium in a 3 L and 10 L single-use standard bag with 3 L and 5 L initial wv and 100 and 70 rpm shaking frequency with a shaking diameter of 50 mm, respectively. For perfusion, an alternating tangential flow system (ATF2, Repligen) with a cut-off of 0.4 µm (SB10-X) and 0.5 µm (SB3-X), respectively, was used. Following an initial batch phase of 2-3 days, perfusion was initiated. After a complete media exchange, cells in the 3 L vessel module were infected with a fusogenic oncolytic virus (rVSV-NDV, recombinant vesicular stomatitis virus-Newcastle disease virus) at a cell concentration of 44.5x106 cells/mL at a multiplicity of infection (MOI) of 10-4. The obtained data were compared to a cultivation of BHK-21 cells in the standard SB10-X module (infection at a cell concentration of 12.5x106 cells/mL with yellow fever virus WHO 17D-213/77 with an MOI of 10-3) and to a cultivation in a 1 L STR. The novel 3 L vessel module allowed for a successful and direct scale-down utilizing the SB10-X backbone without the need for further optimization. For both the SB10-X and the 3 L vessel module, the ATF system was successfully coupled and cell concentrations of 32.7x106 cells/mL and 45.9x106 cells/mL were reached with high viabilities above 98%, respectively. A faster doubling time (tD=22 h) was observed in the 3 L vessel module compared to the SB10-X system (tD=27 h). For rVSV-NDV production, similar infectious virus titers were reached compared to perfusion cultivations of BHK-21 cells in a 1 L STR. Volumetric media consumption was significantly reduced in the 3 L vessel module, facilitating the implementation of OSB systems in non-industrial research environments. All in all, we demonstrated the adaptability and scalability of the single-use OSB system for the production of various viruses in HCD perfusion mode. References [1] Gallo-Ramirez, L. E., A. Nikolay, Y. Genzel, and U. Reichl. 2015. Bioreactor concepts for cell culture-based viral vaccine production. Expert Rev Vaccines 14 (9):1181-95. doi: 10.1586/14760584.2015.1067144 [2] Klöckner W, Diederichs S, Büchs J. Orbitally shaken single-use bioreactors. Adv Biochem Eng Biotechnol. 2014;138:45-60. doi: 10.1007/10_2013_188. PMID: 23604207

Long-term propagation of influenza A virus and its defective interfering particles: Analyzing dynamic competition to select antiviral candidates

Influenza A virus (IAV) is a major threat to human health. A potential antiviral therapy against influenza disease could be the intranasal application of defective interfering particles (DIPs) [1,2]. During intracellular IAV replication, these IAV DIPs are randomly generated. They contain at least one defective interfering (DI) RNA, typically a genome segment with a large internal deletion, rendering them replication-incompetent. During co-infection with infectious standard virus (STV), DIPs impede STV replication via a growth advantage [3] and by stimulation of the innate immune response [4]. In this work, we profiled the propagation competition between a variety of DIPs for selection toward accumulation of highly interfering DIPs in Madin-Darby canine kidney (MDCK) suspension cell culture. To that end, we propagated IAV and its DIPs over 21 days using a small-scale two-stage cultivation system. Illumina-based next-generation sequencing (NGS) in combination with a lately reported bioinformatic pipeline was utilized to detect and quantify specific deletion junctions within the virus population [5]. During long-term propagation, both the infectious and total virus titers oscillated periodically, a characteristic pattern of DIP and STV interplay [6]. NGS analysis revealed that the highest de novo formation and accumulation of DI vRNAs occurred on the polymerase-encoding segments. Moreover, we identified an accumulation of short DI vRNAs with an optimum fragment length underlining their replication advantage. Deletion junctions were usually situated near both vRNA ends. For efficient DI vRNA propagation, retaining the incorporation signal but not the entire bundling signal was required. Few DI vRNAs propagated to high levels toward the end of cultivation, while the level of others declined. Reverse genetics was utilized to generate purely clonal DIPs derived from DI vRNAs of segment 1 that showed the highest increase in accumulation during cultivation. For this, genetically engineered adherent and suspension MDCK cells complementing the defect in segment 1 were employed [7,2]. During co-infection with STV, these DIPs displayed a higher interfering efficacy relative to DIPs derived from less competitive DI vRNAs. Please click Download on the upper right corner to see the full abstract

Influenza A virus OP7 defective interfering particles: Cell culture-based production and antiviral efficacy in vivo

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Coordinated optimization of visual cortical maps (I) Symmetry-based analysis

In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of OP columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about an hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference.Comment: 90 pages, 16 figure

Coordinated optimization of visual cortical maps (II) Numerical studies

It is an attractive hypothesis that the spatial structure of visual cortical architecture can be explained by the coordinated optimization of multiple visual cortical maps representing orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we defined a class of analytically tractable coordinated optimization models and solved representative examples in which a spatially complex organization of the orientation preference map is induced by inter-map interactions. We found that attractor solutions near symmetry breaking threshold predict a highly ordered map layout and require a substantial OD bias for OP pinwheel stabilization. Here we examine in numerical simulations whether such models exhibit biologically more realistic spatially irregular solutions at a finite distance from threshold and when transients towards attractor states are considered. We also examine whether model behavior qualitatively changes when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. Our numerical results support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the spatially irregular architecture of the visual cortex. We discuss several alternative scenarios and additional factors that may improve the agreement between model solutions and biological observations.Comment: 55 pages, 11 figures. arXiv admin note: substantial text overlap with arXiv:1102.335

The sounds of science - A symphony for many instruments and voices

Sounds of Science is the first movement of a symphony for many (scientific) instruments and voices, united in celebration of the frontiers of science and intended for a general audience. John Goodenough, the maestro who transformed energy usage and technology through the invention of the lithium-ion battery, opens the programme, reflecting on the ultimate limits of battery technology. This applied theme continues through the subsequent pieces on energy-related topics - the sodium-ion battery and artificial fuels, by Martin Månsson - and the ultimate challenge for 3D printing, the eventual production of life, by Anthony Atala. A passage by Gerianne Alexander follows, contemplating a related issue: How might an artificially produced human being behave? Next comes a consideration of consciousness and free will by Roland Allen and Suzy Lidström. Further voices and new instruments enter as Warwick Bowen, Nicolas Mauranyapin and Lars Madsen discuss whether dynamical processes of single molecules might be observed in their native state. The exploitation of chaos in science and technology, applications of Bose-Einstein condensates and the significance of entropy follow in pieces by Linda Reichl, Ernst Rasel and Roland Allen, respectively. Mikhail Katsnelson and Eugene Koonin then discuss the potential generalisation of thermodynamic concepts in the context of biological evolution. Entering with the music of the cosmos, Philip Yasskin discusses whether we might be able to observe torsion in the geometry of the Universe. The crescendo comes with the crisis of singularities, their nature and whether they can be resolved through quantum effects, in the composition of Alan Coley. The climax is Mario Krenn, Art Melvin and Anton Zeilinger\u27s consideration of how computer code can be autonomously surprising and creative. In a harmonious counterpoint, his \u27Guidelines for considering AIs as coauthors\u27, Roman Yampolskiy concludes that code is not yet able to take responsibility for coauthoring a paper. An interlude summarises a speech by Zdeněk Papoušek. In a subsequent movement, new themes emerge as we seek to comprehend how far we have travelled along the path to understanding, and speculate on where new physics might arise. Who would have imagined, 100 years ago, a global society permeated by smartphones and scientific instruments so sophisticated that genes can be modified and gravitational waves detected

Symmetriebrechung und Musterselektion in Modellen der visuellen Entwicklung

Die Antworteigenschaften von Neuronen im visuellen Kortex bilden räumliche Darstellungen, sogenannte Karten, von verschiedenen Stimuluseigenschaften wie zum Beispiel Orientierungspreferenz (OP) oder Okulare Dominanz (OD). Diese Arbeit untersucht makroskopische Modelle der Entwicklung solcher Karten, welche durch die Zeitentwicklung von Ordnungsparameterfeldern beschrieben wird. Es ist plausibel, dass die Entwicklung der Karten ein Prozess der Optimierung der kortikalen Verbindungen ist und daher wird angenommen, dass die Dynamik aus einem Energiefunktional abgeleitet werden kann. Da experimentelle Befunde darauf hin deuten, dass verschiedene Karten nicht unabhängig voneinander sind untersuchen wir die gemeinsame Optimierung verschiedener Karten. Wir verwenden verallgemeinerte Swift-Hohenberg Gleichungen wobei alle Terme, welche in die Dynamik eingehen, durch Symmetriebetrachtungen gerechtfertigt werden. Diese Felddynamik wird mit zwei Methoden untersucht: Erstens anhand einer schwach nichtlinearen Analyse welche die Entwicklung der Karten nahe der musterbildenden Schwelle beschreibt und durch Amplitudengleichungen gegeben ist. Zweitens durch direkte numerische Simulation unter Verwendung eines voll impliziten Integrationsschemas.Wir untersuchen zunächst die gemeinsame Entwicklung von OP und OD Karten unter Verwendung verschiedener Energiefunktionale welche zu einer Kopplung der Karten führen. Unsere Ergebnisse zeigen Gemeinsamkeiten und spezifische Unterschiede auf, welche verschiedene Optimierungsprinzipien auf das räumliche Layout der Karten haben. Darüber hinaus zeigen wir, dass der Einfluss der OD Karte eine Lösung für das Problem der Stabilität von sogenannten Pinwheels, topologischen Defekten in OP Karten, bietet. In diesem Modell zerfällt die ungekoppelte OP Karte in Pinwheel-freie Streifenmuster. Für starke Kopplung zwischen den Karten und im Falle der Überrepresentation eines Auges jedoch werden Pinwheel-reiche Lösungen stabil, wobei die Pinwheels in einem Kristallgitter angeordnet sind. Daraufhin führen wir nicht-lokale Wechselwirkunsterme in die Dynamik ein um langreichweitige Verbindungen zwischen kortikalen Neuronen abzubilden. Wir zeigen, dass dies zu räumlich irregulären und Pinwheel-reichen Mustern führen kann. Weiterhin stellen wir eine mögliche Erklärung für die Speziesunterschiede im OD Karten Layout vor, indem wir unterschiedliche typische Wellenlängen der OP und OD Karten betrachten. Die ungekoppelte OP Dynamik besitzt zahlreiche stationäre Lösungen. Wir stellen eine umfassende Charakterisierung dieser großen Menge stationärer Lösungen vor, untersuchen ihre Stabiliätseigenschaften und untersuchen insbesondere wie die Stabilität von unrealistischen Lösungen ausgeschlossen werden kann. Eine Klasse an stationären Lösungen ist dominant d.h. Sie enthält alle energetischen Grundzustände des Modells. Diese Grundzustände sind darüber hinaus energetisch entartet. Wir finden zwei Mechanismen welche diese Entartung aufheben und daher zur Musterselektion führen: Korrekturen in höherer Ordnung in den Amplitudengleichungen und die Brechung einer Symmetrie der Felddynamik, die so genannte Permutationssymmetrie. Für beide Fälle bestimmen wir lokale Minima und energetische Grundzustände und untersuchen die Auswirkungen der Musterselektion auf die quantitativen Eigenschaften wie ihre Pinwheeldichte.Diese Arbeit stellt Modelle für die Entwicklung von Karten im visuellen Kortex vor und zeigt, dass das Vorhandensein oder die Abwesenheit bestimmter Symmetrien wichtig für das Auftreten realistischer Karten ist. Wir finden Modelle welche zu Karten mit einem realistischen räumlichen Layout führen die darüber hinaus auch quantitativ den experimentell bestimmten Karten ähneln