High-strength bulk Al-based bimodal ultrafine eutectic composite with enhanced plasticity

An in situ bulk ultrafine bimodal eutectic Al-Cu-Si composite was synthesized by solidification. This heterostructured composite with microstructural length scale hierarchy in the eutectic microstructure, which combines an ultrafine-scale binary cellular eutectic (alpha-Al + Al2Cu) and a nanometer-sized anomalous ternary eutectic (alpha-Al + Al2Cu + Si), exhibits high fracture strength (1.1 +/- 0.1 GPa) and large compressive plastic strain (11 +/- 2%) at room temperature. The improved compressive plasticity of the bimodal-nanoeutectic composite originates from homogeneous and uniform distribution of inhomogeneous plastic deformation (localized shear bands), together with strong interaction between shear bands in the spatially heterogeneous structure.

Enhanced Plasticity of Zr-Based Bulk Metallic Glass Matrix Composite with Ductile Reinforcement

A composite material containing uniformly distributed micrometer-sized Nb particles in a Zr-based amorphous matrix was prepared by suction cast. The resulting material exhibits high fractured strength over 1550 MPa and enhanced plastic strain of about 29.7% before failure in uniaxial compression test at room temperature. Studies of the serrations on the stress-strain curves and the shear bands on the fractured samples reveal that the amplitude of the stress drop of each serration step corresponds to the extent of the propagation of a single shear band through the materials. The composite exhibits more serration steps and smaller amplitude of stress drop due to the pinning of shear band propagation by ductile Nb particles.

Microstructure and mechanical properties of a novel Zr-based bulk metallic glass composite

Zr48.5Cu46.5Al5 bulk metallic glass (BMG) composites with diameters of 3 and,4 mm were prepared through suction casting in an arc melting furnace by modulating the alloy composition around the monothetic BMG composition of the high glass forming ability. Microstructural characterization reveals that the composites contain micron-sized CuZr phase with martensite structure, as well as nano-sized Zr2Cu crystalline particles and Cu10Zr7 plate-like phase embedded in an amorphous matrix. Room temperature compression tests showed that the composites exhibited significant strain hardening and obvious plastic strain of 7.7% for 3 nun and 6.4% for 4 nun diameter samples, respectively.

Synthesis Of Plastic Zr-Based Bulk Metallic Glass Matrix Composites By The Copper-Mould Suction Casting And The Bridgman Solidification

Zr-based bulk metallic glass matrix composites with the composition of Zr56.2Ti13.8Nb5.0Cu6.9Ni5.6Be12.(5) were synthesized by the copper-mould suction casting and the Bridgman solidification. The composite, containing a well-developed flowery beta-Zr dendritic phase, was obtained by the Bridgman solidification with the withdrawal velocity of 0.8 mm/s and the temperature gradient of 45 K/mm, and the ultimate strength of 2050 MPa and fracture plastic strain of 14.6% of the composite were achieved, which was mainly interpreted by the homogeneous dispersion of bcc beta-Zr phase in the glass matrix. Crown Copyright (C) 2008 Published by Elsevier B.V. All rights reserved.

Variabilité individuelle de l'allocation fonctionnelle des régions cérébrales perceptives dans l'autisme

Introduction : Une augmentation de la plasticité cérébrale est susceptible d’être impliquée dans la réallocation des régions corticales et dans les nombreuses altérations microstructurelles observées en autisme. Considérant les nombreux résultats démontrant un surfonctionnement perceptif et un fonctionnement moteur atypique en autisme, l’augmentation de la plasticité cérébrale suggère une plus grande variabilité individuelle de l’allocation fonctionnelle chez cette population, plus spécifiquement dans les régions perceptives et motrices. Méthode : Afin de tester cette hypothèse, 23 participants autistes de haut-niveau et 22 non-autistes appariés pour l’âge, le quotient intellectuel, les résultats au test des Matrices de Raven et la latéralité, ont réalisé une tâche d’imitation visuo-motrice dans un appareil d’imagerie par résonnance magnétique fonctionnelle (IRMf). Pour chaque participant, les coordonnées du pic d’activation le plus élevé ont été extraites des aires motrices primaires (Aire de Brodmann 4 (BA4)) et supplémentaires (BA6), du cortex visuo-moteur pariétal supérieur (BA7) ainsi que des aires visuelles primaires (BA17) et associatives (BA18+19) des deux hémisphères. L’étendue des activations, mesurée en fonction du nombre de voxels activés, et la différence d’intensité des activations, calculée en fonction du changement moyen d’intensité du signal ont également été considérées. Pour chaque région d’intérêt et hémisphère, la distance entre la localisation de l’activation maximale de chaque participant par rapport à celle de la moyenne de son groupe a servi de variable d’intérêt. Les moyennes de ces distances individuelles obtenues pour chaque groupe et chacune des régions d’intérêt ont ensuite été soumises à une ANOVA à mesures répétées afin de déterminer s’il existait des différences de variabilité dans la localisation des activations entre les groupes. Enfin, l’activation fonctionnelle générale à l’intérieur de chaque groupe et entre les groupes a également été étudiée. Résultats : Les résultats démontrent qu’une augmentation de la variabilité individuelle en terme de localisation des activations s’est produite à l’intérieur des deux groupes dans les aires associatives motrices et visuelles comparativement aux aires primaires associées. Néanmoins, malgré le fait que cette augmentation de variabilité dans les aires associatives soit partagée, une comparaison directe de celle-ci entre les groupes a démontré que les autistes présentaient une plus grande variabilité de la localisation des activations fonctionnelles dans le cortex visuo-moteur pariétal supérieur (BA7) et les aires associatives visuelles (BA18+19) de l’hémisphère gauche. Conclusion : Des stratégies différentes et possiblement uniques pour chaque individu semblent être observées en autisme. L’augmentation de la variabilité individuelle de la localisation des activations fonctionnelles retrouvée chez les autistes dans les aires associatives, où l’on observe également davantage de variabilité chez les non-autistes, suggère qu’une augmentation et/ou une altération des mécanismes de plasticité est impliquée dans l’autisme.

Presynaptic Anchoring of PKA by AKAP7 is Required for Pattern Separation by Dentate Gyrus

Thesis (Ph.D.)--University of Washington, 2016-06

Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala

Learning and memory depend on signaling mole- cules that affect synaptic efficacy. The cytoskeleton has been implicated in regulating synaptic transmission but its role in learning and memory is poorly understood. Fear learning depends on plasticity in the lateral nucleus of the amygdala. We therefore examined whether the cytoskeletal-regulatory protein, myosin light chain kinase, might contribute to fear learning in the rat lateral amygdala. Microinjection of ML-7, a specific inhibitor of myosin light chain kinase, into the lateral nucleus of the amygdala before fear conditioning, but not immediately afterward, enhanced both short-term memory and long-term memory, suggesting that myosin light chain kinase is involved specifically in memory acquisition rather than in posttraining consolidation of memory. Myosin light chain kinase inhibitor had no effect on memory retrieval. Furthermore, ML-7 had no effect on behavior when the train- ing stimuli were presented in a non-associative manner. An- atomical studies showed that myosin light chain kinase is present in cells throughout lateral nucleus of the amygdala and is localized to dendritic shafts and spines that are postsynaptic to the projections from the auditory thalamus to lateral nucleus of the amygdala, a pathway specifically impli- cated in fear learning. Inhibition of myosin light chain kinase enhanced long-term potentiation, a physiological model of learning, in the auditory thalamic pathway to the lateral nu- cleus of the amygdala. When ML-7 was applied without as- sociative tetanic stimulation it had no effect on synaptic responses in lateral nucleus of the amygdala. Thus, myosin light chain kinase activity in lateral nucleus of the amygdala appears to normally suppress synaptic plasticity in the cir- cuits underlying fear learning, suggesting that myosin light chain kinase may help prevent the acquisition of irrelevant fears. Impairment of this mechanism could contribute to pathological fear learning.

Heparin-binding growth-associated molecule (HB-GAM) in activity-dependent neuronal plasticity in hippocampus

Cell adhesion and extracellular matrix (ECM) molecules play a significant role in neuronal plasticity both during development and in the adult. Plastic changes in which ECM components are implicated may underlie important nervous system functions, such as memory formation and learning. Heparin-binding growthassociated molecule (HB-GAM, also known as pleiotrophin), is an ECM protein involved in neurite outgrowth, axonal guidance and synaptogenesis during perinatal period. In the adult brain HB-GAM expression is restricted to the regions which display pronounced synaptic plasticity (e.g., hippocampal CA3-CA1 areas, cerebral cortex laminae II-IV, olfactory bulb). Expression of HB-GAM is regulated in an activity-dependent manner and is also induced in response to neuronal injury. In this work mutant mice were used to study the in vivo function of HB-GAM and its receptor syndecan-3 in hippocampal synaptic plasticity and in hippocampus-dependent behavioral tasks. Phenotypic analysis of HBGAM null mutants and mice overexpressing HB-GAM revealed that opposite genetic manipulations result in reverse changes in synaptic plasticity as well as behavior in the mutants. Electrophysiological recordings showed that mice lacking HB-GAM have an increased level of long-term potentiation (LTP) in the area CA1 of hippocampus and impaired spatial learning, whereas animals with enhanced level of HB-GAM expression have attenuated LTP, but outperformed their wild-type controls in spatial learning. It was also found that GABA(A) receptor-mediated synaptic transmission is altered in the transgenic mice overexpressing HB-GAM. The results suggest that these animals have accentuated hippocampal GABAergic inhibition, which may contribute to the altered glutamatergic synaptic plasticity. Structural studies of HB-GAM demonstrated that this protein belongs to the thrombospondin type I repeat (TSR) superfamily and contains two β-sheet domains connected by a flexible linker. It was found that didomain structure is necessary for biological activity of HB-GAM and electrophysiological phenotype displayed by the HB-GAM mutants. The individual domains displayed weaker binding to heparan sulfate and failed to promote neurite outgrowth as well as affect hippocampal LTP. Effects of HB-GAM on hippocampal synaptic plasticity are believed to be mediated by one of its (co-)receptor molecules, namely syndecan-3. In support of that, HB-GAM did not attenuate LTP in mice deficient in syndecan-3 as it did in wild-type controls. In addition, syndecan-3 knockout mice displayed electrophysiological and behavioral phenotype similar to that of HB-GAM knockouts (i.e. enhanced LTP and impaired learning in Morris water-maze). Thus HB-GAM and syndecan-3 are important modulators of synaptic plasticity in hippocampus and play a role in regulation of learning-related behavior.

Tailored interface and enhanced elastic modulus in epoxy-based composites in presence of branched poly(ethyleneimine) grafted multiwall carbon nanotubes

In this study, branched poly(ethyleneimine), BPEI, was synthesized from carboxylic acid terminated multi-walled carbon nanotubes (c-MWNTs) and characterized using FTIR, TEM and TGA. The BPEI was then chemically grafted onto MWNTs to enhance the interfacial adhesion with the epoxy matrix. The epoxy composites with c-MWNTs and the BPEI-g-MWNTs were prepared using a sonication and mechanical stirring method, followed by curing at 100 degrees C and post-curing at 120 degrees C. The dynamic mechanical thermal analysis showed an impressive 49% increment in the storage elastic modulus in the composites. In addition, the nanoindentation on the composites exhibited significant improvement in the hardness and decrease in the plasticity index in the presence of the BPEI-g-MWNTs. Thus, epoxy composites with BPEI-g-MWNTs can be further explored as self-healing materials.

Time-dependent nanoscale plasticity in nanocrystalline nickel rods and tubes

Time-dependent nanoscale plasticity of nanocrystalline nickel at room temperature was critically explored through a series of micropillar creep and quasi-static compression experiments on rod and tube specimens fabricated by electron beam lithography and electroplating. Enhanced creep rates in tubes as compared to rods, establishes the facilitating role played by the free surface in time-dependent deformation. Creep stress exponent, n, and strain-rate sensitivity, m, were compared to examine connections between creep and the rate-dependent plasticity, if any. (C) 2015 Elsevier Ltd. All rights reserved.

Toughness Of Ni/Al2O3 Interfaces As Dependent On Micron-Scale Plasticity And Atomistic-Scale Separation

Ceramic/metal interfaces were studied that fail by atomistic separation accompanied by plastic dissipation in the metal. The macroscopic toughness of the specific Ni alloy/Al2O3 interface considered is typically on the order of ten times the atomistic work of separation in mode I and even higher if combinations of mode I and mode II act on the interface. Inputs to the computational model of interface toughness are: (i) strain gradient plasticity applied to the Ni alloy with a length parameter determined by an indentation test, and (ii) a potential characterizing mixed mode separation of the interface fit to atomistic results. The roles of the several length parameters in the strain gradient plasticity are determined for indentation and crack growth. One of the parameters is shown to be of dominant importance, thus establishing that indentation can be used to measure the relevant length parameter. Recent results for separation of Ni/Al2O3 interfaces computed by atomistic methods are reviewed, including a set of results computed for mixed mode separation. An approximate potential fit to these results is characterized by the work of separation, the peak separation stress for normal separation and the traction-displacement relation in pure shearing of the interface. With these inputs, the model for steady-state crack growth is used to compute the toughness of the interface under mode I and under the full range of mode mix. The effect of interface strength and the work of separation on macroscopic toughness is computed. Fundamental implications for plasticity-enhanced toughness emerge.

Macrophages Control Vascular Stem/Progenitor Cell Plasticity Through Tumor Necrosis Factor-α-Mediated Nuclear Factor-κB Activation

Objective: Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process.

Approach and Results: We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α–mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation.

Conclusions: Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α–mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.

The role of retinoic acid in long-term memory formation and synaptic plasticity in the mollusc Lymnaea stagnalis

The active metabolite of vitamin A, retinoic acid (RA), is involved in memory formation and hippocampal plasticity in vertebrates. A similar role for retinoid signaling in learning and memory formation has not previously been examined in an invertebrate species. However, the conservation of retinoid signaling between vertebrates and invertebrates is supported by the presence of retinoid signaling machinery in invertebrates. For example, in the mollusc Lymnaea stagnalis the metabolic enzymes and retinoid receptors have been cloned from the CNS. In this study I demonstrated that impairing retinoid signaling in Lymnaea by either inhibiting RALDH activity or using retinoid receptor antagonists, prevented the formation of long-term memory (LTM). However, learning and intermediate-term memory were not affected. An additional finding was that exposure to constant darkness (due to the light-sensitive nature of RA) itself enhanced memory formation. This memory-promoting effect of darkness was sufficient to overcome the inhibitory effects of RALDH inhibition, but not that of a retinoid receptor antagonist, suggesting that environmental light conditions may influence retinoid signaling. Since RA also influences synaptic plasticity underlying hippocampal-dependent memory formation, I also examined whether RA would act in a trophic manner to influence synapse formation and/or synaptic transmission between invertebrate neurons. However, I found no evidence to support an effect of RA on post-tetanic potentiation of a chemical synapse. Retinoic acid did, however, reduce transmission at electrical synapses in a cell-specific manner. Overall, these studies provide the first evidence for a role of RA in the formation of implicit long-term memories in an invertebrate species and suggest that the role of retinoid signaling in memory formation has an ancient origin.

Development and plasticity of locomotor circuits in the zebrafish spinal cord

A fundamental goal in neurobiology is to understand the development and organization of neural circuits that drive behavior. In the embryonic spinal cord, the first motor activity is a slow coiling of the trunk that is sensory-independent and therefore appears to be centrally driven. Embryos later become responsive to sensory stimuli and eventually locomote, behaviors that are shaped by the integration of central patterns and sensory feedback. In this thesis I used a simple vertebrate model, the zebrafish, to investigate in three manners how developing spinal networks control these earliest locomotor behaviors. For the first part of this thesis, I characterized the rapid transition of the spinal cord from a purely electrical circuit to a hybrid network that relies on both chemical and electrical synapses. Using genetics, lesions and pharmacology we identified a transient embryonic behavior preceding swimming, termed double coiling. I used electrophysiology to reveal that spinal motoneurons had glutamate-dependent activity patterns that correlated with double coiling as did a population of descending ipsilateral glutamatergic interneurons that also innervated motoneurons at this time. This work (Knogler et al., Journal of Neuroscience, 2014) suggests that double coiling is a discrete step in the transition of the motor network from an electrically coupled circuit that can only produce simple coils to a spinal network driven by descending chemical neurotransmission that can generate more complex behaviors. In the second part of my thesis, I studied how spinal networks filter sensory information during self-generated movement. In the zebrafish embryo, mechanosensitive sensory neurons fire in response to light touch and excite downstream commissural glutamatergic interneurons to produce a flexion response, but spontaneous coiling does not trigger this reflex. I performed electrophysiological recordings to show that these interneurons received glycinergic inputs during spontaneous fictive coiling that prevented them from firing action potentials. Glycinergic inhibition specifically of these interneurons and not other spinal neurons was due to the expression of a unique glycine receptor subtype that enhanced the inhibitory current. This work (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggests that glycinergic signaling onto sensory interneurons acts as a corollary discharge signal for reflex inhibition during movement. v In the final part of my thesis I describe work begun during my masters and completed during my doctoral degree studying how homeostatic plasticity is expressed in vivo at central synapses following chronic changes in network activity. I performed whole-cell recordings from spinal motoneurons to show that excitatory synaptic strength scaled up in response to decreased network activity, in accordance with previous in vitro studies. At the network level, I showed that homeostatic plasticity mechanisms were not necessary to maintain the timing of spinal circuits driving behavior, which appeared to be hardwired in the developing zebrafish. This study (Knogler et al., Journal of Neuroscience, 2010) provided for the first time important in vivo results showing that synaptic patterning is less plastic than synaptic strength during development in the intact animal. In conclusion, the findings presented in this thesis contribute widely to our understanding of the neural circuits underlying simple motor behaviors in the vertebrate spinal cord.