Learning and memory storage is believed to occur at the synaptic connections between neurons. During the last decades it has become clear that synapses are plastic at short and long time scales. Furthermore, experiments have shown that short and long-term synaptic plasticity interact. It remains unclear, however, how is this interaction implemented and how does it impact information processing and learning in cortical networks. In this thesis I present results on the mechanisms and function of this interaction. On the mechanistic level this form of plasticity is known to rely on a presynaptic coincidence mechanism, which requires the activation of presynaptic NMDA receptors (preNMDARs). In a collaborative effort I used mathematical modeling combined with experiments to show that preNMDARs reroute information flow in local circuits during high-frequency firing, by specifically impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells. In order to accurately characterize how do preNMDARs regulate the release machinery, I developed a probabilistic inference framework that provides a distribution over the relevant parameter space, rather than simple point estimates. This approach allowed me to propose better experimental protocols for short-term plasticity inference and to reveal connection-specific synaptic dynamics in the layer-5 canonical microcircuit. This framework was then extended to infer short-term plasticity from preNMDAR pharmacological blockade data. The results show that preNMDARs up-regulate the baseline release probability and the depression time-constant, which is consistent with experimental analysis and that their impact appears to be connection-specific. I also show that a preNMDAR phenomenological model captures the frequency-dependence activation of preNMDARs. Furthermore, preNMDARs increase the signal-to-noise ratio of synaptic responses. These results show that preNMDARs specifically up-regulate high frequency synaptic information transmission. Finally, I introduce a pre- and postsynaptic unified mathematical model of spike-timing- dependent synaptic plasticity. I show that this unified model captures a wide range of short-term and long-term synaptic plasticity data. Functionally, I demonstrate that this segregation into pre- and postsynaptic factors explains some observations on receptive field development and enable rapid relearning of previously stored information, in keeping with Ebbinghaus’s memory savings theory.

Nous avons identifié comment les propriétés fonctionnelles des microcircuits GABAergiques dustriatum se mettent en place depuis la période embryonnaire jusqu’à l’adulte, et comment elles sont modifiées dans un modèle adulte pharmacologique (6-hydroxydopamine) ou génétique(PINK1 KO) de la maladie de Parkinson. Les neurones de projection (MSNs) immatures du striatum génèrent une séquence d’activités spontanées : des spikes calciques isolés et des plateaux calciques dans des petites assemblées de neurones connectés par des jonctions gap(E14-P8) puis des bouffées de spikes synchronisées d’origine synaptique (P6-P7). Ensuite les MSNs deviennent silencieux in vitro juste avant l’apparition de la locomotion du fait de l’expression du courant K de la rectification entrante et de la perte de la composante NR2C/Ddes réponses synaptiques cortico-striatales. Enfin dans les deux modèles murins de Parkinson,les courants synaptiques GABAergiques spontanés des MSNs deviennent géants ou en bouffées du fait du dysfonctionnement d’un seul type d’interneurone GABAergique. Ces résultats montrent l’importance de déterminer l’impact des altérations précoces du système dopaminergique sur le développement des microcircuits GABAergiques du striatum / We investigated how the functional properties of the mouse GABAergic microcircuits of the striatum mature from embryonic to adult stages and how they are altered in a pharmacological(6-OHDA) or genetic (PINK 1 KO) adult model of Parkinson’s disease (PD). The dominant population of immature projection neurons, the medium spiny neurons (MSNs) generates asequence of spontaneous calcium activities: calcium spikes and synchronized gap junction driven calcium plateaus (E14-P8) followed by synapse-driven synchronized calcium spikes (P6-P7). Then they become silent in vitro (P8-P10) just before the onset of locomotion (P10-P12), because of the parallel expression of the K+ rectifying current and loss of the NR2C/Dcomponent of NMDA receptor-mediated cortico-striatal responses. In addition, we show that thetonic low frequency, spontaneous GABAergic activity of MSNs switches to a gigantic or bursting pattern in both PD models. This switch is due to only one subtype of GABAergic interneuron which entrains the striatal microcircuits in abnormal GABAergic oversynchrony. This study reflects the need for developmental investigations on the impact of early alteration of the dopaminergic system on striatal GABAergic microcicuits

Avant d'approvisionner des lots de composants pour la fabrication de systèmes orbitaux, les grandes agences du spatial (CNES, ESA, NASA, JAXA…) ainsi que les industriels du spatial (EADS, Thales,…) doivent s'assurer de la fiabilité des lots proposés par les fabricants de circuits intégrés. Dans le but d'assurer la fiabilité des composants, des tests sont réalisés suivant des recommandations afin de sélectionner et trier les composants suivant leur tenue à différents modes de défaillance. Parmi tous ces tests, certains sont typiques des applications spatiales : les tests de tenue à la dose. Cette spécificité des tests de tenue à la dose de composants destinés à des applications spatiales est due au fait que l'environnement spatial est un environnement radiatif qui provoque une ionisation dans les matériaux constituant le satellite. Suite à cette ionisation des charges sont créées dans la matière et induisent des modifications au sein des matériaux qui composent les circuits intégrés, ce qui peut provoquer des dérives de leurs caractéristiques électriques. Ces dérives des paramètres électriques en environnement spatial peuvent être perçues comme un vieillissement accéléré des composants électroniques, et des tests sont donc dédiés à prédire et s'assurer du bon fonctionnement des composants même après ce vieillissement accéléré provoqué par la dose. Dans ce travail de thèse nous nous intéressons à l'applicabilité d'une technique de test accéléré des composants bipolaires développée à l'UM2: 'La technique des Débits Commutés'. Une étude de l'effet de la polarisation pendant irradiation a été mené au cours de ce travail de thèse, afin d'appréhender l'impact de la polarisation des composants bipolaires sur les estimations obtenues de façon accélérée grâce à cette technique. / Before supplying lots of components for the manufacture of orbital systems, large space agencies (CNES, ESA, NASA, JAXA ...) and the Industrial Space (EADS, Thales, ...) should ensure the reliability lots offered by manufacturers of integrated circuits. In order to ensure reliability of components, tests are performed following recommendations to select and sort the components according to their resistance to different failure modes. Of all these tests, some are typical for space applications: tests held in the dose. The specificity of the tests held at the dose of components for space applications due to the fact that the environment is a space radiation environment which causes ionization in the materials of the satellite. Following this ionization charges are created in the material and induce changes in the materials that comprise integrated circuits, which can cause drift of their electrical characteristics. These abuses of the electrical parameters in a space environment can be viewed as accelerated aging of electronic components, and tests are dedicated to predict and verify the correct operation of the components even after the accelerated aging caused by dose. In this thesis we investigate the applicability of a technique for accelerated testing of components developed in bipolar UM2: 'The technique of Switched Flows'. A study of the effect of the polarization during irradiation was conducted during this thesis, to understand the impact of the polarization of the bipolar components on the estimates obtained in an accelerated manner using this technique.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18874号 / 医博第3985号 / 新制||医||1008(附属図書館) / 31825 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 山田 亮, 教授 福山 秀直 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This thesis contains both Parts A and B. / <p> Xenon induced flux oscillations are possible in large thermal reactors operating at high powers because of the inter-play between the xenon concentration, reactivity, and thermal flux, and the fact that xenon is produced mainly by radioactive decay of I-135, which has a half-life of 6.7 hours. Due to these nuclear characteristics along with size and operating conditions of the Pickering and Bruce cores, these oscillations in flux are inherently unstable with respect to xenon. That is, a local perturbation in reactivity will result in a divergent and cyclic time and space variation in the thermal flux distribution in the core.</p> <p> One group diffusion theory and a simple perturbation analysis yield for a bare thermal reactor, a threshold in the average flux level ∅ which satisfies (1) M^2λij^2 / αxe - αT/αxe ∅ = 1/1+λxe/σxe∅ - μxe / 1+(λxe + λ1)/σxe∅ for oscillations in ijth mode of the flux distribution (see Figure 1) M^2 is the migration area in cm^2, αxe is the reactivity load of Xe-135 at high flux levels; αT is the fuel temperature coefficient expressed in terms of reactivity change per unit flux. The function f(∅) depends only upon the decay constants λxe of Xe-135 and λ1 of I-135; μxe is the fraction of Xe-135 produced directly from the fission of the fuel rather than through iodine decay (which fraction is denoted by μ1). The dimensionless parameter λij^2 depends only upon the shape of the flux distribution and is equal to the difference between the bulking of the ijth mode and the fundamental model.</p> <p> The Bruce and Pickering reactors are used as models in this study to determine the threshold power level at which xenon instability is possible and in which mode this instability occurs.</p> <p> Bruce is found to be unstable in the fundamental and first azimuthal mode for fresh and equilibrium fuel conditions, and stable for the radial, axial and higher azimuthal modes.</p> <p> Pickering, on the other hand, is unstable for the equilibrium fuel condition in the fundamental and first azimuthal modes only and is stable in every mode except the fundamental in the fresh fuel condition.</p> (Part A of Thesis)-------------------------------------------------------------------------------------------------------(Part B of Thesis) </p> Trimming of thin-film resistor components by an electrical arc is investigated in this report as an inexpensive and simple alternative to the laser trim and mechanical scribe methods. A multitude of tests were effected on Garrett Manufacturing Limited production circuits containing nichrome thin film resistors. These tests included Temperature Coefficient of Resistivity, resistance stability, substrate damage, noise performance, dynamic trim with active devices operating, width of cut as compared to mechanical scribe and laser trim techniques, and optimum parameters for trimming. In all cases the trimmed circuits were within the design specifications of the resistor properties under test. It is the conclusion of the author that the obvious attributes of the arc-trim method as well as its outstanding performance in the above tests, warrants its serious consideration as a viable alternative to the laser trim and mechanical scribe methods of altering resistance levels.</p> / Thesis / Master of Engineering (MEngr)