Long-term changes in synaptic transmission of the lateral amygdala induced by strong "in vitro" activation

Résumé : L'amygdale latérale (AL) joue un .rôle essentiel dans la plasticité synaptique à la base du conditionnement de la peur. Malgré le faite que la majorité des cellules de l'AL reçoivent les afférentes nécessaires, une potentialisation dans seulement une partie d'entre elles est obligatoire afin que l'apprentissage de la peur ait lieu. Il a été montré que ces cellules expriment la forme active de CREB, et celui-ci a été associé aux cellules dites de type 'nonaccomrnodating' (nAC). Très récemment, une étude a impliqué les circuits récurrents de l'AL dans le conditionnement de la peur. Un lien entre ces deux observations n'a toutefois jamais été établi. t Nous avons utilisé un protocole in vitro de forte activation de l'AL, résultant dans l'induction de 'bursts' provenant de l'hippocampe et se propageant jusqu'à l'AL. Dans l'AL ces 'bursts' atteignent toutes les cellules et se propagent à travers plusieurs chemins. Utilisant ce protocole, nous avons, pour la première fois pu associer dans l'AL, des cellules connectées de manière récurrente avec des cellules de type nAC. Aussi bien dans ces dernières que dans les cellules de type 'accommodating' (AC), une diminution dans la transmission inhibitrice, à la fois exprimée de manière pré synaptique mais également indépendant de la synthèse de protéine a pu être observé. Au contraire, une potentialisation induite et exprimée au niveau pré synaptique ainsi que dépendante de la synthèse de protéine a pu être trouvé uniquement dans les cellules de type nAC. De plus, une hyperexcitabilité, dépendante des récepteurs NMDA a pu être observé, avec une sélection préférentielle des cellules du type nAC dans la génération de bursts. Nous avons également pu démontrer que la transformation d'un certain nombre de cellules de type AC en cellules dites nAC accompagnait cette augmentation générale de l'excitabilité de l'AL. Du faite da la grande quantité d'indices suggérant une connexion entre le système noradrénergique et les états de peur/d'anxiété, les effets d'une forte activation de l'AL sur ce dernier ont été investigués et ont révélés une perte de sa capacité de modulation du 'spiking pattern'. Finalement, des changements au niveau de l'expression d'un certain nombre de gènes, incluant celui codant pour le BDNF, a pu être trouvé à la suite d'une forte activation de l'AL. En raison du lien récemment décrit entre l'expression de la forme active de CREB et des cellules de type nAC ainsi que celui de l'implication des cellules de l'AL connectés de manière récurrente dans l'apprentissage de la peur, nos résultats nous permettent de suggérer un modèle expliquant comment la potentialisation des connections récurrentes entre cellules de type nAC pourrait être à la base de leur recrutement sélectif pendant le conditionnement de la peur. De plus, ils peuvent offrir des indices par rapport aux mécanismes à travers lesquels une sous population de neurones peut être réactivée par une stimulation externe précédemment inefficace, et induire ainsi un signal suffisamment fort pour qu'il soit transmit aux structures efférentes de l'AL. Abstract : The lateral nucleus of the amygdala (LA) is critically involved in the plasticity underlying fear-conditioned learning (Sah et al., 2008). Even though the majority of cells in the LA receive the necessary sensory inputs, potentiation in only a subset is required for fear learning to occur (Repa et al., 2001; Rumpel et al., 2005). These cells express active CREB (CAMP-responsive element-binding protein) (Han et al., 200, and this was related to the non-accommodating (nAC) spiking phenotype (Viosca et al., 2009; Zhou et al., 2009). In addition, a very recent study implicated recurrently connected cells of the LA in fear conditioned learning (Johnson et al., 2008). A link between the two observations has however never been made. In rats, we used an in vitro protocol of strong activation of the LA, resulting in bursting activity, which spread from the hippocampus to the LA. Within the LA, this activity reached all cells and spread via a multitude of pathways. Using this model, we were able to link, for the first time, recurrently connected cells in the LA with cells of the nAC phenotype. While we found a presynaptically expressed, protein synthesis independent decrease in inhibitory synaptic transmission in both nAC and accommodating (AC) cells, only nAC cells underwent a presynaptically induced and expressed, protein synthesis dependent potentiation. Moreover we observed an NMDA dependent hyperexcitability of the LA, with a preferential selection of nAC cells into burst generation. The transformation of a subset of AC cells into nAC cells accompanied this general increase in LA excitability. Given the considerable evidence suggesting a relationship between the central noradrenergic (NA) system and fear/anxiety states (Itoi, 2008), the effects of strong activation of the LA on the noradrenergic system were investigated, which revealed a loss of its modulatory actions on cell spiking patterns. Finally, we found changes in the expression levels of a number of genes; among which the one coding for $DNF, to be induced by strong activation of the LA. In view of the recently described link between nAC cells and expression of pCREB (phosphorylated cAMP-responsive element-binding protein) as well as the involvement of recurrently connected cells of the LA in fear-conditioned learning, our findings may provide a model of how potentiation of recurrent connections between nAC neurons underlies their recruitment into the fear memory trace. Additionally, they may offer clues as to the mechanisms through which a selected subset of neurons can be reactivated by smaller, previously ineffective external stimulations to respond with a sufficiently strong signal, which can be transmitted to downstream targets of the LA.

Investigation of High-Strength Bolt-Tightening Verification Techniques, RB07-014

The current means and methods of verifying that high-strength bolts have been properly tightened are very laborious and time consuming. In some cases, the techniques require special equipment and, in other cases, the verification itself may be somewhat subjective. While some commercially available verification techniques do exist, these options still have some limitations and might be considered costly options. The main objectives of this project were to explore high-strength bolt-tightening and verification techniques and to investigate the feasibility of developing and implementing new alternatives. A literature search and a survey of state departments of transportation (DOTs) were conducted to collect information on various bolt-tightening techniques such that an understanding of available and under-development techniques could be obtained. During the literature review, the requirements for materials, inspection, and installation methods outlined in the Research Council on Structural Connections specification were also reviewed and summarized. To guide the search for finding new alternatives and technology development, a working group meeting was held at the Iowa State University Institute for Transportation October 12, 2015. During the meeting, topics central to the research were discussed with Iowa DOT engineers and other professionals who have relevant experiences.

Identification of neuronal network properties from the spectral analysis of calcium imaging signals in neuronal cultures

Neuronal networks in vitro are prominent systems to study the development of connections in living neuronal networks and the interplay between connectivity, activity and function. These cultured networks show a rich spontaneous activity that evolves concurrently with the connectivity of the underlying network. In this work we monitor the development of neuronal cultures, and record their activity using calcium fluorescence imaging. We use spectral analysis to characterize global dynamical and structural traits of the neuronal cultures. We first observe that the power spectrum can be used as a signature of the state of the network, for instance when inhibition is active or silent, as well as a measure of the network's connectivity strength. Second, the power spectrum identifies prominent developmental changes in the network such as GABAA switch. And third, the analysis of the spatial distribution of the spectral density, in experiments with a controlled disintegration of the network through CNQX, an AMPA-glutamate receptor antagonist in excitatory neurons, reveals the existence of communities of strongly connected, highly active neurons that display synchronous oscillations. Our work illustrates the interest of spectral analysis for the study of in vitro networks, and its potential use as a network-state indicator, for instance to compare healthy and diseased neuronal networks.

Schizophrenia: glutathione deficit as a new vulnerability factor for disconnectivity syndrome

(from the journal abstract) Schizophrenia, a major psychiatric disease, affects individuals in the centre of their personality. Its aetiology is not clearly established. In this review, we will present evidence that patients suffering of schizophrenia present a brain deficit in glutathione, a major endogenous redox regulator and antioxidant. We will also show that, in experimental models, a decrease in glutathione, particularly during development, induces morphological, electrophysiological and behavioural anomalies consistent with those observed in the disease. In the cerebrospinal fluid of drug-naive schizophrenics, glutathione level was decreased by 27% and its direct metabolite of glutathione by 16%. Glutathione level in prefrontal cortex of patients, measured by magnetic resonance spectroscopy, was 52% lower than in controls. Patients' fibroblasts reveal a decrease in mRNA levels of the two glutathione synthesising enzymes, glutamatecysteine ligase modulatory subunit (GCLM) and glutathione synthetase. GCLM expression level in fibroblasts correlates negatively with symptoms severity. Glutathione is an important endogenous redox regulator and neuroactive substance. It is protecting cells from damage by reactive oxygen species generated, among others, by dopamine metabolism. A glutathione deficit-induced oxidative stress would lead to lipid peroxidation and micro-lesions at the level of dendritic spines, a synaptic damage responsible for abnormal nervous connections or structural disconnectivity. On the other hand, a glutathione deficit could also lead to a functional disconnectivity by depressing NMDA neurotransmission, in analogy to phencyclidine effects. Present experimental data are consistent with the proposed hypothesis: decreasing pharmacologically glutathione level in experimental models, with or without blocking dopamine (DA) uptake (GBR12909), induces morphological, electrophysiological and behavioural changes similar to those observed in patients. In summary, a deficit of glutathione and/or glutathione-related enzymes during early development would lead to both a functional and a structural disconnectivity, which could be at the basis of some perceptive, cognitive and behavioural troubles of the disease. It could constitute a major vulnerability factor for schizophrenia. Attempts to restore physiological glutathione functions could open new therapeutic avenues. This translational research, made possible by a close interaction between clinicians and neuroscientists, should also pave the way to the identification of biological markers for schizophrenia. In turn, they should allow early diagnostic and hopefully preventive intervention to this devastating disease. (PsycINFO Database Record (c) 2005 APA, all rights reserved)

Sea-level changes and ammonite faunal turnover during the Lias/Dogger transition in the western Tethys

The aim of this paper was to investigate the possible connections between ammonite faunal turnover and the eustatic events recorded in Tethyan sequences during the middle Toarcian/early Bajocian time interval. For this we have analysed the biostratigraphic ranges, at the subzone level, of approximately 600 ammonite species belonging to 160 genera from several selected sections of the western Tethys (Mediterranean and Submediterranean provinces). The analysis of taxon ranges enabled us to plot curves for ammonite faunal turnovers, inter-subzonal distance, and diversity. Comparing the mentioned curves with Tethyan sequences [Hardenbol et al., 19981, we find that sea-level changes correlate well with origination and extinction events and faunal diversity. Most of the faunal turnovers correlate with stratigraphic events. Extinction events with their corresponding decrease in diversity correlate with regressive intervals and with major or minor sequence boundaries. Origination events and their corresponding increase in diversity were clearly connected with transgressions in Tethyan sequences. In several cases, the major sequence boundary and the subsequent transgressive phase correlate with major ammonite faunal turnover, whereas minor or medium sequence boundaries generally gave rise to minor or medium turnovers.

A Continuous Span Aluminum Girder Concrete Deck Bridge - Part 2 of 2: Fatigue Tests of Aluminum Girders, Final Report, 1997

In 1957, the Iowa State Highway Commission, with financial assistance from the aluminum industry, constructed a 220-ft (67-m) long, four-span continuous, aluminum girder bridge to carry traffic on Clive Road (86th Street) over Interstate 80 near Des Moines, Iowa. The bridge had four, welded I-shape girders that were fabricated in pairs with welded diaphragms between an exterior and an interior girder. The interior diaphragms between the girder pairs were bolted to girder brackets. A composite, reinforced concrete deck served as the roadway surface. The bridge, which had performed successfully for about 35 years of service, was removed in the fall of 1993 to make way for an interchange at the same location. Prior to the bridge demolition, load tests were conducted to monitor girder and diaphragm bending strains and deflections in the northern end span. Fatigue testing of the aluminum girders that were removed from the end spans were conducted by applying constant-amplitude, cyclic loads. These tests established the fatigue strength of an existing, welded, flange-splice detail and added, welded, flange-cover plates and horizontal web plate attachment details. This part, Part 2, of the final report focuses on the fatigue tests of the aluminum girder sections that were removed from the bridge and on the analysis of the experimental data to establish the fatigue strength of full-size specimens. Seventeen fatigue fractures that were classified as Category E weld details developed in the seven girder test specimens. Linear regression analyses of the fatigue test results established both nominal and experimental stress-range versus load cycle relationships (SN curves) for the fatigue strength of fillet-welded connections. The nominal strength SN curve obtained by this research essentially matched the SN curve for Category E aluminum weldments given in the AASHTO LRFD specifications. All of the Category E fatigue fractures that developed in the girder test specimens satisfied the allowable SN relationship specified by the fatigue provisions of the Aluminum Association. The lower-bound strength line that was set at two standard deviations below the least squares regression line through the fatigue fracture data points related well with the Aluminum Association SN curve. The results from the experimental tests of this research have provided additional information regarding behavioral characteristics of full-size, aluminum members and have confirmed that aluminum has the strength properties needed for highway bridge girders.

A connectome-based comparison of diffusion MRI schemes.

Diffusion MRI has evolved towards an important clinical diagnostic and research tool. Though clinical routine is using mainly diffusion weighted and tensor imaging approaches, Q-ball imaging and diffusion spectrum imaging techniques have become more widely available. They are frequently used in research-oriented investigations in particular those aiming at measuring brain network connectivity. In this work, we aim at assessing the dependency of connectivity measurements on various diffusion encoding schemes in combination with appropriate data modeling. We process and compare the structural connection matrices computed from several diffusion encoding schemes, including diffusion tensor imaging, q-ball imaging and high angular resolution schemes, such as diffusion spectrum imaging with a publically available processing pipeline for data reconstruction, tracking and visualization of diffusion MR imaging. The results indicate that the high angular resolution schemes maximize the number of obtained connections when applying identical processing strategies to the different diffusion schemes. Compared to the conventional diffusion tensor imaging, the added connectivity is mainly found for pathways in the 50-100mm range, corresponding to neighboring association fibers and long-range associative, striatal and commissural fiber pathways. The analysis of the major associative fiber tracts of the brain reveals striking differences between the applied diffusion schemes. More complex data modeling techniques (beyond tensor model) are recommended 1) if the tracts of interest run through large fiber crossings such as the centrum semi-ovale, or 2) if non-dominant fiber populations, e.g. the neighboring association fibers are the subject of investigation. An important finding of the study is that since the ground truth sensitivity and specificity is not known, the comparability between results arising from different strategies in data reconstruction and/or tracking becomes implausible to understand.

Geochemical compositions of Neogene phosphatic brachiopods: Implications for ancient environmental and marine conditions

Isotopic and trace element compositions of Miocene and Pliocene phosphatic brachiopods (Lingulidae and Discinidae) from southern North Sea, the Central Paratethys and the Atlantic coast of Europe were investigated in order to trace past environmental conditions and marine connections between the northern boreal and the southern subtropical-tropical marine basins. The North Sea genus Glottidia yielded low epsilon(Nd) and high delta O-18(PO4) values through the Mio-Pliocene indicating cold habitat temperature where the local seawater was dominated by the Atlantic Ocean. In contrast, the Middle Miocene Lingulidae and Discinidae of the Paratethys inhabited warm subtropical seawater with the possible influence of the Indian Ocean via the Mediterranean, as supported by their average epsilon(Nd) value of -8.3. The combined geochemical data support a thermal and marine separation of the Paratethys from the North Sea with no direct connection or major exchange of water from the Miocene onwards. The temperature in the Paratethys was very similar to that inferred from brachiopods from the Middle Miocene of western France, but the seawater epsilon(Nd) value here is identical to that of contemporaneous Atlantic Ocean. A Late Miocene lingulid brachiopod from southern Portugal has a high delta O-18(PO4), similar to the specimens investigated from the North Sea, reflecting either a deep water habitat or formation after the onset of major global cooling that resulted in an increased delta O-18 value of seawater. The epsilon(Nd) value of -8.4 for this site is compatible with an influence of Mediterranean outflow. (C) 2012 Elsevier B.V. All rights reserved.

Ultrastructural analysis of neuronal plasticity in the adult mouse

ABSTRACT Adult neuronal plasticity is a term that corresponds to a set of biological mechanisms allowing a neuronal circuit to respond and adapt to modifications of the received inputs. Mystacial whiskers of the mouse are the starting point of a major sensory pathway that provides the animal with information from its immediate environment. Through whisking, information is gathered that allows the animal to orientate itself and to recognize objects. This sensory system is crucial for nocturnal behaviour during which vision is not of much use. Sensory information of the whiskers are sent via brainstem and thalamus to the primary somatosensory area (S1) of the cerebral cortex in a strictly topological manner. Cell bodies in the layer N of S 1 are arranged in ring forming structures called barrels. As such, each barrel corresponds to the cortical representation in layer IV of a single whisker follicle. This histological feature allows to identify with uttermost precision the part of the cortex devoted to a given whisker and to study modifications induced by different experimental conditions. The condition used in the studies of my thesis is the passive stimulation of one whisker in the adult mouse for a period of 24 hours. It is performed by glueing a piece of metal on one whisker and placing the awake animal in a cage surrounded by an electromagnetic coil that generates magnetic field burst inducing whisker movement at a given frequency during 24 hours. I analysed the ultrastructure of the barrel corresponding the stimulated whisker using serial sections electron microscopy and computer-based three-dimensional reconstructions; analysis of neighbouring, unstimulated barrels as well as those from unstimulated mice served as control. The following elements were structurally analyzed: the spiny dendrites, the axons of excitatory as well as inhibitory cells, their connections via synapses and the astrocytic processes. The density of synapses and spines is upregulated in a barrel corresponding to a stimulated whisker. This upregulation is absent in the BDNF heterozygote mice, indicating that a certain level of activity-dependent released BDNF is required for synaptogenesis in the adult cerebral cortex. Synpaptogenesis is correlated with a modification of the astrocytes that place themselves in closer vicinity of the excitatory synapses on spines. Biochemical analysis revealed that the astrocytes upregulate the expression of transporters by which they internalise glutamate, the neurotransmitter responsible for the excitatory response of cortical neurons. In the final part of my thesis, I show that synaptogenesis in the stimulated barrel is due to the increase in the size of excitatory axonal boutons that become more frequently multisynaptic, whereas the inhibitory axons do not change their morphology but form more synapses with spines apposed to them. Taken together, my thesis demonstrates that all the cellular elements present in the neuronal tissue of the adult brain contribute to activity-dependent cortical plasticity and form part of a mechanism by which the animal responds to a modified sensory experience. Throughout life, the neuronal circuit keeps the faculty to adapt its function. These adaptations are partially transitory but some aspects remain and could be the structural basis of a memory trace in the cortical circuit. RESUME La plasticité neuronale chez l'adulte désigne un ensemble de mécanismes biologiques qui permettent aux circuits neuronaux de répondre et de s'adapter aux modifications des stimulations reçues. Les vibrisses des souris sont un système crucial fournissant des informations sensorielles au sujet de l'environnement de l'animal. L'information sensorielle collectée par les vibrisses est envoyée via le tronc cérébral et le thalamus à l'aire sensorielle primaire (S 1) du cortex cérébral en respectant strictement la somatotopie. Les corps cellulaires dans la couche IV de S 1 sont organisés en anneaux délimitant des structures nommées tonneaux. Chaque tonneau reçoit l'information d'une seule vibrisse et l'arrangement des tonneaux dans le cortex correspond à l'arrangement des vibrisses sur le museau de la souris. Cette particularité histologique permet de sélectionner avec certitude la partie du cortex dévolue à une vibrisse et de l'étudier dans diverses conditions. Le paradigme expérimental utilisé dans cette thèse est la stimulation passive d'une seule vibrisse durant 24 heures. Pour ce faire, un petit morceau de métal est collé sur une vibrisse et la souris est placée dans une cage entourée d'une bobine électromagnétique générant un champ qui fait vibrer le morceau de métal durant 24 heures. Nous analysons l'ultrastructure du cortex cérébral à l'aide de la microscopie électronique et des coupes sériées permettant la reconstruction tridimensionnelle à l'aide de logiciels informatiques. Nous observons les modifications des structures présentes : les dendrites épineuses, les axones des cellules excitatrices et inhibitrices, leurs connections par des synapses et les astrocytes. Le nombre de synapses et d'épines est augmenté dans un tonneau correspondant à une vibrisse stimulée 24 heures. Basé sur cela, nous montrons dans ces travaux que cette réponse n'est pas observée dans des souris hétérozygotes BDNF+/-. Cette neurotrophine sécrétée en fonction de l'activité neuronale est donc nécessaire pour la synaptogenèse. La synaptogenèse est accompagnée d'une modification des astrocytes qui se rapprochent des synapses excitatrices au niveau des épines dendritiques. Ils expriment également plus de transporteurs chargés d'internaliser le glutamate, le neurotransmetteur responsable de la réponse excitatrice des neurones. Nous montrons aussi que les axones excitateurs deviennent plus larges et forment plus de boutons multi-synaptiques à la suite de la stimulation tandis que les axones inhibiteurs ne changent pas de morphologie mais forment plus de synapses avec des épines apposées à leur membrane. Tous les éléments analysés dans le cerveau adulte ont maintenu la capacité de réagir aux modifications de l'activité neuronale et répondent aux modifications de l'activité permettant une constante adaptation à de nouveaux environnements durant la vie. Les circuits neuronaux gardent la capacité de créer de nouvelles synapses. Ces adaptations peuvent être des réponses transitoires aux stimuli mais peuvent aussi laisser une trace mnésique dans les circuits.

A new early and automated MRI-based predictor of motor improvement after stroke.

OBJECTIVES: In this study, we investigated the structural plasticity of the contralesional motor network in ischemic stroke patients using diffusion magnetic resonance imaging (MRI) and explored a model that combines a MRI-based metric of contralesional network integrity and clinical data to predict functional outcome at 6 months after stroke. METHODS: MRI and clinical examinations were performed in 12 patients in the acute phase, at 1 and 6 months after stroke. Twelve age- and gender-matched controls underwent 2 MRIs 1 month apart. Structural remodeling after stroke was assessed using diffusion MRI with an automated measurement of generalized fractional anisotropy (GFA), which was calculated along connections between contralesional cortical motor areas. The predictive model of poststroke functional outcome was computed using a linear regression of acute GFA measures and the clinical assessment. RESULTS: GFA changes in the contralesional motor tracts were found in all patients and differed significantly from controls (0.001 ≤ p < 0.05). GFA changes in intrahemispheric and interhemispheric motor tracts correlated with age (p ≤ 0.01); those in intrahemispheric motor tracts correlated strongly with clinical scores and stroke sizes (p ≤ 0.001). GFA measured in the acute phase together with a routine motor score and age were a strong predictor of motor outcome at 6 months (r(2) = 0.96, p = 0.0002). CONCLUSION: These findings represent a proof of principle that contralesional diffusion MRI measures may provide reliable information for personalized rehabilitation planning after ischemic motor stroke. Neurology® 2012;79:39-46.

Mechanisms underlying functional recovery after in vivo focal cerebral ischemia : from preconditioning to diffusion MRI

Version abregée L'ischémie cérébrale est la troisième cause de mort dans les pays développés, et la maladie responsable des plus sérieux handicaps neurologiques. La compréhension des bases moléculaires et anatomiques de la récupération fonctionnelle après l'ischémie cérébrale est donc extrêmement importante et représente un domaine d'intérêt crucial pour la recherche fondamentale et clinique. Durant les deux dernières décennies, les chercheurs ont tenté de combattre les effets nocifs de l'ischémie cérébrale à l'aide de substances exogènes qui, bien que testées avec succès dans le domaine expérimental, ont montré un effet contradictoire dans l'application clinique. Une approche différente mais complémentaire est de stimuler des mécanismes intrinsèques de neuroprotection en utilisant le «modèle de préconditionnement» : une brève insulte protège contre des épisodes d'ischémie plus sévères à travers la stimulation de voies de signalisation endogènes qui augmentent la résistance à l'ischémie. Cette approche peut offrir des éléments importants pour clarifier les mécanismes endogènes de neuroprotection et fournir de nouvelles stratégies pour rendre les neurones et la glie plus résistants à l'attaque ischémique cérébrale. Dans un premier temps, nous avons donc étudié les mécanismes de neuroprotection intrinsèques stimulés par la thrombine, un neuroprotecteur «préconditionnant» dont on a montré, à l'aide de modèles expérimentaux in vitro et in vivo, qu'il réduit la mort neuronale. En appliquant une technique de microchirurgie pour induire une ischémie cérébrale transitoire chez la souris, nous avons montré que la thrombine peut stimuler les voies de signalisation intracellulaire médiées par MAPK et JNK par une approche moléculaire et l'analyse in vivo d'un inhibiteur spécifique de JNK (L JNK) .Nous avons également étudié l'impact de la thrombine sur la récupération fonctionnelle après une attaque et avons pu démontrer que ces mécanismes moléculaires peuvent améliorer la récupération motrice. La deuxième partie de cette étude des mécanismes de récupération après ischémie cérébrale est basée sur l'investigation des bases anatomiques de la plasticité des connections cérébrales, soit dans le modèle animal d'ischémie transitoire, soit chez l'homme. Selon des résultats précédemment publiés par divers groupes ,nous savons que des mécanismes de plasticité aboutissant à des degrés divers de récupération fonctionnelle sont mis enjeu après une lésion ischémique. Le résultat de cette réorganisation est une nouvelle architecture fonctionnelle et structurelle, qui varie individuellement selon l'anatomie de la lésion, l'âge du sujet et la chronicité de la lésion. Le succès de toute intervention thérapeutique dépendra donc de son interaction avec la nouvelle architecture anatomique. Pour cette raison, nous avons appliqué deux techniques de diffusion en résonance magnétique qui permettent de détecter les changements de microstructure cérébrale et de connexions anatomiques suite à une attaque : IRM par tenseur de diffusion (DT-IR1V) et IRM par spectre de diffusion (DSIRM). Grâce à la DT-IRM hautement sophistiquée, nous avons pu effectuer une étude de follow-up à long terme chez des souris ayant subi une ischémie cérébrale transitoire, qui a mis en évidence que les changements microstructurels dans l'infarctus ainsi que la modification des voies anatomiques sont corrélés à la récupération fonctionnelle. De plus, nous avons observé une réorganisation axonale dans des aires où l'on détecte une augmentation d'expression d'une protéine de plasticité exprimée dans le cône de croissance des axones (GAP-43). En appliquant la même technique, nous avons également effectué deux études, rétrospective et prospective, qui ont montré comment des paramètres obtenus avec DT-IRM peuvent monitorer la rapidité de récupération et mettre en évidence un changement structurel dans les voies impliquées dans les manifestations cliniques. Dans la dernière partie de ce travail, nous avons décrit la manière dont la DS-IRM peut être appliquée dans le domaine expérimental et clinique pour étudier la plasticité cérébrale après ischémie. Abstract Ischemic stroke is the third leading cause of death in developed countries and the disease responsible for the most serious long-term neurological disability. Understanding molecular and anatomical basis of stroke recovery is, therefore, extremely important and represents a major field of interest for basic and clinical research. Over the past 2 decades, much attention has focused on counteracting noxious effect of the ischemic insult with exogenous substances (oxygen radical scavengers, AMPA and NMDA receptor antagonists, MMP inhibitors etc) which were successfully tested in the experimental field -but which turned out to have controversial effects in clinical trials. A different but complementary approach to address ischemia pathophysiology and treatment options is to stimulate and investigate intrinsic mechanisms of neuroprotection using the "preconditioning effect": applying a brief insult protects against subsequent prolonged and detrimental ischemic episodes, by up-regulating powerful endogenous pathways that increase resistance to injury. We believe that this approach might offer an important insight into the molecular mechanisms responsible for endogenous neuroprotection. In addition, results from preconditioning model experiment may provide new strategies for making brain cells "naturally" more resistant to ischemic injury and accelerate their rate of functional recovery. In the first part of this work, we investigated down-stream mechanisms of neuroprotection induced by thrombin, a well known neuroprotectant which has been demonstrated to reduce stroke-induced cell death in vitro and in vivo experimental models. Using microsurgery to induce transient brain ischemia in mice, we showed that thrombin can stimulate both MAPK and JNK intracellular pathways through a molecular biology approach and an in vivo analysis of a specific kinase inhibitor (L JNK1). We also studied thrombin's impact on functional recovery demonstrating that these molecular mechanisms could enhance post-stroke motor outcome. The second part of this study is based on investigating the anatomical basis underlying connectivity remodeling, leading to functional improvement after stroke. To do this, we used both a mouse model of experimental ischemia and human subjects with stroke. It is known from previous data published in literature, that the brain adapts to damage in a way that attempts to preserve motor function. The result of this reorganization is a new functional and structural architecture, which will vary from patient to patient depending on the anatomy of the damage, the biological age of the patient and the chronicity of the lesion. The success of any given therapeutic intervention will depend on how well it interacts with this new architecture. For this reason, we applied diffusion magnetic resonance techniques able to detect micro-structural and connectivity changes following an ischemic lesion: diffusion tensor MRI (DT-MRI) and diffusion spectrum MRI (DS-MRI). Using DT-MRI, we performed along-term follow up study of stroke mice which showed how diffusion changes in the stroke region and fiber tract remodeling is correlating with stroke recovery. In addition, axonal reorganization is shown in areas of increased plasticity related protein expression (GAP 43, growth axonal cone related protein). Applying the same technique, we then performed a retrospective and a prospective study in humans demonstrating how specific DTI parameters could help to monitor the speed of recovery and show longitudinal changes in damaged tracts involved in clinical symptoms. Finally, in the last part of this study we showed how DS-MRI could be applied both to experimental and human stroke and which perspectives it can open to further investigate post stroke plasticity.

Neuronal death in the development of the vertebrate central nervous system

Neuronal death occurs naturally in the development of the vertebrate central nervous system, deleting large numbers of neurons at the time when afferent and efferent connections are being formed. It is these that regulate it, by means of anterograde and retrograde survival signals that depend on trophic molecules and electrical activity. Possible roles include the regulation of neuronal numbers (numerical matching) and the elimination of axonal targeting errors.

An Empirical Study on Faculty Perceptions and Teaching Practices of Wikipedia

Some faculty members from different universities around the world have begun to use Wikipedia as a teaching tool in recent years. These experiences show, in most cases, very satisfactory results and a substantial improvement in various basic skills, as well as a positive influence on the students' motivation. Nevertheless and despite the growing importance of e-learning methodologies based on the use of the Internet for higher education, the use of Wikipedia as a teaching resource remains scarce among university faculty.Our investigation tries to identify which are the main factors that determine acceptance or resistance to that use. We approach the decision to use Wikipedia as a teaching tool by analyzing both the individual attributes of faculty members and the characteristics of the environment where they develop their teaching activity. From a specific survey sent to all faculty of the Universitat Oberta de Catalunya (UOC), pioneer and leader in online education in Spain, we have tried to infer the influence of these internal and external elements. The questionnaire was designed to measure different constructs: perceived quality of Wikipedia, teaching practices involving Wikipedia, use experience, perceived usefulness and use of 2.0 tools. Control items were also included for gathering information on gender, age, teaching experience, academic rank, and area of expertise.Our results reveal that academic rank, teaching experience, age or gender, are not decisive factors in explaining the educational use of Wikipedia. Instead, the decision to use it is closely linked to the perception of Wikipedia's quality, the use of other collaborative learning tools, an active attitude towards web 2.0 applications, and connections with the professional non-academic world. Situational context is also very important, since the use is higher when faculty members have got reference models in their close environment and when they perceive it is positively valued by their colleagues. As far as these attitudes, practices and cultural norms diverge in different scientific disciplines, we have also detected clear differences in the use of Wikipedia among areas of academic expertise. As a consequence, a greater application of Wikipedia both as a teaching resource and as a driver for teaching innovation would require much more active institutional policies and some changes in the dominant academic culture among faculty members.

Linear and nonlinear terrain deformation maps from a reduced set of interferometric SAR images

In this paper, an advanced technique for the generation of deformation maps using synthetic aperture radar (SAR) data is presented. The algorithm estimates the linear and nonlinear components of the displacement, the error of the digital elevation model (DEM) used to cancel the topographic terms, and the atmospheric artifacts from a reduced set of low spatial resolution interferograms. The pixel candidates are selected from those presenting a good coherence level in the whole set of interferograms and the resulting nonuniform mesh tessellated with the Delauney triangulation to establish connections among them. The linear component of movement and DEM error are estimated adjusting a linear model to the data only on the connections. Later on, this information, once unwrapped to retrieve the absolute values, is used to calculate the nonlinear component of movement and atmospheric artifacts with alternate filtering techniques in both the temporal and spatial domains. The method presents high flexibility with respect to the required number of images and the baselines length. However, better results are obtained with large datasets of short baseline interferograms. The technique has been tested with European Remote Sensing SAR data from an area of Catalonia (Spain) and validated with on-field precise leveling measurements.

Timing of Capacity Change: Models for Capital Intensive Industry

The suitable timing of capacity investments is a remarkable issue especially in capital intensive industries. Despite its importance, fairly few studies have been published on the topic. In the present study models for the timing of capacity change in capital intensive industry are developed. The study considers mainly the optimal timing of single capacity changes. The review of earlier research describes connections between cost, capacity and timing literature, and empirical examples are used to describe the starting point of the study and to test the developed models. The study includes four models, which describe the timing question from different perspectives. The first model, which minimizes unit costs, has been built for capacity expansion and replacement situations. It is shown that the optimal timing of an investment can be presented with the capacity and cost advantage ratios. After the unit cost minimization model the view is extended to the direction of profit maximization. The second model states that early investments are preferable if the change of fixed costs is small compared to the change of the contribution margin. The third model is a numerical discounted cash flow model, which emphasizes the roles of start-up time, capacity utilization rate and value of waiting as drivers of the profitable timing of a project. The last model expands the view from project level to company level and connects the flexibility of assets and cost structures to the timing problem. The main results of the research are the solutions of the models and analysis or simulations done with the models. The relevance and applicability of the results are verified by evaluating the logic of the models and by numerical cases.