INTERCELLULAR AND SYSTEM-LEVEL ASPECTS OF THE METABOLIC INTERACTIONS BETWEEN NEURONS AND GLIA

Quand on parle de l'acide lactique (aussi connu sous le nom de lactate) une des premières choses qui vient à l'esprit, c'est son implication en cas d'intense activité musculaire. Sa production pendant une activité physique prolongée est associée avec la sensation de fatigue. Il n'est donc pas étonnant que cette molécule ait été longtemps considérée comme un résidu du métabolisme, possiblement toxique et donc à éliminer. En fait, il a été découvert que le lactate joue un rôle prépondérant dans le métabolisme grâce à son fort potentiel énergétique. Le cerveau, en particulier les neurones qui le composent, est un organe très gourmand en énergie. Récemment, il a été démontré que les astrocytes, cellules du cerveau faisant partie de la famille des cellules gliales, utilisent le glucose pour produire du lactate comme source d'énergie et le distribue aux neurones de manière adaptée à leur activité. Cette découverte a renouvelé l'intérêt scientifique pour le lactate. Aujourd'hui, plusieurs études ont démontré l'implication du lactate dans d'autres fonctions de la physiologie cérébrale. Dans le cadre de notre étude, nous nous sommes intéressés au rapport entre neurones et astrocytes avec une attention particulière pour le rôle du lactate. Nous avons découvert que le lactate possède la capacité de modifier la communication entre les neurones. Nous avons aussi décrypté le mécanisme grâce auquel le lactate agit, qui est basé sur un récepteur présent à la surface des neurones. Cette étude montre une fonction jusque-là insoupçonnée du lactate qui a un fort impact sur la compréhension de la relation entre neurones et astrocytes. - Relatively to its volume, the brain uses a large amount of glucose as energy source. Furthermore, a tight link exists between the level of synaptic activity and the consumption of energy equivalents. Astrocytes have been shown to play a central role in the regulation of this so-called neurometabolic coupling. They are thought to deliver the metabolic substrate lactate to neurons in register to glutamatergic activity. The astrocytic uptake of glutamate, released in the synaptic cleft, is the trigger signal that activates an intracellular cascade of events that leads to the production and release of lactate from astrocytes. The main goal of this thesis work was to obtain detailed information on the metabolic and functional interplay between neurons and astrocytes, in particular on the influence of lactate besides its metabolic effects. To gain access to both spatial and temporal aspects of these dynamic interactions, we used optical microscopy associated with specific fluorescent indicators, as well as electrophysiology. In the first part of this thesis, we show that lactate decreases spontaneous neuronal, activity in a concentration-dependent manner and independently of its metabolism. We further identified a receptor-mediated pathway underlying this modulatory action of lactate. This finding constituted a novel mechanism for the modulation of neuronal transmission by lactate. In the second part, we have undergone a characterization of a new pharmacological tool, a high affinity glutamate transporter inhibitor. The finality of this study was to investigate the detailed pharmacological properties of the compound to optimize its use as a suppressor of glutamate signal from neuron to astrocytes. In conclusion, both studies have implications not only for the understanding of the metabolic cooperation between neurons and astrocytes, but also in the context of the glial modulation of neuronal activity. - Par rapport à son volume, le cerveau utilise une quantité massive de glucose comme source d'énergie. De plus, la consommation d'équivalents énergétiques est étroitement liée au niveau d'activité synaptique. Il a été montré que dans ce couplage neurométabolique, un rôle central est joué par les astrocytes. Ces cellules fournissent le lactate, un substrat métabolique, aux neurones de manière adaptée à leur activité glutamatergique. Plus précisément, le glutamate libéré dans la fente synaptique par les neurones, est récupéré par les astrocytes et déclenche ainsi une cascade d'événements intracellulaires qui conduit à la production et libération de lactate. Les travaux de cette thèse ont visé à étudier la relation métabolique et fonctionnelle entre neurones et astrocytes, avec une attention particulière pour des rôles que pourrait avoir le lactate au-delà de sa fonction métabolique. Pour étudier les aspects spatio-temporels de ces interactions dynamiques, nous avons utilisé à la fois la microscopie optique associée à des indicateurs fluorescents spécifiques, ainsi que l'électrophysiologie. Dans la première partie de cette thèse, nous montrons que le lactate diminue l'activité neuronale spontanée de façon concentration-dépendante et indépendamment de son métabolisme. Nous avons identifié l'implication d'un récepteur neuronal au lactate qui sous-tend ce mécanisme de régulation. La découverte de cette signalisation via le lactate constitue un mode d'interaction supplémentaire et nouveau entre neurones et astrocytes. Dans la deuxième partie, nous avons caractérisé un outil pharmacologique, un inhibiteur des transporteurs du glutamate à haute affinité. Le but de cette étude était d'obtenir un agent pharmacologique capable d'interrompre spécifiquement le signal médié par le glutamate entre neurones et astrocytes pouvant permettre de mieux comprendre leur relation. En conclusion, ces études ont une implication non seulement pour la compréhension de la coopération entre neurones et astrocytes mais aussi dans le contexte de la modulation de l'activité neuronale par les cellules gliales.

Regulated exocytosis from astrocytes physiological and pathological related aspects.

Astrocytes have traditionally been considered ancillary, satellite cells of the nervous system. However, it is a very recent acquisition that glial cells generate signaling loops which are integral to the brain circuitry and participate, interactively with neuronal networks, in the processing of information. Such a conceptual breakthrough makes this field of investigation one of the hottest in neuroscience, as it calls for a revision of past theories of brain function as well as for new strategies of experimental exploration of brain function. Glial cells are electrically not excitable, and it was only the use of optical recording techniques together with calcium sensitive dyes, that allowed the chemical excitability of glial cells to become apparent. Studies using these new techniques have shown for the first time that glial cells are activated by surrounding synaptic activity and translate neuronal signals into their own calcium code. Intracellular calcium concentration([Ca2+]i) elevations in glial cells have then shown to underlie spatial transfer of information in the glial network, accompanied by release of chemical transmitters (gliotransmitters) such as glutamate and back-signaling to neurons. As a consequence, optical imaging techniques applied to cell cultures or intact tissue have become a state-of-the-art technology for studying glial cell signaling. The molecular mechanisms leading to release of "gliotransmitters," especially glutamate, from glia are under debate. Accumulating evidence clearly indicates that astrocytes secrete numerous transmitters by Ca(2+)-dependent exocytosis. This review will discuss the mechanisms underlying the release of chemical transmitters from astrocytes with a particular emphasis to the regulated exocytosis processes.

Citizenship education in Switzerland before, during and after the First World War

Citizenship education was intensively discussed during the 1910s. Patriotic ideals and the love of the fatherland were described with diligence in teachers' journals. After the outbreak of the World War I, Swiss teachers reacted immediately to the new circumstances and published lessons in their weekly teacher journals for every day of school for different grade levels. These lessons comprised current events and civic education as well as didactical instructions for the teacher. In pupils' essays, citizens are often depicted as religious members of society who are industrious and hardworking, whereas in the journals, religious aspects are related to peace but not to citizenship education. As a multilingual and neutral country, Switzerland struggled with major domestic problems due to the cultural conflict between the French- and the German-speaking regions, especially during wartime. However, teachers promoted unity from the beginning. Therefore, changes and continuities during this decade concerning citizenship education are of crucial research interest. The practical sections of teachers' journals, including lessons and didactical instructions, and pupils' essays provide insight into what happened in the classrooms. Which forms of national identity and citizenship were taught in classrooms before, during and shortly after WW1 in public schools in Switzerland? How did pupils describe the current issues of war and citizenship?

Aspects de la représentation de l'autre dans les romans grecs et "Les Métamorphoses" d'Apulée

Les romans grecs et les Métamorphoses d'Apulée - même si les modalités sont différentes pour ce dernier - sont des fictions en prose qui fonctionnent autour de topoi auxquels la figure de l'Autre n'échappe pas. Bien que le monde grec soit alors radicalement différent de ce qu'il était au Ve siècle avant J.-C, période à laquelle l'identité grecque est construite par opposition à la figure du barbare, les romanciers qui prennent la plume à partir du 1er siècle avant notre ère utilisent un certain nombre de stéréotypes hérités de l'époque classique, alors mise à l'honneur par le mouvement de la Seconde Sophistique. Il s'agit d'étudier dans le détail certains éléments de la représentation de l'Autre pour déterminer qui il est, comment il se comporte, ce qui le constitue en Autre. Puis, à partir de cette esquisse, nécessairement incomplète, d'évaluer ce que cette représentation peut induire sur l'image de l'identité grecque à l'époque impériale, par le jeu de miroir que F. Hartog a décelé dans l'oeuvre d'Hérodote. Une première partie est consacrée aux rapports entre l'homme et l'animal ainsi qu'à l'image de la sauvagerie, ce qui permet d'explorer les bornes romanesques de l'humanité. La seconde partie s'attache à des éléments que l'époque classique a plus particulièrement mis en avant pour distinguer les Grecs des non-Grecs : le critère de la langue, l'art de faire la guerre et le discours politique qui est tenu sur les institutions barbares. La troisième partie étudie la place des dieux et des pratiques religieuses dans la définition de l'Autre. J'espère ainsi contribuer à la compréhension du genre romanesque et des représentations culturelles de l'empire « gréco-romain ». -- The Greek novels and The Metamorphoses of Apuleius, even if it is in different terms for the last, are prose fictions which are based on topoi, and the figure of the Other is one of them. Although the Greek world was radically different of what it was in the fifth century BC, time during which Greek identity is contructed as opposed to the figure of the barbaros, the authors of novels, who wrote from the first century BC onward, used some stereotypes inherited from classical period, which was celebrated by the Second Sophistic movement. The aim of this thesis is to study in detail some elements of the representation of the Other to determine who it is, how he behaves, what makes him other. Then, from this sketch, necessarily incomplete, to evaluate what this representation says about the image of Greek identity in the imperial age, according to the play of the mirror detected by F. Hartog in the text of Herodotus. The first part of the thesis is dedicated to the relationship between man and animal and to the image of savagery, in order to explore the novelistic limits of humanity. The second part concentrates on elements that classical period had particularly insisted on to promote the distinction between Greeks and non-Greeks : the linguistic criterion, the way to make war, and the politic discourse on the barbaric institutions. The third part study the place of the gods and of religious practices in the definition of the Other. I hope to contribute to the understanding of novel genre and of cultural representations of the « greco- roman- empire ».

La dépendance à l'égard de l'environnement lors de lésions cérébrales: conduites d'imitation, de préhension et d'utilisation [Environmental dependence in brain lesions: imitative behavior, prehension and utilization].

This paper reviews the literature on clinical signs such as imitation behavior, grasp reaction, manipulation of tools, utilization behavior, environmental dependency, hyperlexia, hypergraphia and echolalia. Some aspects of this semiology are of special interest because they refer to essential notions such as free-will and autonomy.

A collaborative approach for incorporating forensic case data into crime investigation using criminal intelligence analysis and visualisation

There is an increasing awareness that the articulation of forensic science and criminal investigation is critical to the resolution of crimes. However, models and methods to support an effective collaboration between these partners are still poorly expressed or even lacking. Three propositions are borrowed from crime intelligence methods in order to bridge this gap: (a) the general intelligence process, (b) the analyses of investigative problems along principal perspectives: entities and their relationships, time and space, quantitative aspects and (c) visualisation methods as a mode of expression of a problem in these dimensions. Indeed, in a collaborative framework, different kinds of visualisations integrating forensic case data can play a central role for supporting decisions. Among them, link-charts are scrutinised for their abilities to structure and ease the analysis of a case by describing how relevant entities are connected. However, designing an informative chart that does not bias the reasoning process is not straightforward. Using visualisation as a catalyser for a collaborative approach integrating forensic data thus calls for better specifications.

Genetic survey of "spinturnix sp" (Acari, Mesostigmata) and their bat hosts in Western Palearctic

SUMMARY : The coevolution between two intimately associated organisms, like host and parasite, is a widely investigated theme in evolutionary biology. Recently, the use of genetic data in the study of host-parasite systems evidences that the genetic information from some parasites can complement genetic data from their hosts and thus may help to better understand their host's evolutionary history. Phylogenetic and population genetic aspects of bat parasites have been poorly investigated. Spinturnicid mites are highly specialized ectoparasites, exclusively associated with bats and therefore represent an ideal model to extant our knowledge on bat and parasite biology and on their coevolutionary history. In this thesis, I developed several molecular markers (mitochondrial DNA) to compare the genetic patterns of Spinturnix mites with their bat hosts at different levels. The molecular co-phylogeny between Spinturnix sp. and their bat hosts suggests a partial cospeciation and the occurrence of failure to speciate events and multiple host switches. Thus, Spinturnix mites do not exactly mirror the phylogenetic pattern of their hosts, despite their intimate association. Similar roosting habits of the hosts seem to promote host switches between different species, as far as ecological conditions are favourable. The phylogeographic study of the Maghrebian bat M. punicus in the Mediterranean area confirms the presence of M. punicus in North Africa, Corsica and Sardinia and highlights that islands and mainland are genetically highly divergent. The comparison between the parasitic mite S. myoti and the Maghrebian bat suggests that the phylogeographic pattern of the mite is moulded by its host, with open water as main barrier for host and parasite dispersal. Moreover, the unique presence of a European S. myoti lineage on M. punicus from Corsica strongly suggests the former presence of mouse-eared bats (M. myotis and/or M. blythii) in Corsica. By highlighting the probable presence of a nowadays locally extinct host species, S. myoti may represent a good proxy for inferring complex evolutionary history of bat hosts. Finally, population genetic surveys of S. myoti and S. bechsteinii suggest that these mites benefit from close contacts between individuals during the mating season and/or hibernation to disperse among remote colonies. The contrasted genetic patterns of these two distinct bat-mite systems evidence that bat social structure is a determinant factor of the genetic structure of mite populations. Altogether, this PhD thesis demonstrates the usefulness of parasites to gather information about their bat hosts. In addition, my results illustrate how different ecological and biological characteristics of bat species allow the emergence of a surprising diversity in the genetic patterns of the parasites, which may contribute to the diversification and speciation of parasites. RESUME : La co-évolution entre deux organismes intimement liés, comme un parasite et son hôte, fait partie des questions largement étudiées en biologie évolutive. Récemment, l'utilisation de données génétique dans l'étude des interactions hôte-parasite a montré que l'information génétique de certains parasites peut compléter les données génétiques de l'hôte et ainsi peut éclairer l'histoire évolutive de leur hôte. Très peu études ont étudié les interactions entre les chauves-souris et leurs parasites d'un point de vue moléculaire. Les acariens du genre Spinturnix sont des ectoparasites très spécialisés exclusivement associés aux chauves-souris. Ils représentent donc un model idéal pour élargir nos connaissances tant sur l'écologie des parasites de chauves-souris que sur leur coévolution. Durant cette thèse, plusieurs marqueurs moléculaires (ADN mitochondrial) ont été développés pour ainsi comparer la distribution de la variation génétique des parasites du genre Spinturnix avec celle de leurs hôtes, et ceci à différents niveaux. Tout d'abord, la co-phylogénie moléculaire entre les espèces de Spinturnix et les leurs hôtes révèle une co-spéciation partielle ainsi que la présence d'événement de non spéciation et de transferts horizontaux. Ces parasites ne reflètent donc pas entièrement l'histoire évolutive de leurs hôtes, malgré leurs intimes associations. La cohabitation de plusieurs espèces de chauves-souris dans un même gîte permet aux parasites un transfert entre différentes espèces, atténuant ainsi leur degré de co-spéciation. Deuxièmement, l'étude phylogéographique du marin du Maghreb dans le bassin Méditerranéen confirme sa présence en Afrique du Nord, en Corse et en Sardaigne. La comparaison avec un de ses parasites S. myoti suggère que la répartition génétique de S. myoti est façonnée par celle de leurs hôtes, avec les étendues d'eau comme barrière principale tant à la dispersion de l'hôte que de son parasite. De plus, la présence unique d'une lignée européenne de ces parasites sur des marins du Maghreb de Corse suggère fortement la présence du grand ou petit marin en Corse dans le passé. En reflétant la présence potentielle à un endroit donné d'une espèce de chauve-souris actuellement disparue, S. myoti peut représenter une bonne alternative pour comprendre l'histoire évolutive complexe des chauves-souris. Finalement, l'étude des structures génétiques des populations des parasites S. myoti et S. bechsteinii suggère que les contacts corporels entre chauves-souris durant la saison de reproduction ou l'hibernation peuvent permettre la dispersion des parasites entre des colonies éloignées géographiquement. La différence de structure génétique entre ces deux associations particulières montre que la structure génétique des populations de parasites dépend fortement des traits d'histoire de vie de son hôte. Dans l'ensemble, cette thèse démontre l'importance des parasites pour amener des informations sur leurs hôtes, les chauves-souris. Elle illustre aussi comment les différences écologique et biologique des différentes espèces de chauves-souris peuvent amener une étonnante diversité de structure génétique au sein de populations de parasites, ce qui peut peut-être contribuer à la diversification et à la spéciation des parasites.

Changing Religiosity, Changing Politics? The Influence of 'Belonging' and 'Believing' on Political Attitudes in Switzerland

Starting from theories of secularization and of religious individualization, we propose a two-dimensional typology of religiosity and test its impact on political attitudes. Unlike classic conceptions of religiosity used in political studies, our typology simultaneously accounts for an individual's sense of belonging to the church (institutional dimension) and his/her personal religious beliefs (spiritual dimension). Our analysis, based on data from the World Values Survey in Switzerland (1989-2007), shows two main results. First, next to evidence of religious decline, we also find evidence of religious change with an increase in the number of people who "believe without belonging." Second, non-religious individuals and individuals who believe without belonging are significantly more permissive on issues of cultural liberalism than followers of institutionalized forms of religiosity.

Use of DNA profiles for investigation using a simulated national DNA database: Part II. Statistical and ethical considerations on familial searching.

Familial searching consists of searching for a full profile left at a crime scene in a National DNA Database (NDNAD). In this paper we are interested in the circumstance where no full match is returned, but a partial match is found between a database member's profile and the crime stain. Because close relatives share more of their DNA than unrelated persons, this partial match may indicate that the crime stain was left by a close relative of the person with whom the partial match was found. This approach has successfully solved important crimes in the UK and the USA. In a previous paper, a model, which takes into account substructure and siblings, was used to simulate a NDNAD. In this paper, we have used this model to test the usefulness of familial searching and offer guidelines for pre-assessment of the cases based on the likelihood ratio. Siblings of "persons" present in the simulated Swiss NDNAD were created. These profiles (N=10,000) were used as traces and were then compared to the whole database (N=100,000). The statistical results obtained show that the technique has great potential confirming the findings of previous studies. However, effectiveness of the technique is only one part of the story. Familial searching has juridical and ethical aspects that should not be ignored. In Switzerland for example, there are no specific guidelines to the legality or otherwise of familial searching. This article both presents statistical results, and addresses criminological and civil liberties aspects to take into account risks and benefits of familial searching.

The subjectivist interpretation of probability and the problem of individualisation in forensic science

This paper presents and discusses further aspects of the subjectivist interpretation of probability (also known as the 'personalist' view of probabilities) as initiated in earlier forensic and legal literature. It shows that operational devices to elicit subjective probabilities - in particular the so-called scoring rules - provide additional arguments in support of the standpoint according to which categorical claims of forensic individualisation do not follow from a formal analysis under that view of probability theory.