Statistical approaches for synaptic characterization

Synapses are fascinatingly complex transmission units. One of the fundamental features of synaptic transmission is its stochasticity, as neurotransmitter release exhibits variability and possible failures. It is also quantised: postsynaptic responses to presynaptic stimulations are built up of several and similar quanta of current, each of them arising from the release of one presynaptic vesicle. Moreover, they are dynamic transmission units, as their activity depends on the history of previous spikes and stimulations, a phenomenon known as synaptic plasticity. Finally, synapses exhibit a very broad range of dynamics, features, and connection strengths, depending on neuromodulators concentration [5], the age of the subject [6], their localization in the CNS or in the PNS, or the type of neurons [7]. Addressing the complexity of synaptic transmission is a relevant problem for both biologists and theoretical neuroscientists. From a biological perspective, a finer understanding of transmission mechanisms would allow to study possibly synapse-related diseases, or to determine the locus of plasticity and homeostasis. From a theoretical perspective, different normative explanations for synaptic stochasticity have been proposed, including its possible role in uncertainty encoding, energy-efficient computation, or generalization while learning. A precise description of synaptic transmission will be critical for the validation of these theories and for understanding the functional relevance of this probabilistic and dynamical release. A central issue, which is common to all these areas of research, is the problem of synaptic characterization. Synaptic characterization (also called synaptic interrogation [8]) refers to a set of methods for exploring synaptic functions, inferring the value of synaptic parameters, and assessing features such as plasticity and modes of release. This doctoral work sits at the crossroads of experimental and theoretical neuroscience: its main aim is to develop statistical tools and methods to improve synaptic characterization, and hence to bring quantitative solutions to biological questions. In this thesis, we focus on model-based approaches to quantify synaptic transmission, for which different methods are reviewed in Chapter 3. By fitting a generative model of postsynaptic currents to experimental data, it is possible to infer the value of the synapse’s parameters. By performing model selection, we can compare different modelizations of a synapse and thus quantify its features. The main goal of this thesis is thus to develop theoretical and statistical tools to improve the efficiency of both model fitting and model selection. A first question that often arises when recording synaptic currents is how to precisely observe and measure a quantal transmission. As mentioned above, synaptic transmission has been observed to be quantised. Indeed, the opening of a single presynaptic vesicle (and the release of the neurotransmitters it contains) will create a stereotypical postsynaptic current q, which is called the quantal amplitude. As the number of activated presynaptic vesicles increases, the total postsynaptic current will increase in step-like increments of amplitude q. Hence, at chemical synapses, the postsynaptic responses to presynaptic stimulations are built up of k quanta of current, where k is a random variable corresponding to the number of open vesicles. Excitatory postsynaptic current (EPSC) thus follows a multimodal distribution, where each component has its mean located to a multiple kq with k 2 N and has a width corresponding to the recording noise σ. If σ is large with respect to q, these components will fuse into a unimodal distribution, impeding the possibility to identify quantal transmission and to compute q. How to characterize the regime of parameters in which quantal transmission can be identified? This question led us to define a practical identifiability criterion for statistical model, which is presented in Chapter 4. In doing so, we also derive a mean-field approach for fast likelihood computation (Appendix A) and discuss the possibility to use the Bayesian Information Criterion (a classically used model selection criterion) with correlated observations (Appendix B). A second question that is especially relevant for experimentalists is how to optimally stimulate the presynaptic cell in order to maximize the informativeness of the recordings. The parameters of a chemical synapse (namely, the number of presynaptic vesicles N, their release probability p, the quantal amplitude q, the short-term depression time constant τD, etc.) cannot be measured directly, but can be estimated from the synapse’s postsynaptic responses to evoked stimuli. However, these estimates critically depend on the stimulation protocol being used. For instance, if inter-spike intervals are too large, no short-term plasticity will appear in the recordings; conversely, a too high stimulation frequency will lead to a depletion of the presynaptic vesicles and to a poor informativeness of the postsynaptic currents. How to perform Optimal Experiment Design (OED) for synaptic characterization? We developed an Efficient Sampling-Based Bayesian Active Learning (ESB-BAL) framework, which is efficient enough to be used in real-time biological experiments (Chapter 5), and propose a link between our proposed definition of practical identifiability and Optimal Experiment Design for model selection (Chapter 6). Finally, a third biological question to which we ought to bring a theoretical answer is how to make sense of the observed organization of synaptic proteins. Microscopy observations have shown that presynaptic release sites and postsynaptic receptors are organized in ring-like patterns, which are disrupted upon genetic mutations. In Chapter 7, we propose a normative approach to this protein organization, and suggest that it might optimize a certain biological cost function (e.g. the mean current or SNR after vesicle release). The different theoretical tools and methods developed in this thesis are general enough to be applicable not only to synaptic characterization, but also to different experimental settings and systems studied in physiology. Overall, we expect to democratize and simplify the use of quantitative and normative approaches in biology, thus reducing the cost of experimentation in physiology, and paving the way to more systematic and automated experimental designs

Ecological and physiological effects of soil management practices on earthworm communities in French vineyards

International audienceIn recent literature, very few studies have reported the use of the combination of indicators from ecological communities and ecotoxicity biomarkers in field experiments to assess agricultural quality. Therefore, the aim of this study was to determine the influence of three soil management practices of vine inter-rows (chemical weeding, mechanical weeding and grass-covering) on earthworms, in the Gaillac vineyard (South-West France). The sampling, identification and counts of earthworms were performed in spring and autumn over three years in order to determine the influence of the management practices. Focussing on the most abundant species, Aporrectodea nocturna, biomarker assays (glutathione-S-transferase (GST), catalase (CAT) and cholinesterase (ChE) activities) were conducted to check physiological disturbances that are indirectly linked to soil management practices. A strong influence of soil management practices was highlighted on earthworm ecology and physiology in the vine inter-rows. Chemical weeding favoured worm proliferation, but proportionally decreased the number of epi-anecic species. Mechanical weeding dramatically decreased the total number of earthworms, both adults and juveniles, and their biomass. Under these soil farming practices, variations of metabolisation and anti-oxidant enzyme activities were observed, suggesting an increase in pesticide bioavailability. Grass-covering seemed to be the best practice, at least from an environmental point of view. Neurotoxicity enzyme (cholinesterase) activity in vineyard earthworms was not affected by pollutants conventionally sprayed on the vineyard, regardless of soil agricultural practice. It was concluded that soil management practices can both modify earthworm communities and physiology, inducing variations of the following factors: protection against predators, environmental conditions and availability of pesticide and nutrients

Efficient sampling-based Bayesian Active Learning for synaptic characterization

Bayesian Active Learning (BAL) is an efficient framework for learning the parameters of a model, in which input stimuli are selected to maximize the mutual information between the observations and the unknown parameters. However, the applicability of BAL to experiments is limited as it requires performing high-dimensional integrations and optimizations in real time. Current methods are either too time consuming, or only applicable to specific models. Here, we propose an Efficient Sampling-Based Bayesian Active Learning (ESB-BAL) framework, which is efficient enough to be used in real-time biological experiments. We apply our method to the problem of estimating the parameters of a chemical synapse from the postsynaptic responses to evoked presynaptic action potentials. Using synthetic data and synaptic whole-cell patch-clamp recordings, we show that our method can improve the precision of model-based inferences, thereby paving the way towards more systematic and efficient experimental designs in physiology

Caractérisation et modélisation de la transformation martensitique dans l’acier austénitique instable 301

Cette étude concerne un acier austénitique instable AISI 301 fourni à l'état écroui. Les essais mécaniques sont réalisés à différentes températures et vitesses de sollicitations suivant différentes orientations. Un modèle phénoménologique prenant en compte les effets de la transformation martensitique sur le comportement mécanique a été implanté dans le code de calcul par éléments finis Abaqus/Explicit.Les résultats des simulations de pliage obtenus  sont comparés à des essais expérimentaux

Identifiability of a Binomial Synapse

Synapses are highly stochastic transmission units. A classical model describing this stochastic transmission is called the binomial model, and its underlying parameters can be estimated from postsynaptic responses to evoked stimuli. The accuracy of parameter estimates obtained via such a model-based approach depends on the identifiability of the model. A model is said to be structurally identifiable if its parameters can be uniquely inferred from the distribution of its outputs. However, this theoretical property does not necessarily imply practical identifiability. For instance, if the number of observations is low or if the recording noise is high, the model's parameters can only be loosely estimated. Structural identifiability, which is an intrinsic property of a model, has been widely characterized; but practical identifiability, which is a property of both the model and the experimental protocol, is usually only qualitatively assessed. Here, we propose a formal definition for the practical identifiability domain of a statistical model. For a given experimental protocol, this domain corresponds to the set of parameters for which the model is correctly identified as the ground truth compared to a simpler alternative model. Considering a model selection problem instead of a parameter inference problem allows to derive a non-arbitrary criterion for practical identifiability. We apply our definition to the study of neurotransmitter release at a chemical synapse. Our contribution to the analysis of synaptic stochasticity is three-fold: firstly, we propose a quantitative criterion for the practical identifiability of a statistical model, and compute the identifiability domains of different variants of the binomial release model (uni or multi-quantal, with or without short-term plasticity); secondly, we extend the Bayesian Information Criterion (BIC), a classically used tool for model selection, to models with correlated data (which is the case for most models of chemical synapses); finally, we show that our approach allows to perform data free model selection, i.e., to verify if a model used to fit data was indeed identifiable even without access to the data, but having only access to the fitted parameters

Fêtes du patrimoine maritime et méthode quantitative, intérêts et difficultés duquestionnaire en milieu festif

International audienceL’étude de l’objet festif, du rapport à la mer, des représentations liées au patrimoine a guidé les travaux de doctorat de Camille Gontier. L’enquête de terrain menée en 2018 et organisée via la passation d’un questionnaire à destination du public, d’un questionnaire dédié aux marins, d’observations ethnographiques et d’entretiens semi-directifs vise à rendre compte des types de fêtes en fonction de leur taille, leur modalité d’organisation et enfin de leur implantation territoriale. A partir des données recueillies et de leur traitement, le responsable de cette étude reviendra sur la méthodologie d’enquête dans toute sa diversité en soulignant la complémentarité des différentes approches adoptées

Les fêtes du patrimoine maritime en Bretagne : du "rendez-vous des marins" au festival international, fonctions et usages de la festivité patrimoniale

Appearing on the Breton coast in the early 1980s, maritime heritage festivals have today become classic events in the event calendar. From major international festivals in Brest to gatherings reserved for sailors aboard their traditional boats, including maritime festivals in Paimpol or Douarnenez, heritage events attract a large audience, mobilizing both heritage stakeholders and local authorities, associations, and the local economic fabric. Maritime festivals are thus characterized by the plurality of their uses, their purposes, and their organizations. What does this plurality of functions and social uses of maritime heritage say? What does it also say about the diversity of our cultural relationships with the sea, the coast and popular maritime memories ? This thesis aims to show how the social function of maritime festivals is organized according to two distinct relationships to heritage. The community relationship, carried by the associative heritage movement, includes celebrations as the expression and enhancement of maritime traditions. The corporate report, carried by the local authorities or local associations, mobilizes the maritime festival to express the institutional, social and identity issues of the host territory. Through this classification, we show that heritage events are the object of differents logics of appropriation, but that they also translate the existence and the legitimacy of a patrimonial maritimity common to all of their actors and stakeholders.Apparues sur le littoral breton au début des années 1980, les fêtes du patrimoine maritime sont devenues aujourd’hui des rendez-vous classiques du calendrier événementiel. Des grandes fêtes internationales de Brest, jusqu’aux rassemblements réservés aux marins à bord de leurs bateaux traditionnels en passant par les festivals maritimes de Paimpol ou de Douarnenez, les manifestations patrimoniales attirent un public nombreux. Elles mobilisent autant les acteurs du patrimoine que les collectivités territoriales, les associations, et le tissu économique local. Les fêtes maritimes se caractérisent ainsi par la pluralité de leurs usages, de leurs finalités, et de leurs organisations. Que dit cette pluralité des fonctions et des usages sociaux du patrimoine maritime ? Que dit-elle aussi de la diversité de nos rapports culturels à la mer, au littoral et aux mémoires maritimes populaires ? Cette thèse vise à montrer comment la fonction sociale des fêtes maritimes s’organise selon deux rapports distincts au patrimoine. Le rapport communautaire, porté par le mouvement patrimonial associatif, comprend la fête comme l’expression et la valorisation des traditions maritimes. Le rapport sociétaire, porté par les collectivités territoriales ou les associations locales, mobilise la fête maritime pour exprimer les enjeux institutionnels, sociaux et identitaires du territoire qui l’accueille. A travers cette classification, nous montrons que les manifestations patrimoniales sont l’objet de différentes logiques d’appropriations, mais qu’elles traduisent aussi l’existence et la légitimité d’une maritimité patrimoniale commune à l’ensemble de leurs acteurs et parties prenantes

The maritime heritage festivals in Brittany : from the “meeting of sailors” to the international festival, functions and uses of the heritage festivity

Apparues sur le littoral breton au début des années 1980, les fêtes du patrimoine maritime sont devenues aujourd’hui des rendez-vous classiques du calendrier événementiel. Des grandes fêtes internationales de Brest, jusqu’aux rassemblements réservés aux marins à bord de leurs bateaux traditionnels en passant par les festivals maritimes de Paimpol ou de Douarnenez, les manifestations patrimoniales attirent un public nombreux. Elles mobilisent autant les acteurs du patrimoine que les collectivités territoriales, les associations, et le tissu économique local. Les fêtes maritimes se caractérisent ainsi par la pluralité de leurs usages, de leurs finalités, et de leurs organisations. Que dit cette pluralité des fonctions et des usages sociaux du patrimoine maritime ? Que dit-elle aussi de la diversité de nos rapports culturels à la mer, au littoral et aux mémoires maritimes populaires ? Cette thèse vise à montrer comment la fonction sociale des fêtes maritimes s’organise selon deux rapports distincts au patrimoine. Le rapport communautaire, porté par le mouvement patrimonial associatif, comprend la fête comme l’expression et la valorisation des traditions maritimes. Le rapport sociétaire, porté par les collectivités territoriales ou les associations locales, mobilise la fête maritime pour exprimer les enjeux institutionnels, sociaux et identitaires du territoire qui l’accueille. A travers cette classification, nous montrons que les manifestations patrimoniales sont l’objet de différentes logiques d’appropriations, mais qu’elles traduisent aussi l’existence et la légitimité d’une maritimité patrimoniale commune à l’ensemble de leurs acteurs et parties prenantes.Appearing on the Breton coast in the early 1980s, maritime heritage festivals have today become classic events in the event calendar. From major international festivals in Brest to gatherings reserved for sailors aboard their traditional boats, including maritime festivals in Paimpol or Douarnenez, heritage events attract a large audience, mobilizing both heritage stakeholders and local authorities, associations, and the local economic fabric. Maritime festivals are thus characterized by the plurality of their uses, their purposes, and their organizations. What does this plurality of functions and social uses of maritime heritage say? What does it also say about the diversity of our cultural relationships with the sea, the coast and popular maritime memories ? This thesis aims to show how the social function of maritime festivals is organized according to two distinct relationships to heritage. The community relationship, carried by the associative heritage movement, includes celebrations as the expression and enhancement of maritime traditions. The corporate report, carried by the local authorities or local associations, mobilizes the maritime festival to express the institutional, social and identity issues of the host territory. Through this classification, we show that heritage events are the object of differents logics of appropriation, but that they also translate the existence and the legitimacy of a patrimonial maritimity common to all of their actors and stakeholders

Pluralité des bénévolats et conflits des légitimités au sein d'un club de sport professionnel : le cas du Quimper Volley 29 Élite

The organizational study of Quimper Volley 29 Elite shows that, following the example of the structures stemming from the associative sports movements, this club launched a process of professionalization which leads to relational and organizational difficulties. The object of this report is to question the origin and the meaning of these difficulties exceeding and only systematic approach to understand the way the cultural references of the amateur sport live with the professional dimensions. In that respect, the led work is interested in the various voluntary work according to an ideal-typical approach, and in the cultural, social and symbolic capital that they mobilize to produce different legitimacies of commitment. In so doing, our investigation shows how the position of every voluntary work within the professional field implies an unstable organization and governance that is distant from the rules of the associative democracy.L'étude organisationnelle du Quimper Volley 29 Élite montre que, à l'instar des structures issues du mouvement sportif associatif, ce club de volley-ball a engagé un processus de professionnalisation qui induit des difficultés relationnelles et organisationnelles. L'objet de ce mémoire est de questionner l'origine et le sens de ces difficultés en dépassant une approche uniquement systémique pour comprendre la façon dont les références culturelles du sport amateur cohabitent avec les dimensions professionnelles. En cela, le travail mené s'intéresse aux différents bénévolats selon une approche idéale-typique, et aux capitaux culturels, sociaux et symboliques qu'ils mobilisent afin de produire des légitimités d'engagement distinctes. Ce faisant, notre enquête montre comment la position de chaque bénévolat au sein du champ professionnel implique une organisation instable et une gouvernance éloignée des règles de la démocratie associative

La place des sports collectifs professionnels dans la politique sportive de la Ville de Quimper : une réalité occultée ?

In Quimper, as in many other French towns, the organization of sports activities historically leans on the two essential mainstays that are regional authorities and the associative sports clubs. This classical sharing out answers to the sportsmen and sportswomen's main expectations: the associations organize the activities and the towns take responsability for the necessary investments. So, the existence of professional sports as basketball and volleyball on Quimper territory shakes up this classical pattern leaning on socio-economical references coming from different circles, creating this way an original hybridization process. Consequently, it is difficult for these characteristics to find their place in the local sports project as it leads to a certain misunderstanding between actors that, yet, have to work together.À Quimper, comme dans bien d'autres communes françaises, l'organisation des activités sportives s'appuie historiquement sur les deux piliers essentiels que sont les collectivités territoriales et les clubs de sports associatifs. Cette répartition classique répond en grande partie aux attentes des pratiquants : les associations organisent les activités quand les communes se chargent des investissements nécessaires. L'existence de disciplines sportives professionnelles comme le Basket et le Volley sur le territoire quimpérois vient alors bousculer ce schéma classique en s'appuyant sur des références socio-économiques issues de milieux différents, créant en cela un processus d'hybridation original. Cette caractéristique peine à trouver sa place dans le projet sportif local, entrainant une certaine incompréhension entre des acteurs qui doivent cependant travailler ensemble