ED Sciences de la Vie et de la Santé
Involvement of bacterial genotoxins in cellular cytoskeleton remodelling and carcinogenesis
by Mariana DA SILVA SARAIVA (BoRdeaux Institute of onCology)
The defense will take place at 13h30 - Amphithéatre BBS Université de Bordeaux, Campus Carreire Bâtiment Biologie Santé, 2 rue Hoffmann Martinot, Bordeaux
in front of the jury composed of
- Armelle MENARD - Ingénieure de recherche - Université de Bordeaux - Directeur de these
- Teresa FRISAN - Professeure des universités - Umea University - Rapporteur
- Jean-Philippe NOUGAYREDE - Directeur de recherche - IRSD - Rapporteur
- Fabien DARFEUILLE - Directeur de recherche - Université de Bordeaux - Examinateur
- Mathilde BONNET - Professeure des universités - praticienne hospitalière - Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Université de Clermont Auvergne - Examinateur
The composition of the human microbiota profoundly influences health and disease, impacting the initiation and progression of cancer and even modulating the efficacy of certain anticancer drugs. While Helicobacter pylori is a well-established Type I carcinogen, emerging research highlights the role of other mucosal pathogens that produce potent genotoxins, such as Cytolethal Distending Toxin (CDT) and colibactin, in cancer, particularly in hepatobiliary and intestinal malignancies. These toxins induce DNA damage and genomic instability; however, their contribution to the metastatic transition remains poorly understood. Previous studies link these genotoxins to actin cytoskeleton remodelling with lamellipodia formation, cortactin expression modulation and vinculin relocalization with decreased cell adherence; and to the Epithelial-to-Mesenchymal Transition, a process characterized by the loss of cell-cell junctions, enhanced matrix metalloproteinase activity and cellular motility. Central to this invasive transition is the formation of invadosomes: specialized, F-actin-rich protrusions that enzymatically degrade the extracellular matrix. This thesis explored the hypothesis that bacterial-induced genotoxic stress serves as a novel signalling trigger for invadosome formation, bridging the gap between genotoxic stress and the activation of the cellular invasive machinery. Given cortactin's pivotal role in invadosome formation and the known modulation by CDT, elucidating the post-translational modifications triggered by these toxins was a complementary objective of this study. Our results demonstrate that exposure to CDT and colibactin induces the formation of matrix-degrading invadosomes in hepatic epithelial cell lines. We established a correlation between the formation of proteolytic invadosomes and DNA damage induced either by bacterial genotoxins (CDT/CdtB and colibactin) or by DNA-damaging agents that create distinct lesions, such as ionizing radiation and chemotherapeutic agents (streptozocin, etoposide, and GEMOX components). Mechanistically, this process is supported by oxidative stress, as antioxidant treatments (N-acetylcysteine, resveratrol) significantly attenuated invadosome formation, while pro-oxidants (menadione and H₂O₂) exacerbated it. Furthermore, invadosome formation under genotoxic stress can be attenuated by inhibiting JNK, ATM, or DNA-PK kinases. These results reveal a mechanistic link between oxidative stress, genotoxic signalling, and invadosome formation, suggesting that bacterial genotoxins, alongside DNA-damaging radiotherapies and chemotherapies, can promote cancer cell invasiveness through the formation of invadosomes. Furthermore, mass spectrometry and western blot analyses identified and validated a novel, CdtB-dependent hyperphosphorylation of cortactin at Ser447 in hepatic and intestinal epithelial cells exposed to CdtB. The implication of this phosphorylation in this invasive phenotype remains to be explored. Collectively, these findings demonstrate that bacterial genotoxins modulate host cell signalling to promote a pro-invasive program. By establishing that genotoxic stress triggers invadosome biogenesis via oxidative signalling and potentially through cortactin modification, these insights offer new therapeutic perspectives targeting the proteins and kinases involved in cancer invasive. Keywords: Cytolethal Distending Toxin (CDT), colibactin, invadosomes, cortactin, DNA damage
Distinct dorsal and ventral basal ganglia contributions to value-based decision-making in health and parkinsonism
by Milesa SIMIC (Institut des Maladies Neurodégénératives)
The defense will take place at 14h00 - Amphithéâtre Broca Centre Broca 146 rue Léo Signat 33076 Bordeaux cedex
in front of the jury composed of
- Yulia WORBE - Professeure des universités - praticienne hospitalière - Institut du Cerveau - Rapporteur
- David THURA - Chargé de recherche - Centre de recherche en Neurosciences de Lyon - Rapporteur
- Shauna PARKES - Directrice de recherche - Institut de Neurosciences Cognitives et Intégratives d'Aquitaine - Examinateur
- Jérôme MUNUERA - Chargé de recherche - Institut du Cerveau - Examinateur
Value-based decision-making (DM) relies on processes that evaluate options by assigning them a subjective value, guide action selection and execution, and evaluate consequences by comparing expected and obtained outcomes to update decisions. These processes rely on coordinated activity within distributed brain networks including the basal ganglia (BG). The BG comprise interconnected nuclei modulated by midbrain dopamine and organized into partially overlapping cortico-subcortical circuits along a dorsal-ventral axis. Dorsal circuits are associated with motor and cognitive control, while ventral circuits are linked to valuation/evaluation and motivation. Dysfunctions of these circuits have been implicated in DM deficits observed in Parkinson's disease (PD). However, their distinct contribution to value-based DM in healthy and pathological conditions remains unclear. To address this question, we performed electrophysiological recordings before and after PD induction in key BG nuclei (caudate nucleus, nucleus accumbens (NAc), external globus pallidus and ventral pallidum) in non-human primates performing a value-based DM task in which expected values (EVs) varied with reward magnitude and probability. We examined how decision variables (value- and action-related signals) associated with losses and gains are encoded and organized across BG structures. Behavior scaled with EV: higher EV options were chosen more accurately, elicited fewer omissions and were associated with faster decision times, linking valuation to behavioral engagement and vigor. Single-unit recordings revealed a functional gradient across structures: dorsal regions preferentially encoded action-related parameters, while value encoding increased ventrally. EV representations were non-linear with maximal sensitivity at the loss-gain transition. Population-level neural dynamics revealed distinct neural trajectory geometries across EVs, particularly at this transition in ventral regions, where trajectory separation and divergence increased, while spatial signals were more segregated dorsally. Decoding analyses supported this dissociation: EV was best decoded from ventral populations, whereas spatial parameters were most accurately decoded from dorsal populations. Thus, representation of value and action signals across BG structures is distributed but organized. To examine DM deficits in PD, we induced progressive dopaminergic depletion using chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and compared healthy, early, and late disease stages. Dopamine loss led to marked task disengagement and reduced movement vigor, accompanied by changes in neuronal encoding despite preserved decision performance. The most pronounced alterations occurred in the ventral striatum, including a late-stage decrease in value encoding in NAc neurons, while pallidal representations of decision variables were largely intact. Analysis of cue-evoked changes in neural response magnitude (neural gain) showed maintained differentiation between performed and omitted trials and revealed systematic co-shifts between disengagement and the increasing prevalence of omission-like low-gain neural states across disease stages. Dopamine depletion may therefore shift global network states (from engaged to disengaged) rather than abolish valuation. Together, this work supports a functional organization of the BG during value-based DM in which ventral circuits preferentially encode value, including non-linear loss-gain sensitivity, while dorsal circuits preferentially encode action-related variables. Dopaminergic depletion primarily affects motivation and task engagement through shifts in global neural states and selective vulnerability of ventral striatal circuits, while pallidal populations may help sustain accurate decision performance by maintaining representations of task-relevant decision variables.
ED Sciences Physiques et de l'Ingénieur
How can we support building users towards more energy-efficient practices?
by Minh Phuong HUYNH (I2M - Institut de Mécanique et d'Ingénierie de Bordeaux)
The defense will take place at 14h00 - Bat. A29 - Amphithéâtre G 351 cours de la Libération CS 10004 33405 Talence CEDEX
in front of the jury composed of
- Laurent MORA - Professeur - Université de Bordeaux - Directeur de these
- Béatrice ROUSSILLON - Professeure - Université Grenoble Alpes - Examinateur
- Monika WOLOSZYN - Professeure - Université Savoie Mont Blanc - Rapporteur
- Stephane PLOIX - Professeur - Grenoble INP - Rapporteur
- Marie-Lise PANNIER - Maîtresse de conférences - Université d'Angers - Examinateur
Energy and resources are consumed in the residential sector to support occupants' daily needs. Not only physical characteristics and environmental conditions, but the energy consumption in the residential sector is also influenced by occupant behaviour. Given the environmental consequences of energy over-consumption, promoting energy-efficient behaviours among residential occupants is essential. However, behaviours are driven by external factors and internal socio-psychological mechanisms, making them inherently complex to analyze. Consequently, designing effective interventions – deliberate actions or strategies aimed at influencing behaviour – remains challenging. Furthermore, assessing the effectiveness of interventions solely through observable outcomes can lead to incomplete or misleading conclusions. In this thesis, a multidisciplinary approach is implemented to provide a comprehensive understanding of one's behaviour. An energy-consuming behaviour is examined from both technical and socio-psychological perspectives. The technical approach identifies issues in existing behaviours, potential alternative solutions, and the practical challenges associated with behaviour change. The socio-psychological approach, in turn, focuses on occupants' underlying values, motivations, and decision-making processes. By integrating these insights, more effective interventions can be tailored to each case, with a focus on the specific socio-psychological factors that facilitate or hinder the adoption and maintenance of new behaviours. The methodology for designing contextualized interventions is based on recent work by Cabezas-Rivière (2024). A methodology detecting changes in occupant behaviour in the residential sector integrates both quantitative and qualitative data, to determine whether behavioural change occurs and to explain the underlying reasons for change, stagnation, or relapse. The methodology consists of four steps: Data collection, Characteristics extraction, Hypothesis test implementation, and Results justification. The effectiveness of the interventions is examined quantitatively through changes in occupants' actions and activities, their associated impacts, and the evolution of occupants' socio-psychological factors. The methodology's validation was explored through empirical testing focused on dishwasher use across four French households. The results varied across the study cases. After the experiment, the effectiveness of the interventions was quantified, allowing for comparison across the case studies. Overall, the multidisciplinary approach provides a deeper understanding of the behaviour of individuals or households, which supports the design of tailored interventions that are more likely to succeed than non-contextualized interventions. Additionally, by combining a quantitative comparison of behavioural characteristics with qualitative justifications provided by occupants, the proposed methodology bridges the gap between quantitative detection and qualitative understanding—between knowing that a behaviour has changed and understanding why and how it happened. Finally, by jointly examining changes in attitudes, behaviours, and their associated impacts, the methodology ensures a comprehensive assessment of behaviour change, and allows for a robust evaluation of interventions' effectiveness.