ED Sciences de la Vie et de la Santé
Determinants of hypertension complications
by Arthur ORIEUX (Biologie des maladies cardiovasculaires)
The defense will take place at 14h00 - Salle de réunion INSERM UMR1034 - Biology of Cardiovascular Diseases Avenue de Magellan - 33600 Pessac France
in front of the jury composed of
- Sébastien RUBIN - Professeur des universités - praticien hospitalier - INSERM UMR1034 - Biology of Cardiovascular Diseases - Directeur de these
- Gervaise LOIRAND - Directrice de recherche - UMR 1087/CNRS UMR 6291 Unité de Recherche de l'Institut du Thorax - Examinateur
- Axel MONTAGNE - Professeur associé - UK Dementia Research Institute at Edinburgh - Rapporteur
- Hafid AIT OUFELLA - Professeur des universités - praticien hospitalier - U970 - Paris Centre de Recherche Cardiovasculaire (PARCC), Université Paris Cité, INSERM - Examinateur
- Dominique GUERROT - Professeur des universités - praticien hospitalier - UMR INSERM 1096 - ENVI (Endothélium, valvulopathies et insuffisance cardiaque) - Rapporteur
Hypertension is a major determinant of brain, kidney, cardiac and retinal injury. However, the severity of these complications is not determined by blood pressure level alone. Under comparable hemodynamic exposure, some subjects develop severe target-organ damage, whereas others remain relatively protected. This thesis aimed to identify mechanisms of susceptibility and resilience to hypertensive complications, with a particular focus on the cerebral microcirculation, the blood-brain barrier and type I interferon (IFN-I)-associated programs. We first characterized a mouse model that dissociates blood pressure elevation from tissue vulnerability. During chronic angiotensin II infusion, C57BL/6J and 129S1/SvImJ mice developed comparable increases in blood pressure, but only 129S1/SvImJ mice developed severe multi-organ injury, including blood-brain barrier disruption, cognitive impairment, albuminuria, podocyte injury, cardiac remodeling and retinal involvement. This model shows that genetic background and local target-organ responses shape the trajectory of hypertensive injury. Transcriptomic analysis of isolated brain microvessels then revealed early differences between the two strains, involving innate immune programs, endothelial responses and IFN-I-associated signaling. In 129S1/SvImJ mice, the early reduction of several IFN-I-associated genes suggested an insufficient or maladaptive microvascular response to the hypertensive challenge. To test the functional role of this pathway, we studied IFNAR1-deficient mice on a C57BL/6J background. Impaired IFN-I signaling unmasked vulnerability to angiotensin II-induced injury in a strain that is normally resistant, with renal injury and increased blood-brain barrier permeability to small solutes despite comparable blood pressure. These findings suggest that IFN-I signaling is not merely a signature associated with resistance, but may contribute to tissue protection during the hypertensive challenge. Pharmacological modulation experiments were then performed in hypertensive 129S1/SvImJ mice. Low-dose LPS stimulation and STING activation by the murine agonist DMXAA modulated IFN-I-associated responses and were accompanied by attenuation of selected phenotypes, including early albuminuria and increased blood-brain barrier permeability. These data do not indicate that inflammation is intrinsically protective, nor that the observed effects are exclusively IFN-I-dependent. Rather, they suggest that early, controlled activation of innate immune pathways may promote an adaptive response to the hypertensive challenge. Overall, this thesis proposes that hypertensive complications result from an interaction between hemodynamic stress, genetic susceptibility, microvascular responses and local immune regulation. It highlights the concept of microvascular resilience, defined as the capacity of a tissue to preserve the integrity of its microcirculation and specialized barriers despite chronic hypertensive exposure. IFN-I signaling emerges as a candidate pathway of this resilience, whose effects likely depend on the cellular compartment, signal intensity, timing and spatial localization. These findings provide a framework for understanding individual variability in hypertensive target-organ injury and for identifying microvascular signatures of risk or protection.
Cortico-cortical circuits of perceptual decision-making
by Léa PELTIER (Institut Interdisciplinaire de Neurosciences)
The defense will take place at 14h00 - Salle de conférence CARF 146 Rue Léo Saignat, CARF, 33000 Bordeaux
in front of the jury composed of
- Frédéric GAMBINO - Directeur de recherche - Université de Bordeaux - Directeur de these
- Sami EL-BOUSTANI - Associate Professor - University of Geneva - Rapporteur
- Isabelle FéRéZOU - Directrice de recherche - Université Paris-Saclay - Rapporteur
- Marion RIVALAN - Chaire de professeur junior - Université Paris-Saclay - Examinateur
- Mathieu WOLFF - Directeur de recherche - Université de Bordeaux - Examinateur
Perceptual decision-making is a crucial everyday cognitive process, allowing individuals to adapt to their constantly changing environment. Indeed, all our senses are gathering information from the world, and we perform a lot of different actions to adapt to it. Such a process performed in naturalistic conditions – involving the whole body in a complex environment – requires the conjoint action of several brain areas. In this embodied perspective, several recent papers show that a specific area can be involved in distinct processes like perception, decision and motor planning. Moreover, naturalistic stimuli and behavior have been shown to engage differently cortical areas than more reductionist ones, therefore questioning the use of some paradigms to study complex cognition and the generalization of the data obtained. The aim of this project is to investigate the differential involvement of the primary somatosensory cortex and the secondary motor cortex related to the whiskers and their communication during several cognitive processes occurring during a naturalistic perceptual decision-making task combining challenging exploration and risky decision-making. We will use a combination of techniques such as lesions and electrophysiological recordings on freely moving animals, and computational tools to classify the modular components of the behavior between which the animal is switching. This project is paving the way to understand subsecond neural processes underlying subsecond rich behavior. The results of this project should shed a new light on long standing questions in neuroscience on the serial and parallel hypotheses of the brain functioning. It will also provide new understanding to the confounding observations lesions of some areas can have striking effect or not at all. It will also help to understand the constant sensory feedbacks received by the brain that are fundamental in the neuro-prosthetic field traditionally focusing on motor control.