Le travail présenté dans ce mémoire avait pour but de synthétiser de nouvelles molécules dontl’architecture donne accès à des complexes organométalliques fluorescents aux propriétésintéressantes pour le photovoltaïque et la théranostique. Ce projet a donc abordé plusieurs pointsprincipaux.La première partie a été consacrée à la synthèse de nouveaux complexes organométalliquesphotoniques à base de titanocènes et de métalloporphyrines visant à la conception de cellulessolaires. Après une brève introduction, nous avons présenté la synthèse des complexes de titane etde métalloporphyrines dans le premier chapitre. En particulier, nous avons décrit la synthèse descomposés modèles et les difficultés rencontrées lors du passage aux dérivés porphyriniques.Cependant, au grès des résultats et des opportunités, le projet a été peu à peu tourné versl’application de ce type d’objet « complexe organométallique – fluorophore » au domaine médicalet plus particulièrement de la théranostique.La deuxième partie de ce manuscrit traite de l’application de ce type de composés à la théranostiqueet plus précisément aux théranostiques optiques. Elle commence par une introduction détaillée quidéfinit les enjeux de cette thématique émergente autant du point de vue de l’imagerie que de lathérapie. Dans le deuxième chapitre, nous avons présenté la synthèse d’agents théranostiquesprésentant un fragment métallique à activité thérapeutique lié à un BODIPY, sonde fluorescenteconnue pour ses propriétés optiques intéressantes. Leur caractérisation et l’étude de leurs propriétésbiologiques sont également décrites. Le troisième chapitre porte sur la synthèse de complexeshétérobimétalliques incorporant des métaux d’intérêt pour l’oncologie. Ces complexes sontégalement développés pour la recherche d’agents théranostiques. Le ligand utilisé pour l’imageriemédicale est la porphyrine. Ce chapitre inclut aussi les études photophysiques de nos complexes. / The goal of my PhD thesis was to synthesize new molecules, which give access to fluorescentorganometallic complexes with interesting properties for photovoltaic and theranostic. In thisproject, several main points have been studied.The first part of this manuscript concerns the synthesis of new metallocene and metalloporphyrinsbasedorganometallic complexes to the design of solar cells. After a short introduction, wepresented the synthesis of titanium complexes and metalloporphyrins in the first chapter. Inparticular, we described the synthesis of model compounds and the difficulties encountered duringthe transition to porphyrin derivatives. However, in view of results obtained and opportunities, theproject has gradually turned towards the application of this type of object « organometallic complex- fluorophore » to the medical field and more particularly the theranostic.The second part of this manuscript describes the application of this type of compounds to thetheranostic field and more specifically the optical theranostic. It begins with a detailed introductionthat defines the challenges of this emerging topic both from the point of view of the imaging astherapy. In the second chapter, we presented the synthesis of theranostic agents including a metalfragment with therapeutic activity linked to a BODIPY, a fluorescent probe known for itsinteresting optical properties. Their characterization and study of their biological properties are alsodescribed. The third chapter focuses on the synthesis of heterobimetallic complexes incorporatingmetals of interest in oncology. These complexes are also being developed for research theranosticagents. The ligand used for medical imaging is the porphyrin. This part also includes thephotophysical studies of our complexes.

L’objectif de cette thèse est la validation fonctionnelle d’implants rétiniens pour la restauration fonctionnelle de la vision chez des patients non voyants suite à la perte de leurs photorécepteurs. Ce travail a été réalisé sur modèle animal et a évalué expérimentalement de nouveaux protocoles de stimulation. Tout d’abord nous avons utilisé la technique de spectroscopie d’impédance pour simuler mathématiquement l’interface tissu-implantafin de caractériser la présence d’un espace entre le tissu et l’implant. La seconde partie compare par imagerie optique (IO) les caractéristiques de la réponse corticale évoquée par stimulation visuelle ou électrique de la rétine par prothèse sous rétinienne. Nous avons retrouvé que la taille de l’activation par l’implant rétinien est beaucoup plus grande que son correspondant visuel. Dans une troisième partie, est réalisée une évaluation in vitro de la performance des stimulations sur rétine isolée pour définir comment les cellules ganglionnaires réagissent à différents modes de stimulations. Ce travail a permis d’établir la courbe des réponses en fonction de l’intensité des stimulations électriques. Enfin, la thèse décrit un modèle animal de dégénérescence rétinienne qui présente des désorganisations de la rétine externe. Une analyse en IO a été réalisée sur ce modèle afin d’évaluer la réponse corticale aux stimuli visuels et électriques. Ce travail de thèse, par des approches physiques et physiologiques complémentaires, apporte un certain nombre de réponses qui devraient permettre d’améliorer l’utilisation de futures prothèses rétiniennes par une adaptation physique des matrices d’électrodes ou des patrons de stimulations utilisées / The aim of this thesis is the functional validation of retinal implants used for vision restoration in blind patients due to the loss of photoreceptors. This work was designed to develop an animal model to experimentally validate prototypes of new implants and new stimulation protocols pattern. Firstly we used the technique of impedance spectroscopy to simulate mathematically the tissue/implant interface. These data confirm the importance of reducing the space between the stimulating electrodes and retinal tissue, as well as the importance of physical characteristics of the electrical stimulus used. In a second approach, we have compared responses of visual cortical neuronal population using optical imaging (OI), evoked either by visual or electric retinal stimulation through subretinal prosthesis. This approach has demonstrated that the stimulation of an electrode induces cortical activation that the size of the cortical response to the retinal implant stimulation is much larger than its corresponding visual stimulus. In the third part, I performed in vitro experiment to measure the performance of stimulation at the level of ganglion cells of isolated retina. We have quantified the response curve as a function of the intensity of the electrical stimulation. Finally, the thesis describes a new animal model of outter retinal degeneration. OI was also performed on this model to assess the response to the visual and retinal prosthesis stimulations. This thesis, through complementary physical and physiological approaches, provides a number of responses that can potentially improve the use of retinal prostheses through specification of their design or patterns of stimulation.

Selon l’organisation mondiale de la santé, dans les pays en développement, la proportion de personnes obèses a presque triplé depuis 1980 et presque doublé dans les pays à revenu élevé. Parmi ces statistiques, en France, 16,8% des hommes et 17,4% des femmes sont obèses. Les taux mondiaux d'obésité devraient monter au cours de la prochaine décennie pour atteindre un cinquième des adultes en 2025. L'obésité est due à de multiples facteurs, dont la consommation excessive d’aliments riches en gras et en sucres, ainsi que des facteurs génétiques, psychosociaux et environnementaux. L'incidence de maladies telles que le cancer, le diabète et les maladies cardiovasculaires est supérieure chez les personnes obèses. L’obésité a également un impact néfaste sur le fonctionnement du cerveau, ce qui entraîne davantage d’accidents vasculaires cérébraux et des maladies neurodégénératives chez les personnes obèses. Une activité cérébrale normale impose des besoins énergétiques dynamiques qui sont satisfaits par le flux sanguin cérébral (Cerebral Blood Flow, CBF). La perfusion adéquate des tissus cérébraux au bon moment et au bon endroit parmi les quelques 160 milliards de cellules qui composent le cerveau adulte humain est vital. Malgré des données obtenues sur des tranches de cerveau concernant les problèmes de barrière hémato-encéphalique chez les personnes obèses, le devenir du CBF au cours de l'obésité n'a pas encore été étudié. Une des raisons à cela est la difficulté à enregistrer le CBF in vivo et de le suivre dans le temps, pendant une activation cérébrale et sur une large échelle avec une résolution spatio-temporelle appropriée. Afin d'évaluer l'influence de l'obésité sur le CBF, au repos et pendant la stimulation sensorielle, nous avons développé une technique optique appelée l'imagerie de contraste laser par exposition multiple (MESI). La technique repose sur le calcul du contraste de speckle, qui est lié à la vitesse des diffuseurs (globules rouges). Il permet une imagerie superficielle à large champ des variations relatives de flux sanguin dans le cortex de la souris. Nous avons caractérisé les performances du système en utilisant des fantômes microfluidiques. L’acquisition du contraste pour différentes durées d’exposition permet de discriminer les diffuseurs statiques et dynamiques (en mouvement) et donc d’obtenir une image quantitative des variations du CBF. Nous avons étudié l'activation cérébrale en utilisant la stimulation olfactive par des flux d'odeurs contrôlés présentés à la souris anesthésiée. Le bulbe olfactif est une structure sensorielle essentielle des mammifères pour le codage des odeurs et il est bien adapté à l'imagerie optique car l’activité neuronale et vasculaire est détectée dans les régions superficielles de cette structure. Nous avons observé une diminution significative du CBF évoqué par stimulation odorante chez les souris obèses (sous régime hyperlipidique) par rapport aux souris témoins (sous régime standard). Chez les souris contrôles, les variations de CBF sont élevées dans les vaisseaux sanguins de grand diamètre et diminuent dans les vaisseaux sanguins de petit calibre. Cette variation dépendant du diamètre est perdue chez les souris obèses qui présentent même un CBF significativement réduit au repos, au cours d'une activité vasculaire spontanée. De plus, afin de mieux comprendre la morphologie du système vasculaire, nous avons commencé l’étude par iDISCO de la densité et la distribution des vaisseaux dans l’ensemble du cerveau in vitro chez des souris obèses comparées aux contrôles. En conclusion, les résultats obtenus sur le CBF chez les souris obèses par la mise au point d’une technique d’imagerie optique à large champ MESI, indiquent que l'obésité impacte le fonctionnement vasculaire en dérégulant le débit sanguin cérébral. / Obesity is a global health threat. Since 1980 the proportion of obese or overweight individuals tripled in developing countries and doubled in high-income countries. In France 16.8% of men and 17.4% of women are obese. In the actual tendency persists, one-fifth of adults worldwide will be obese by 2025. Obesity is characterized by exaggerated weight gain and accumulation of fat tissue and is due to multiple factors including excessive consumption of high fat-sweet food and genetic, psychosocial and environmental factors. It is linked to an increase in the incidence of diseases such as cancer, diabetes and cardiovascular disease. Obesity has also a detrimental impact on brain function leading to higher rate of stroke and neurodegenerative diseases. Normal brain activity imposes dynamic energy requirements. Energy needs are fulfilled by Cerebral Blood Flow (CBF) to perfuse the brain tissue at the right time and the right place among the hundred of billons of cells that compose the human adult brain. Although dysfunction of the blood brain barrier was observed in brain slices, the fate of CBF during obesity in vivo is unknown. One reason for this is the difficulty to record CBF over time in vivo and to follow the time course of activation of large populations of cells with an appropriate spatiotemporal resolution. In order to evaluate the influence of obesity on CBF, at rest and during sensory stimulation, we have developed an optical technique termed multi-exposure speckle contrast imaging (MESI). In the last years, MESI has been validated for imaging relative changes in CBF at the surface of the rodent brain in vivo, the standard mammalian model for brain studies. The technique relies on the calculation of the spatial speckle contrast, which is related to the velocity of scatterers (red blood cells), and allows wide-field imaging of CBF at the mesoscopic level. We have characterized the performances of the system using microfluidic phantoms. We further demonstrated the ability of our MESI system to discriminate the moving and static diffusers contribution and therefore to provide accurate estimate of CBF changes in vivo. The olfactory bulb is a major hub for the processing of olfactory information in the brain of all mammals. It is well suited for optical imaging of brain activation since neuronal and vascular activities are detected very superficial at the surface of this structure. Using MESI, we have studied brain activation in control and obese mice. We have performed olfactory activation by delivering controlled odorants fluxes to anesthetized mice. We observed a significant decrease in odor-evoked CBF with a loss of diameter-dependent regulation of CBF in obese mice (high fat diet) compared to control lean mice (standard diet). We showed that CBF regulation was lost in obese mice even at rest without any stimulation. Furthermore, to gain insights into the morphology of the vascular network, we started the study of the vessels density and distribution in the entire brain using an in vitro iDISCO approach in obese mice compared to control mice. Overall, these findings indicate that obesity can adversely affect CBF at rest and in response to neuronal activation in vivo.

We can affirm to apprehend a system in its totality only when we know how it behaves under its natural operating conditions. However, in the face of the complexity of the world, science can only evolve by simplifications, which paradoxically hide a good deal of the very mechanisms we are interested in. On the other hand, scientific enterprise is very tightly related to the advances in technology and the latter inevitably influences the manner in which the scientific experiments are conducted. Due to this factor, experimental conditions which would have been impossible to bring into laboratory not more than 20 years ago, are today within our reach. This thesis investigates neuronal integrative processes by using a variety of theoretical and experimental techniques wherein the approximation of ecologically relevant conditions within the laboratory is the common denominator. The working hypothesis of this thesis is that neurons and neuronal systems, in the sensory and higher cortices, are specifically adapted, as a result of evolutionary processes, to the sensory signals most likely to be received under ecologically relevant conditions. In order to conduct the present study along this line, we first recorded movies with the help of two microcameras carried by cats exploring a natural environment. This resulted in a database of binocular natural movies that was used in our theoretical and experimental studies. In a theoretical study, we aimed to understand the principles of binocular disparity encoding in terms of spatio-temporal statistical properties of natural movies in conjunction with simple mathematical expressions governing the activity levels of simulated neurons. In an unsupervised learning scheme, we used the binocular movies as input to a neuronal network and obtained receptive fields that represent these movies optimally with respect to the temporal stability criterion. Many distinctive aspects of the binocular coding in complex cells, such as the phase and position encoding of disparity and the existence of unbalanced ocular contributions, were seen to emerge as the result of this optimization process. Therefore we conclude that the encoding of binocular disparity by complex cells can be understood in terms of an optimization process that regulates activities of neurons receiving ecologically relevant information. Next we aimed to physiologically characterize the responses of the visual cortex to ecologically relevant stimuli in its full complexity and compare these to the responses evoked by artificial, conventional laboratory stimuli. To achieve this, a state-of-the-art recording method, voltage-sensitive dye imaging was used. This method captures the spatio-temporal activity patterns within the millisecond range across large cortical portions spanning over many pinwheels and orientation columns. It is therefore very well suited to provide a faithful picture of the cortical state in its full complexity. Drifting bar stimuli evoked two major sets of components, one coding for the position and the other for the orientation of the grating. Responses to natural stimuli involved more complex dynamics, which were locked to the motion present in the natural movies. In response to drifting gratings, the cortical state was initially dominated by a strong excitatory wave. This initial spatially widespread hyper-excitatory state had a detrimental effect on feature selectivity. In contrast, natural movies only rarely induced such high activity levels and the onset of inhibition cut short a further increase in activation level. An increase of 30% of the movie contrast was estimated to be necessary in order to produce activity levels comparable to gratings. These results show that the operating regime within which the natural movies are processed differs remarkably. Moreover, it remains to be established to what extent the cortical state under artificial conditions represents a valid state to make inferences concerning operationally more relevant input. The primary visual cortex contains a dense web of neuronal connections linking distant neurons. However the flow of information within this local network is to a large extent unknown under natural stimulation conditions. To functionally characterize these long-range intra-areal interactions, we presented natural movies also locally through either one or two apertures and analyzed the effects of the distant visual stimulation on the local activity levels. The distant patch had a net facilitatory effect on the local activity levels. Furthermore, the degree of the facilitation was dependent on the congruency between the two simultaneously presented movie patches. Taken together, our results indicate that the ecologically relevant stimuli are processed within a distinct operating regime characterized by moderate levels of excitation and/or high levels of inhibition, where facilitatory cooperative interactions form the basis of integrative processes. To gather better insights into the motion locking phenomenon and test the generalizability of the local cooperative processes toward larger scale interactions, we resorted to the unequalized temporal resolution of EEG and conducted a multimodal study. Inspired from the temporal properties of our natural movies, we designed a dynamic multimodal stimulus that was either congruent or incongruent across visual and auditory modalities. In the visual areas, the dynamic stimulation unfolded neuronal oscillations with frequencies well above the frequency spectrum content of the stimuli and the strength of these oscillations was coupled to the stimuli's motion profile. Furthermore, the coupling was found to be stronger in the case where the auditory and visual streams were congruent. These results show that the motion locking, which was so far observed in cats, is a phenomenon that also exists in humans. Moreover, the presence of long-range multimodal interactions indicates that, in addition to local intra-areal mechanisms ensuring the integration of local information, the central nervous system embodies an architecture that enables also the integration of information on much larger scales spread across different modalities. Any characterization of integrative phenomena at the neuronal level needs to be supplemented by its effects at the behavioral level. We therefore tested whether we could find any evidence of integration of different sources of information at the behavioral level using natural stimuli. To this end, we presented to human subjects images of natural scenes and evaluated the effect of simultaneously played localized natural sounds on their eye movements. The behavior during multimodal conditions was well approximated by a linear combination of the behavior under unimodal conditions. This is a strong indication that both streams of information are integrated in a joint multimodal saliency map before the final motor command is produced. The results presented here validate the possibility and the utility of using natural stimuli in experimental settings. It is clear that the ecological relevance of the experimental conditions are crucial in order to elucidate complex neuronal mechanisms resulting from evolutionary processes. In the future, having better insights on the nervous system can only be possible when the complexity of our experiments will match to the complexity of the mechanisms we are interested in.

<p>Cardiovascular disease (CVD) is the leading cause of death worldwide and is expected to increase direct medical costs in the U.S. to $749 billion by the year 2035. Diagnosis of CVD through imaging techniques can improve our understanding of CVD progression and its associated risks through visualization of anatomical features and biological constituents. Non-invasive imaging relies on optimal image quality for visualization of such tissue structures that can be difficult to identify and segment. While various imaging modalities are used to determine tissue characteristics, many lack the spatial resolution that optics-based imaging can provide, which can assess hemodynamic parameters in preclinical models of ischemic disease. Acoustic-based imaging can complement optics-based imaging by providing anatomical and location-specific information of tissues with greater penetration depth. Even with all the advancements in imaging technology, however, limitations still exist in non-invasively, efficiently, and accurately capturing biologically relevant information with adequate spatial and temporal resolution. Furthermore, reproducible feature extraction is difficult due to a lack of standardization in the field, making it difficult to implement when image quality varies. In this work, we implement spatial frequency domain imaging (SFDI), ultrasound, and photoacoustic imaging in preclinical models of 1) peripheral artery disease, 2) traumatic brain injury, and 3) myocardial ischemia to capture imaging biomarkers of vascular and cardiac health in longitudinal studies. We also implement deep learning on preclinical ultrasound and photoacoustic images of the cardiac left ventricle to automatically extract regions of interest to calculate radial strain and oxygen saturation. Eventually findings from this work may help improve clinical cardiovascular disease diagnosis, prognosis, and treatment.</p>

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Following a stroke, normal usage of the impaired limb guides spontaneous recovery across many months or even years; however, recovery is rarely complete. Pre-clinical tools are needed to investigate stroke-induced cortical reorganization over long periods. This thesis aims to characterize stroke impairment and spontaneous recovery in parallel with a battery of behaviour tasks in a mouse model of focal stroke. Young adult Thy1-ChR2 mice were implanted with a transcranial window over the intact skull permitting cortex visualization and enabling longitudinal assessments with light-based motor mapping and intrinsic signal optical imaging. Furthermore, mice were tested on sensorimotor behavioural tasks in parallel to the mapping experiments. These experiments allowed for the quantification of impairments in the sensorimotor cortex and forelimb function while identifying regions within the sensorimotor cortex that show re-mapping associated with behavioural recovery. Following primary motor cortex-stroke induction, both sensory and motor map impairments occurred. Sensory map transient impairments recovered within the same atlas-defined regions two weeks after a primary motor cortex stroke as identified by intrinsic signal optical imaging. In contrast, motor forelimb recovery was observed four weeks after the stroke in the peri-infarct region, the supplemental motor cortex, and the contralesional motor cortex. This recovery was identified through a combination of analyses, including changes in the mapped area and the amplitude of evoked forelimb movements using light-based motor mapping. Behavioural recovery occurred four to six weeks post-stroke, depending on the sensitivity of the task in forelimb impairment. Additionally, the contralesional hemisphere and forelimb did not show impairment acutely but evoked forelimb amplitude was significantly increased by post-stroke week four for both forelimbs. As the first study to conduct within-animal longitudinal spontaneous recovery sensory and motor map experiments using bilateral forelimb and hemispheric representations, we show that 1) photothrombotic stroke impacts both forelimb representations pertained within the ipsilesional hemisphere in LBMM experiments, 2) recovery of the impaired forelimb occurs ipsilesionally and contralesionally and, 3) impairments from stroke observed through motor mapping are functionally relevant and precede behavioural recovery ranging from zero to two or more weeks depending on the motor cortex's involvement in the behavioural task.

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