A key component of natural photosynthesis are the antenna chromophores (chlorophylls and carotenoids) that capture solar energy and direct it towards the reaction centers of photosystems I and II. Highlighted by highly-ordered crystal structures and synthetic tunability via crystal engineering, metal–organic frameworks (MOFs) have the potential to mimic the natural photosynthetic systems in terms of the efficiency and directionality of energy transfer. Owing to their larger surface areas, MOFs have large absorption cross sections, which amplifies the rate of photon collection. Furthermore, MOFs can be constructed using analogues of chlorophyll and carotenoids that can participate in long-range energy transfer. Herein, we aimed to design photoactive MOFs that can execute one of the critical steps involved in photosynthesis - photon collection and subsequent energy transfer. The influence of spatial arrangement of chromophores on the efficiency and directionality of excitation energy transfer (EET) was investigated in a series of mixed-ligand pyrene- and porphyrin-based MOFs. Due to the significant overlap between the emission spectrum of 1,3,6,8-tetrakis(p-benzoic acid)pyrene (TBAPy) and the absorption spectrum of meso-tetrakis(4-carboxyphenyl)porphyrin (TCPP), the co-assembly of these two ligands in a MOF should enable facile energy transfer. Bearing this in mind, three TBAPy-based MOFs with markedly different network topologies (ROD-7, NU-901, and NU-1000) were chosen and a small number of TCPP units were incorporated in their backbone. To gain insight into the photophysical properties of mixed-ligand MOFs, we conducted time-resolved and steady-state fluorescence measurements on them. Stern-Volmer analysis was performed on the fluorescence lifetime data of mixed-ligand MOFs to determine the quenching constants. The quenching constant values for ROD-7, NU-901, NU-1000, and TBAPy solution were found to be 15.03 ± 0.82 M-1, 10.25 ± 0.99 M-1, 8.16 ± 0.41 M-1, and 3.35 ± 0.30 respectively. In addition, the ratio of the fluorescence intensities of TCPP and TBAPy was used to calculate the EET efficiencies in each of the three MOFs. EET efficiencies were in the following order: ROD-7 > NU-901 > NU-1000 > TBAPy-solution. Based on the trends observed for quenching constants and EET efficiencies, two conclusions were drawn: (1) the ligand-to-ligand energy transfer mechanism in MOFs outperforms the diffusion-controlled mechanism in solution phase, (2) energy transfer in MOFs is influenced by their structural parameters and spectral overlap integrals. The enhanced EET efficiency in ROD-7 is attributed to shorter interchromophoric distance, larger orientation factor, and larger spectral overlap integral. Directionality of energy transfer in these MOFs was assessed by calculating excitonic couplings between neighboring TBAPy linkers using the atomic transition charges approach. Rate constants of EET (kEET) along different directions were determined from the excitonic couplings. Based on the kEET values, ROD-7 is expected to demonstrate highly anisotropic EET along the stacking direction. In order to explore the mechanistic aspects of EET in porphyrin-based MOFs, we studied the energy transfer characteristics of PCN-223, a zirconium-based MOF containing TCPP ligands. After performing structural characterization, the photophysical properties of PCN-223 and free TCPP were investigated using steady state and time-resolved spectroscopy. pH-dependent fluorescence quenching experiments were performed on both the MOF and ligand. Stern-Volmer analysis of quenching data revealed that the quenching rate constants for PCN-223 and TCPP were 8.06 ± 1011 M-1s-1 and 2.71 ± 1010 M-1s-1 respectively. The quenching rate constant for PCN-223 is, therefore, an order of magnitude larger than that for TCPP. Additionally, PCN-223 demonstrated a substantially higher extent of quenching (q = 93%) as compared to free TCPP solution (q = 51%), at similar concentrations of quencher. The higher extent of quenching in MOF is attributed to energy transfer from neutral TCPP linkers to N-protonated TCPP linkers. Using the Förster energy transfer model, the rate constant of EET in PCN-223 was calculated. The magnitude of rate constant was in good agreement with the kEET values reported for other porphyrin-based MOFs. Nanosecond transient absorption measurements on PCN-223 revealed the presence of a long-lived triplet state (extending beyond 200 μs) that exhibits the characteristic features of a TCPP-based triplet state. The lifetime of MOF is shorter than that of free ligand, which may be attributed to triplet-triplet energy transfer in the MOF. Lastly, femtosecond transient absorption spectroscopy was employed to study the ultrafast photophysical processes taking place in TCPP and PCN-223. Kinetic analysis of the femtosecond transient absorption data of TCPP and PCN-223 showed the presence of three distinct time components that correspond to: (a) solvent-induced vibrational reorganization of excitation energy, (b) vibrational cooling, and (c) fluorescence. Materials that allow control over the directionality of energy transfer are highly desirable. Core-shell nanocomposites have recently emerged as promising candidates for achieving long-distance, directional energy transfer. For our project, we aim to employ UiO-67-on-PCN‐222 composites as model systems to explore the possibility of achieving directional energy transfer in MOF-based core-shell structures. The core–shell composites were synthesized by following a previously published procedure. Appropriate amounts of Ruthenium(II) tris(5,5′-dicarboxy-2,2′-bipyridine), RuDCBPY, were doped in the shell layer to produce a series of Ru-UiO-67-on-PCN‐222 composites with varying RuDCBPY loadings (CS-1, CS-2, and CS-3). The RuDCBPY-doped core–shell composites were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) imaging, Nitrogen adsorption-desorption isotherms, and diffuse reflectance spectroscopy. Efforts are currently underway to quantify RuDCBPY loadings in CS-1, CS-2, and CS-3. After completing structural characterization, the photophysical properties of CS-1, CS-2, and CS-3 will be investigated with the help of time-resolved and steady-state fluorescence spectroscopy. / Doctor of Philosophy / The pigment−protein complexes in natural photosynthetic units (also known as light harvesting antennas) efficiently capture solar energy and transfer this energy to reaction centers that carry out water splitting reactions. The collective chromophoric behavior of antennas can be replicated by metal-organic frameworks (MOFs). MOFs are crystalline, self-assembled materials composed of metal clusters connected by organic molecules. In this dissertation, we study the factors that govern the energy transfer and light harvesting capabilities of MOFs. In chapter 2, we examined the role of 3D structure of MOFs in energy transfer. In chapter 3, we investigated the influence of pH and temperature on the photophysical properties of MOFs. In chapter 4, we explored the possibility of energy transfer in novel MOF-on-MOF composites. This work is intended to pave the way for the construction of highly efficient MOF-based materials that can serve as the light harvesting and energy-transfer components in solar energy conversion devices.

In this thesis, an output-only experimental modal testing and analysis technique known as the Natural Excitation Technique (NExT) is examined for use with large residential structures and interior cavities. The technique which assumes a random, stationary input causing the response data is reviewed and extended for the first time to include the assumption of an impulse input. This technique is examined with respect to the experimental modal analysis of single and two room residential structures. Each structure is first tested using conventional modal testing methods. Then, NExT is applied using each structure's response to a simulated sonic boom, an impulsive input. The results of these analyses along with the results obtained from a finite element model are compared. Then, the interior cavities enclosed by the residential structures are examined using NExT. Therefore, this thesis also demonstrates the successful use of NExT on acoustic systems for the first time. Three configurations of the interconnected cavities enclosed by the two room structure are considered to study physical phenomena. Both interior pressure response to random, stationary inputs and the sonic boom response are used with NExT to determine modal properties. The results of these analyses are compared to a theoretical analysis. Advantages to using NExT with both the response to a random, stationary input and an impulsive input are demonstrated for structural and acoustic systems. / Master of Science

Nanoscale materials have great applications in many areas. One of these applications is for manufacturing ultra-compact and efficient sensors for chemical and biological molecule detection. Noble metals, such as gold (Au) and silver (Ag), because of their distinguished optical property"localized surface plasmon resonances (LSPRs) that exhibit low loss, are ideal materials to fabricate these nanoscale plasmonic particles or structures. This work addresses the synthesis, characterization, and sensing applications of Au and Ag nanoparticles (NPs). The progress on certain subjects related to our work"NP synthesis, surface functionalization, Au sphere-film structure and two-photon fluorescence"are reviewed in Chapter 1. We also show the calculation results of LSPRs of Au nanosphere suspensions using Mie theory. The measured extinction spectra of Au nanosphere suspensions agree with the calculated results very well. Chapter 2 is a chapter describing the chemical synthesis of a variety of NPs, such as Ag prisms and cubes, Au spheres, rods, and bipyramids. These experiments involved different synthetic mechanisms and methods which enabled us to prepare NPs with desired shapes and optical properties. To put these NPs into application, it is desirable and sometimes necessary to functionalize their surfaces. In Chapter 3, we present the functionalization of Ag cubes with poly(allylamine hydrochloride) (PAH) and poly(allylamine hydrochloride)-dithiocarbamate (PAH-DTC), which follows our previous work on Au NPs. The purpose of studying Ag instead of Au is to use the stronger plasmonic enhancement in Ag when applied to two-photon imaging applications. However, we found that PAH-DTC shrank the Ag cubes. We also functionalized the cationic hexadecyltrimethylammonium bromide (CTAB)-stabilized Au NRs with anionic poly(sodium 4-styrenesulfonate) (PSS). Coated with the strong polyelectrolyte PSS, the NRs become more manageable and can be stable for over six months and are easily immobilized onto positively charged substrate. We put PSS-functionalized Au NPs into use and studied their adsorption process onto PAH-coated optical fiber tapers by monitoring the transmission light through the fiber. When the diameter of the fiber taper gets smaller, stronger coupling occurred between transmitted light inside the taper and the Au NPs on the taper surface (cylinder). This coupling resulted in a loss of the guided light at the plasmon resonance wavelength of the NPs. By monitoring this loss, we can study the adsorption rate of Au NPs onto the fiber. In Chapter 4, we used Au nanospheres to study the adsorption rate on substrates with different curvatures. We also established a theoretical model to explain this phenomenon for cylindrical surface as well as planar and spherical surfaces. Our results fit well with the theory, which predicts that particle adsorption rates depend strongly on surface geometry, and can exceed the planar surface deposition rate by over two orders of magnitude when the diffusion length of the particle is large compared to the surface curvature. In Chapter 5, we studied the optical properties of Au nanospheres separated from a thick Au film by a polyelectrolyte multilayer (PEM) film assembled from PAH and PSS under specific pH condition. The PEM film undergoes swelling and shrinking when the environmental pH is changed as a result of charging and discharging of the polyelectrolytes. Therefore, the PEM film provides an efficient means to tune the distance between Au spheres and Au film. The extinction peak blue-shifted as much as 100 nm when the pH of the water changed from pH 10 to pH 3 for 100 nm diameter Au spheres on a PEM film assembled at pH 9.5. Our preliminary estimates that the gap between sphere and surface can be as small as a few nm even though the film itself is tens of nm thick when it is not constrained by Au spheres. We studied two-photon excitation fluorescence (TPEF) from Ag triangles in Chapter 6. The triangles were fabricated by nanosphere lithography, which used convective self-assembly to make the nanosphere mask. The LSPRs of the nanotriangles were tuned to be in the 800--900 nm range to match with the Ti:Sapphire pulse laser at 880 nm. We found that certain spots on the fluorescence images gave rise to larger fluorescence intensity than rest of the area. SEM imaging reveals that the unusually bright spots seen on the surface were related to regions where the triangles transformed to spherical particles. The larger intensity is tentatively ascribed to the plasmon resonance of those spherical particles in ~400 nm range. / Ph. D.

Recent studies have utilized spanwise traveling waves to alter the turbulent boundary layer with the aim of reducing skin friction drag. Spanwise traveling waves are a promising active drag reduction technique; however, the wave generation methods used in previous studies are bulky and could not be practically implemented. This research has developed an implementable traveling wave generation method and then fundamentally demonstrated how it changes the turbulent boundary layer, which is in a manner consistent with skin friction/shear stress reduction. Traveling waves were generated on a two-dimensional surface using low-profile piezoelectric actuators, in an open-loop fashion, and with minimal frequency limitations. The wave generation method was developed to generate tailored traveling wave patterns; thus, yielding control over the propagation direction, number of wave-fronts, and regions of the surface containing traveling waves. These tailored traveling waves have the capacity not just for affecting the boundary layer, but also for other applications such as propulsion. The implementable traveling wave generation method was then tested in a low-speed wind tunnel and shown to alter the structure of the turbulent boundary layer. The boundary layer is pushed off the wall, and the viscous sublayer is thickened, indicating a reduction in shear stress. Analysis of the boundary layer at positions phase-locked to the wave oscillation suggests that the traveling waves induce a phase-lag effect in the flow. This phase-lag produces a stretching of the viscous sublayer and may contribute to the skin friction reduction. The effects of standing waves on the turbulent boundary layer were also investigated and compared with traveling waves. The results indicate that both wave types alter the boundary layer in the same manner. Standing waves are simpler to generate than traveling waves, suggesting that standing waves may be an effective skin friction reduction method. Before traveling or standing waves can be implemented, further research is necessary to investigate the interaction between the wave pattern and the turbulent phenomena and also to quantify the skin friction reduction and overall net energy usage. / Ph. D. / Recent studies have utilized spanwise traveling waves to alter the turbulent boundary layer with the aim of reducing skin friction drag. Spanwise traveling waves are a promising active drag reduction technique; however, the wave generation methods used in previous studies are bulky and could not be practically implemented. This research has developed an implementable traveling wave generation method and then fundamentally demonstrated how it changes the turbulent boundary layer, which is in a manner consistent with skin friction/shear stress reduction. Traveling waves were generated on a two-dimensional surface using low-profile piezoelectric actuators, in an open-loop fashion, and with minimal frequency limitations. The wave generation method was developed to generate tailored traveling wave patterns; thus, yielding control over the propagation direction, number of wave-fronts, and regions of the surface containing traveling waves. These tailored traveling waves have the capacity not just for affecting the boundary layer, but also for other applications such as propulsion. The implementable traveling wave generation method was then tested in a low-speed wind tunnel and shown to alter the structure of the turbulent boundary layer. The boundary layer is pushed off the wall, and the viscous sublayer is thickened, indicating a reduction in shear stress. Analysis of the boundary layer at positions phase-locked to the wave oscillation suggests that the traveling waves induce a phase-lag effect in the flow. This phase-lag produces a stretching of the viscous sublayer and may contribute to the skin friction reduction. The effects of standing waves on the turbulent boundary layer were also investigated and compared with traveling waves. The results indicate that both wave types alter the boundary layer in the same manner. Standing waves are simpler to generate than traveling waves, suggesting that standing waves may be an effective skin friction reduction method. Before traveling or standing waves can be implemented, further research is necessary to investigate the interaction between the wave pattern and the turbulent phenomena and also to quantify the skin friction reduction and overall net energy usage.

The main focus of this present work is to study how mechanical steady state traveling waves can be generated and propagated through one dimensional media by applying forces. By steady state traveling waves we refer to propagating mechanical waves in a finite medium that never exhibit reflections at the boundaries and continuously move from one end of the structure to the other. Mechanical waves can be classified as traveling, standing and hybrid waves that are the results of the interplay of excitation forces, applied force locations, and the boundary conditions of the structure. Traveling waves carry energy through a defined medium while standing waves keep energy at certain areas that are associated with the modes of excitation. To understand the interaction of systems that exhibit traveling waves with their surrounding media (i.e., swimming flagella, manta ray locomotion), it is crucial to first understand the wave propagation and what is desired in these structural systems. The parameters that affect the generation and propagation of waves should be welldefined to control and manipulate the desired system’s response. One-dimensional string and rod equations are studied with various boundary conditions to generate steady-state traveling waves in a string and longitudinal traveling waves in a rod. Two excitation forces are applied to a string and a rod near the boundaries to understand the generation and propagation of traveling and standing waves at various frequencies. The work examines the quality of the wave propagation in a string, and in a rod. A cost function approach is applied to identify the quality of such waves. Furthermore, steady-state square traveling waves are generated in a string and in-plane in a rod, both theoretically and experimentally. To the authors’ knowledge this is the first time this has been attempted in the literature. Determining the quality of traveling waves and understanding the parameters on the wave propagation of a string and rod can lead to further understand and leverage various engineering disciplines such as mechanical actuation mechanisms, propulsion of flagella, and the basilar membrane in the ear’s cochlea. / Master of Science / This work presents how mechanical steady state traveling waves can be generated and propagated through structures by applying forces. By steady state traveling waves we refer to propagation of mechanical waves in a finite medium that never exhibits reflections at the boundaries and continuously moves from one end of the structure to the other. Mechanical waves can be classified as traveling, standing and hybrid waves that are the results of applied forces, their locations, and the boundary conditions of the structure. Traveling waves carry energy through a defined medium while standing waves keep energy at certain areas. To understand the interaction of systems that exhibit traveling waves with their surrounding media, it is crucial to first understand the wave propagation and what is desired in these structural systems. The parameters that affect the generation and propagation of waves should be well-defined to control and manipulate the desired system’s behavior. In this study, two excitation forces are applied to a string and a rod near the boundaries to understand the generation and propagation of traveling and standing waves at various frequencies. The work examines the quality of the wave propagation in a string, and in a rod. Steady-state square traveling waves are generated in a string and in-plane in a rod, both theoretically and experimentally. To the authors’ knowledge this is the first time this has been attempted in the literature. Determining the quality of traveling waves and understanding the parameters on the wave propagation of a string and rod can lead to further understand and leverage various engineering disciplines such as mechanical actuation mechanisms, propulsion of flagella, and the basilar membrane in the ear’s cochlea.

No / Most inhibitory signals are mediated via γ-aminobutyric acid (GABA) receptors whereas glutamate receptors mediate most excitatory signals (Trends Neurosci 14:515–519, 1991; Annu Rev Neurosci 17:31–108, 1994). Many factors influence the regulation of excitatory and inhibitory synaptic inputs on a given neuron. One important factor is the subtype of neurotransmitter receptor present not only at the correct location to receive the appropriate signals but also their abundance at synapses (Pharmacol Rev 51: 7–61, 1999; Cold Spring Harb Perspect Biol 3, 2011). GABAB receptors are G-protein-coupled receptors and different subunits dimerise to form a functional receptor. GABAB receptor subunits are widely expressed in the brain and by assembling different isoform combinations and accessory proteins they produce variety of physiological and pharmacological profiles in mediating both inhibitory and excitatory neurotransmission. This chapter will describe the understanding of the molecular mechanisms underlying GABAB receptor regulation of glutamate and GABAA receptors and how they modulate excitatory and inhibitory neurotransmission.

This thesis presents a comprehensive modal analysis on an asphalt roller, focusing on optimizing excitation and measurement point selection for accurate characterization of the structure’s dynamic behavior. The thesis aims to find out how to select excitation points that ex-cite all mode shapes within a specific frequency range and to find out how to select measurement points that capture the dynamic behavior and mode shapes of the structure within the same frequency range. The method used is an action research method that includes four phases: planning, action, observation, and reflection. The planning phase involves numerical modal analysis, simulations, and selection of excitation and measurement points. The action phase includes experimental measurements preliminary tests, and the actual testing of the structure. The observation covers extracting modal parameters from measurement data and comparing results with simulation predictions. Reflection focuses on evaluating results and adapting the decision-making accordingly. The EODP method provides practical excitation points that successfully active modes consistent with the simulations. The minMAC GA approach identifies measurement points that capture the asphalt roller’s essential dynamic behavior, despite challenges with modal parameter extraction. Even though the mode shapes are not well separated due to the complexity of the structure, high-quality identification of mode shapes was achieved considering impact excitation which gives great insight into the asphalt roller’s dynamic properties. Overall, this research contributes to the understanding of modal analysis on complex mechanical structures, providing effective methods for excitation and measurement point selection. The findings in the study can inform the design and maintenance of similar structures in various engineering applications.

La maladie d'Alzheimer (MA) est la maladie neurodégénérative la plus courante et la cause prédominante de la démence sénile (caractérisé par une perte de mémoire et de raisonnement) et du déclin cognitif. Elle résulte d'une dégénérescence des neurones et d'une atrophie sévère qui commence dans les lobes temporal, pariétal et frontal et dans le gyrus cingulaire, puis dans des régions sous-corticales telles que l'hippocampe et le noyau de Meynert. Des observations récentes chez les patients atteints de la MA ont fait état d'une activité cérébrale anormale, commune à d'autres troubles neurologiques avant la perte des neurones. L'hyperexcitabilité neuronale se manifeste tôt dans la MA, ce qui entraîne une hyperactivité corticale et hippocampique et parfois même une activité épileptiforme et des crises chez la souris et l'homme. Cependant, les mécanismes sous-jacents à l'hyperexcitabilité dans le cerveau de la maladie d'Alzheimer restent obscurs. Une hypothèse importante suggère que l'accumulation d'amyloïde-β perturbe la signalisation inhibitrice médiée par le GABA[indice A]. Le vieillissement normal est également associé à un déclin des fonctions cognitives, indépendamment de tout trouble neurodégénératif. Les causes du déclin cognitif associé au vieillissement (DCAV) sont multiples, mais le facteur clé est l'équilibre entre l'excitation et l'inhibition synaptiques. Comme dans le cas de la maladie d'Alzheimer, une hyperactivité neuronale dans l'hippocampe, une région du cerveau impliquée dans la formation et la rétention de la mémoire, ou une absence de désactivation du réseau du mode par défaut (DMN) ont été décrites dans les troubles cognitifs associés au vieillissement. Pourtant, dans le cortex préfrontal, une région du cerveau cruciale pour les fonctions exécutives, une réduction manifeste de la ramification dendritique se produit avec le vieillissement, entraînant une diminution de la transmission synaptique excitatrice et une augmentation de l'entrée inhibitrice. Les études présentées dans cette thèse visent à identifier les altérations de la transmission synaptique conduisant aux déficits cognitifs associés à la MA et à l'ARCD mais visent également à dévoiler les mécanismes potentiels sous-jacents à l'hyperactivité neuronale. Dans la MA, les résultats présentés ici montrent une perte de fonction de l'extrudeur de chlorure neuronal KCC2, responsable du maintien de la robustesse de l'inhibition médiée par le GABA[indice A]. La restauration de KCC2 chez les souris porteuses de mutations liées à la maladie d'Alzheimer a permis d'inverser les déficits de mémoire spatiale et les dysfonctionnements sociaux, reliant la dyshoméostasie des chlorures au déclin cognitif lié à la maladie d'Alzheimer. Avec le vieillissement normal, un sous-ensemble de souris a développé des déficits de mémoire non spatiale, un comportement de type anxieux et un dysfonctionnement social. Dans ce sous-ensemble de souris âgées atteintes de troubles cognitifs, les niveaux de protéines synaptiques inhibitrices clés étaient élevés dans le cortex préfrontal médian (CPM). L'activation optogénétique des neurones GABAergiques du CPM a modifié le comportement des jeunes souris et a reproduit certaines des déficiences cognitives observées chez les vieilles souris souffrant de troubles cognitifs. D'autre part, lorsque la stimulation optogénétique a été utilisée pour générer un modèle d'hyperactivité neuronale soutenue et chronique dans l'hippocampe de jeunes souris, les niveaux de protéines synaptiques excitatrices et inhibitrices ont été réduits, ce qui indique une perturbation générale de la transmission synaptique. Enfin, et surtout, lorsque l'on compare les protéines modifiées lors d'une stimulation optogénétique chronique chez des souris de type sauvage à celles modifiées par des mutations et des pathologies dans les modèles de la maladie d'Alzheimer, seules quelques protéines sont exprimées différemment. Ces résultats suggèrent que l'hyperactivité neuronale pourrait contribuer directement à la perturbation de la transmission synaptique et à la neuropathologie liée à la MA. En résumé, le déclin cognitif peut se produire avec une inhibition à la fois exagérée et diminuée. Ces deux voies opposées, la première étant observée dans le déclin cognitif lié à l'âge et la seconde étant typique de la MA, perturbent de manière unique le fonctionnement normal du cerveau, ce qui entraîne à son tour un déclin cognitif. Une appréciation de ces résultats peut avoir des implications pour les interventions thérapeutiques dans les deux conditions. Dans l'ensemble, les travaux présentés dans cette thèse soulignent non seulement la contribution de l'altération de la transmission inhibitrice dans le développement du déclin cognitif dans la MA et le vieillissement, mais décrivent également l'implication de l'hyperactivité neuronale dans la perturbation des synapses et la neurodégénération. / Alzheimer's disease (AD) is the most common neurodegenerative disorder and the predominant cause of senile dementia (characterized by a loss of memory and reasoning) and cognitive decline. It results from neuron degeneration and severe atrophy initiating from the temporal, parietal and frontal lobe, the cingulate gyrus and the hippocampus following by subcortical regions such as the the nucleus basalis of Meynert. Recent observations have reported an abnormal brain activity in AD patients, common to other neurological disorders prior to the neuron loss. Neuronal hyperexcitability manifests early in AD which leads to cortical and hippocampal hyperactivity and sometimes even epileptiform activity and seizures in mice and humans. However, the mechanisms underlying hyperexcitability in the AD brain remains elusive. A prominent hypothesis suggests that amyloid-β accumulation disrupts GABA[subscript A]-mediated inhibitory signaling. Normal aging is associated also with a decline in cognitive function independently of any neurodegenerative disorder. The causes of aging associated cognitive decline (ASCD) are multifaceted but a key factor is the imbalance between synaptic excitation and inhibition. Similar to AD, neuronal hyperactivity in the hippocampus, a brain region involved in memory formation and retention, or failure of deactivation of the Default Mode Network (DMN) has been described in ASCD. Yet, in the prefrontal cortex, a brain region crucial for executive functions, an overt reduction in the dendritic branching occurs with aging resulting in diminished excitatory synaptic transmission together with an increase in the inhibitory input. The studies presented in this thesis aim to identify alterations in synaptic transmission leading to cognitive deficits associated with AD and ARCD but also aim to unveil potential mechanisms underlying neuronal hyperactivity. In AD, the results presented here show a loss of function of the neuronal chloride extruder KCC2, responsible for maintaining the robustness of GABA[subscript A]-mediated inhibition. Restoring KCC2 in mice carrying AD-linked mutations reversed spatial memory deficits and social dysfunction linking chloride dyshomeostasis with AD-related cognitive decline. With normal aging, a subset of mice developed non-spatial memory impairments, anxiety-like behavior, and social dysfunction. In this subset of cognitively impaired old mice, the levels of key inhibitory synaptic proteins were elevated within the medial prefrontal cortex (mPFC). Activating mPFC GABAergic neurons optogenetically altered the behavior of young mice and mimicked some of the cognitive impairments found in the old, cognitively impaired mice. On the other hand, when optogenetic stimulation was used to generate a model of sustained, chronic neuronal hyperactivity in the hippocampus of young mice, both excitatory and inhibitory synaptic proteins levels were reduced pointing to a general disruption of synaptic transmission. Finally, and more importantly, when we compared the proteins altered upon chronic optogenetic stimulation in wild-type mice to that altered due to mutations and pathology in AD models, only a few proteins where differently expressed. These results suggest that neuronal hyperactivity could contribute directly to the disruption of synaptic transmission and the neuropathology linked to AD. To sum up, cognitive decline can occur with both exaggerated and diminished inhibition. These two opposing paths, with the first seen in age-related cognitive decline, and the second being typical to AD, uniquely disrupt normal brain functioning which in turn leads to cognitive decline. An appreciation of these findings can have implications for therapeutic interventions in the two conditions. Taken together, the work presented in this thesis not only highlights the contribution of altered inhibitory transmission in the development of cognitive decline in AD and aging, but also describes the involvement of neuronal hyperactivity in synapse disruption and neurodegeneration.

Titre de l'écran-titre (visionné le 30 novembre 2023) / Dans cette thèse, la dynamique d'excitation électronique et d'ionisation de H₂ dans une impulsion laser intense est étudiée en utilisant une approche ab initio pour résoudre numériquement l'équation de Schrödinger dépendante du temps (TDSE) pour ce système. Nous avons développé une nouvelle méthodologie utilisant des fonctions B-Splines comme base de développement des fonctions d'onde multi-configurationnelles du système. Afin de décrire et d'analyser la dynamique d'ionisation et d'excitation électronique, nous faisons appel au programme MEDYS (Many-Electron-Dynamics System), conçu à notre laboratoire en interne, et dont l'adaptation en base B-Spline pour donner la version MEDYS-BSpline est un des objectifs de la thèse. Ce programme utilise une méthode d'interaction de configuration dépendante du temps (TDCI) pour décrire la dynamique temporelle de l'ionisation sur les voies de l'espace lié et celui des cations. En application de la méthodologie, le travail continue avec la détermination du régime d'ionisation, tunnel ou multiphotonique, quand la molécule H₂ est soumise à un rayonnement intense dans l'infra-rouge proche (de longueur d'onde λ = 800 nm). Le travail entreprend également une évaluation numérique de l'approximation du Champ Fort en comparant les résultats de calculs de la dynamique électronique utilisant l'approximation de Strong Field Approximation (SFA) avec ceux utilisant une représentation complète et non-SFA du propagateur de l'électron ionisé. / In this thesis, the dynamics of electronic excitation and ionization of H₂ in an intense laser pulse are studied using an ab initio approach to numerically solve the time-dependent Schrödinger equation (TDSE) for this system. We have developed a new methodology using B-Spline functions as a basis for developing the multiconfigurational wave functions of the system. To describe and analyze the dynamics of ionization and electronic excitation, we employ the in-house program called Many-Electron-Dynamics System (MEDYS), and one of the objectives of the thesis is to adapt it to the B-Spline basis, resulting in the MEDYS-BSpline version. This program utilizes a time-dependent configuration interaction (TDCI) method to describe the temporal dynamics of ionization in both bound and cationic states. Applying this methodology, the work continues with the determination of the ionization regime, either tunneling or multiphoton, when H₂ is subjected to intense radiation in the near-infrared (wavelength λ = 800 nm). The work also undertakes a numerical evaluation of the Strong Field Approximation (SFA) by comparing the results of electronic dynamics calculations using the SFA approximation with those using a full and non-SFA representation of the ionized electron propagator.

Le mouvement animal, présent lors d’expériences in vivo effectuées à l’aide de microscopie à effet deux photons, nuit à l’observation de phénomènes biologiques et à l’analyse subséquente des flux vidéos acquis. Ceci s’explique entre autres par le fait que, dû au sectionnement optique, tout déplacement dans l’axe z (perpendiculaire au plan d’imagerie) modifie drastiquement l’image et ne permet qu’une observation instable de l’échantillon examiné. En appliquant une fonction de hachage aux images acquises, nous produisons des vecteurs décrivant les qualités perceptuelles de ces images ; ces vecteurs peuvent alors servir à comparer les images une à une, en temps réel. Ces comparaisons nous permettent de réunir les images en groupes correspondant à des plans z distincts. Ainsi, du processus de hachage, de comparaison et de groupage d’images résulte une méthode logicielle de compensation de mouvement en temps réel qui peut être utilisée dans le cadre d’expériences biologiques en laboratoire. / Animal movement during in vivo two-photon microscopy experiments hinders efforts at observing biological phenomena and the subsequent analysis of the acquired video streams. One of the reasons for this is that, due to optical sectioning, any displacement in the z-axis (perpendicular to the plane of imaging) dramatically changes the collected image and thus provides the experimenter with an unstable view of the imaged sample. By applying a hashing function on the acquired video frames, we produce vectors embodying the images’ perceptual qualities; these vectors can then be used to compare the frames one to another, in real-time. These comparisons allow us to group similar images in clusters corresponding to distinct z-planes. In effect, the process of perceptually hashing, comparing and grouping video frames provides us with software-based, real-time movement compensation which can be used in a biological laboratory setting.