Accumulation of amyloid beta (Aβ) in the brain is a pathological hallmark of Alzheimer's disease (AD) and has been shown to lead to synaptic dysfunction and cognitive decline. Recent studies have indicated synapse dysfunction as an early pathology in AD, but how synaptic function is altered by Aβ remains unclear. We hypothesize that neuronal functional stability may be altered by Aβ via dysregulation of homeostatic synaptic plasticity (HSP), a negative-feedback-based regulation that serves to restrain neuronal activity within a physiological range. Here, I show that Aβ can regulate HSP in response to activity deprivation with an over scaling up of postsynaptic AMPAR expression and excitatory synaptic currents. Aβ treatment during activity deprivation increases the surface expression of both calcium-permeable (Cp), GluA2-lacking (CpAMPARs) and regular, GluA2-containing AMPARs. This in turn may make neurons more vulnerable to neuronal injury after a toxic glutamatergic challenge. Homeostatic synaptic scaling requires the PI3K/Akt signaling pathway and expression of CpAMPARs. Consistent with this, I found that blockade of either PI3K or CpAMPARs occludes over-scaling in the presence of Aβ, suggesting that the enhancement of HSP is mediated through homeostatic mechanisms. Furthermore, challenging neurons with glutamate after Aβ-mediated enhancement of HSP shows increased neuronal death. These findings provide a novel mechanism by which Aβ alters neuronal plasticity and calcium homeostasis in the brain, suggesting that the HSP pathway may be a target in clinical treatment of Alzheimer's disease.

Memory is one of the highest cognitive functions that differentiates higher organisms from others because of its fundamental function to all learning and studying process. Recently, it was suggested that lactate works as a signaling molecule in neuronal plasticity system in long-term memory (LTM). These functions are reported only at mice so far, but it would be a universal phenomenon among various higher organisms. Because lactate is organic acid that is involved with energy production, it is of particular interest to know how memory associated genes including lactate-mediated neural plasticity (LMNP) genes get involved during evolution. I here set the purpose of my studies to understand the evolutionary origin and process of these memory-associated genes. Conducting an extensive literature survey, I collected a total of 302 genes of mice as memory associated genes. I, then, compared the number of genes orthologous to the 302 mice memory-associated genes among 11 representative organisms that I have chosen for the present study. As a result, I found that these memory-associated genes emerged at different time points during evolution, even before the emergence time of the organisms where memory function was reported. It suggests that memory function could be evolutionarily established gradually but not at once. Moreover, I examined 386 of LMNP-related genes of mice and other organisms to understand the evolutionary origin and processes of those genes that were identified by RNA-seq analyses (Margineanu et al., 2018). I found that the emergence times of LMNP genes were varied with genes, suggesting that the LMNP system may have been also formed gradually until its completion of the system around at the time of the common ancestor of vertebrates. Interestingly, I found that there are 13 genes overlap between the memory system and the LMNP system, indicating the critical role of those genes in connecting between both systems. From those studies, I conclude that the memory system and LMNP system has been formed by gradual participation of newly emerging genes during evolution, suggesting that the function of LMNP as a signaling molecule may be evolutionarily related to memory system by an unknown system that may exist to link both systems.

Une précision à l’échelle de la milliseconde dans le transfert d'informations entre les neurones est essentielle pour la synchronisation et la plasticité des circuits neuronaux dans le cerveau. Les axones sont des prolongements neuronaux qui assurent la communication via des impulsions électriques ou des potentiels d’action (PA). A cause du manque de myéline et de leur diamètre très fin, les axones de l'hippocampe propagent les PA lentement et ainsi générer des délais de conduction très long (jusqu’à 100 ms) qui sont traditionnellement considérés comme invariants. Cependant, plusieurs études ont montré que l'activité change la morphologie des axones et module le temps de latence de la transmission. Il convient donc de se demander si le diamètre des axones varie en fonction de l'activité pouvant influencer lapropagation des PA.Les diamètres des axones non-myélinisés de l’hippocampe (compris entre 100-350 nm) sont généralement trop petits pour être résolu par la microscopie photonique conventionnelle. Le développement récent de l’imagerie super résolution STED permet désormais l'observation de la dynamique de leur morphologie détaillée dans le tissu vivant. En combinant la microscopie STED, l’électrophysiologie avec enregistrements en champs et patch-clamp dans des tranches de cerveau de souris et des simulations informatiques, nous avons découvert que les axones du CA3 subissent un élargissement de leur diamètre après l'induction de la potentialisation à long terme (PLT). Nous démontrons que cet élargissementde diamètre augmente la vitesse de conduction des PA. Dans l'ensemble, nos résultats indiquent que les axones peuvent réguler leur diamètre de manière dynamique changeant le délai de conduction des PA, ce qui modifie le timing du transfert d’information dans les circuits neuronaux. Cette étude suggère l’existence d’un nouveau type de mécanisme structurel dans le compartiment axonal jouant un rôle pour la plasticité neuronale. / Millisecond timing precision in the transfer of information between neurons is essential for the synchrony and plasticity of neural circuits in the brain. Axons are neuronal extensions that ensure the communication via brief electrical impulses called action potentials (AP). Because they are unmyelinated and are extremely thin, hippocampal axons propagate APsslowly and thus generate long delays of conduction (up to 100 ms) that are traditionally considered invariant. However, recent studies have shown that activity changes the morphology of axons and modulate the latency of transmission, thus raising the question whether axons undergo activity-dependent structural changes that could influence the propagation of APs. The diameter of hippocampal axons (ranging between 100-350 nm) are usually too thin to be properly resolved by conventional light microscopy. However, the development of super resolution STED imaging now enables the observation of their detailed morphological dynamics in living tissue. Using a novel combination of STED microscopy, field recordings, patch-clamp electrophysiology in mouse brain slices and computer simulations we discovered that CA3 axons undergo long-lasting enlargement in their diameter after the induction of long term potentiation (LTP). We provide strong evidence that this diameter enlargement increases AP conduction velocity. Taken together, our findings indicate that axons can dynamically tune AP propagation delays by changing their diameters, thereby altering the timing of information transfer in neural circuits. This study suggests a novel and powerful structural mechanism for neural plasticity.

One of the most interesting extraterrestrial bodies in the Solar System is Europa, the icy satellite of Jupiter. This icy moon might have a sufficiently hospitable environment which could be harbouring life in the subsurface ocean deep under its icy crust. The thesis thoroughly examines the generation process of one of the surface formations called chaotic terrains. These huge areas of ice disruptions which uniquely characterize Europa's surface might play a significant role in the understanding of the inner structure of the moon. The latest research assumes the chaotic terrains form above liquid water lenses perched relatively shallow in the ice shell, however, no numerical simulations have been performed to confirm this theory. The goal of the thesis is to create a model which would validate the theory and explain the formation process of the chaotic terrains. The thesis runs several simulations, and our results suggest these water lenses and the process in the mantle might play a key role in the chaotic terrains formation.

Phenotypic plasticity, the capacity of individuals to respond to changing environments by modifying traits, is critically important in allowing biological innovation in the face of environmental change. My dissertation used the clown anemonefish (Amphiprion percula) study system to explore plasticity in parenting strategies in response to variable ecological and social environments. In Part I, I investigated plasticity in response to ecological environment. First, I explored how resource variation influences parenting strategies. I measured parental behaviors in A. percula under two feeding regimes in the laboratory. I demonstrated that clownfish exhibit plasticity in parental care, and that there is significant among individual variation, i.e., personality, in parenting strategies. Second, I tested how plasticity affects life history strategies in the field. I measured habitat, reproductive, and parental traits in a natural population and found positive correlations between resource availability (anemone size) and body size, reproduction, and parental care. I conducted an experimental manipulation of resource availability and found that reproduction and parental care are plastic, providing a causal link between habitat quality variation and reproductive success in natural populations. In Part II, I investigated plasticity in response to social environment. In my third chapter, I explored how parents utilize social information to optimize their parental investment. I developed a game theory model that provides predictions for how power and punishment influence negotiations between parents over offspring care. The model predicts that the threat of punishment by a powerful parent will result in greater partner effort and, as a result, the offspring receive more total care when there is power and punishment in negotiations. Finally, I tested alternative models along with the model I developed, investigating how parents respond to each other to reach a negotiated settlement over offspring care. I experimentally handicapped one pair member and measured the response of the other parent. I found that anemonefish males and females do not respond directly to changes in their partner’s behavior, contrary to predictions of current negotiation models. Together, results from my dissertation extend our understanding of plasticity of parental care, providing a framework for understanding how parents will respond to changing environments.

Considering the hypothetical core melt down scenario for a light water reactor (LWR) a possible failure mode of the reactor pressure vessel (RPV) and its failure time has to be investigated for a determination of the loadings on the containment. Numerous experiments have been performed accompanied with material properties evaluation, theoretical, and numerical work /REM 1993/, /THF 1997/, /CHU 1999/. For pre- and post-test calculations of Lower Head Failure experiments like OLHF or FOREVER it is necessary to model creep and plasticity processes. Therefore a Fi-nite Element Model is developed at the FZR using a numerical approach which avoids the use of a single creep law employing constants derived from the data for a limited stress and temperature range. Instead of this a numerical creep data base (CDB) is developed where the creep strain rate is evaluated in dependence on the current total strain, temperature and equivalent stress. A main task for this approach is the generation and validation of the CDB. Additionally the implementation of all relevant temperature dependent material properties has been performed. For an evaluation of the failure times a damage model according to an approach of Lemaitre is applied. The validation of the numerical model is performed by the simulation of and com-parison with experiments. This is done in 3 levels: starting with the simulation of sin-gle uniaxial creep tests, which is considered as a 1D-problem. In the next level so called "tube-failure-experiments" are modeled: the RUPTHER-14 and the "MPA-Meppen"-experiment. These experiments are considered as 2D-problems. Finally the numerical model is applied to scaled 3D-experiments, where the lower head of a PWR is represented in its hemispherical shape, like in the FOREVER-experiments. This report deals with the 1D- and 2D-simulations. An interesting question to be solved in this frame is the comparability of the French 16MND5 and the German 20MnMoNi55 RPV-steels, which are chemically nearly identical. Since these 2 steels show a similar behavior, it should be allowed on a lim-ited scale to transfer experimental and numerical data from one to the other.

The brain is capable of plasticity, so that the structural and functional loss that are caused by cortical injury may recover. Neuroinflammatory response can greatly influence post-injury recovery by modulating synaptic plasticity. In our previous work, mesenchymal derived exosomes were found to promote functional recovery by converting microglia from a pro-inflammatory state to an anti-inflammatory state in aged rhesus monkeys after cortical injury in the primary motor cortex. In the present project, we demonstrated the effects of exosomes on synaptic changes and synapse-microglia interactions after lesion in the same monkeys. To further investigate the effects of modulating neuroinflammation on synaptic changes after injury, we also investigated dietary curcumin, an anti-inflammatory substance, in a separate group of monkeys. Both treatments showed an effect as neuroinflammatory modulators that reduced the density of microglial markers, Iba- 1/P2RY12. However, the cortical injury induced synaptic loss was reversed by the exosome treatment, whereas the other anti-inflammatory treatment, curcumin, did not show the same effect. Our results are consistent with previous study that cortical injury induced synaptic loss and microglia activation. Exosomes can both reduce inflammation and synapse loss after injury, but curcumin only showed anti-inflammatory effects. Overall, these data suggested that exosomes and curcumin had different mechanisms of how to modulate inflammation and synaptic properties to promote recovery after cortical injury.

It has been suggested that polyploidization affects the ecological niche of a species, possibly ultimately leading to a shift in the distribution of the species, such as in geographical parthenogenesis. The phenomenon describes the wider distribution and shift of asexuals towards higher altitudes, northern latitudes and more extreme habitats when compared with their closely related sexual relatives. Several hypotheses have been proposed to explain such patterns with lacking empirical evidence because investigations rather focused on single hypotheses, which were rather tested several times independently on multiple organisms than vice versa. Therefore, the present study aimed to tackle the phenomenon of geographical parthenogenesis from multiple angles, i.e. testing several hypotheses simultaneously using Hieracium alpinum as a model system. In the arcto-alpine Asteraceae H. alpinum sexually reproducing diploid individuals occur in a small isolated area in the Eastern and Southern Carpathians, while apomictically reproducing, i.e. asexual reproduction via seeds, triploid plants occupy the remaining and much larger part of the range from the Balkans to the arctic parts of Europe. This implies that asexual triploids have had some fitness / colonization advantage(s), leading to a replacement of sexual diploids...

Neuropsychiatric disorders severely impact quality of life in millions of patients, contributing more Disease Affected Life Years (DALYs) than cancer or cardiovascular disease. The human brain is a complex system of 100 billion neurons connected by 100 trillion synapses, and human studies of neural disease focus on network-level circuit activity changes, rather than on cellular mechanisms. To probe for neural dynamics on the cellular level, animal models such as the nematode C. elegans have been used to investigate the biochemical and genetic factors contributing to neurological disease. C. elegans are ideal for neurophysiological studies due to their small nervous system, neurochemical homology to humans, and compatibility with non-invasive neural imaging. To better study the cellular mechanisms contributing to neurological disease, we developed automated analysis methods for characterizing the behaviors and associated neural activity during sleep and learning in C. elegans: two neural functions that involve a high degree of behavioral and neural plasticity. We developed two methods to study previously uncharacterized spontaneous adult sleep in C. elegans. A large microfluidic device facilitates population-wide assessment of long-term sleep behavior over 12 hours including effects of fluid flow, oxygen, feeding, odors, and genetic perturbations. Smaller devices allow simultaneous recording of sleep behavior and neuronal activity. Since the onset of adult sleep is stochastically timed, we developed a closed-loop sleep detection system that delivers chemical stimuli to individual animals during sleep and awake states to assess state-dependent changes to neural responses. Sleep increased the arousal threshold to aversive chemical stimulation, yet sensory neuron (ASH) and first-layer interneuron (AIB) responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the AVA premotor interneurons, rather than afferent sensory circuits. Traditionally, the study of learning in C. elegans observes taxis on agar plates which present variable environmental conditions that can lead to a reduction in test-to-test reproducibility. We also translated the butanone enhancement learning assay such that animals can be trained and tested all within the controlled environment of a microfluidic device. Using this system, we demonstrated that C. elegans are capable of associative learning by observing stimulus evoked behavioral responses, rather than taxis. This system allows for more reproducible results and can be used to seamlessly study stimulus-evoked neural plasticity associated with learning. Together, these systems provide platforms for studying the connections between behavioral plasticity and neural circuit modulation in sleep and learning. We can use these systems to further our understanding of the mechanisms underlying neural regulation, function, and disorder using human disease models in C. elegans.

New materials, optimized for increased strength, ductility, and other desirable properties, have the potential to improve every aspect of modern living. To achieve these optimums, the necessary technological advancements are impeded mainly by the limits of available material models. Innovations in this field rely on research into the nature of material behavior. While a typical model of material behavior in the region near yield involves the initial linear elastic response, followed by yield and isotropic hardening, this fails to explain various important phenomena that manifest in a range of materials, such as pre-yield nonlinearity, anelasticity, yield point phenomena, hardening stagnation, and the Bauschinger effect. These effects have been explained over the past century with the theories of Cottrell atmospheres, the Orowan by-pass mechanism, and back stress. This manuscript compares data from experimental observation in tantalum to these theories to better understand the micromechanisms occurring near yield. Understanding deformation in this region has significant implications in structural and mechanical engineering, as well has having direct applications in the forming of metals. Forty-four dogbone-shaped samples were cut from 99.99% pure tantalum and pulled in load-unload-load and multi-cycle loop tensile tests at room temperature. The specimens were either single crystal, whose orientations were chosen based on desired active slip mode determined by Schmid factors, or bicrystal, based on the orientation of the single grain boundary. Sample behavior was simulated in both crystal plasticity and General Mesoscale finite element models to assist in interpreting results and in suggesting plausible micromechanisms. The experimental results and crystal plasticity simulations suggest alternate explanations to some of the discussed mechanical theories of near-yield deformation. The combined experimental / modeling approach indicates that other slip systems, besides the conventionally assumed {110}, are activated upon yield; particularly the {112} system. The breakaway model traditionally associated with the yield point phenomenon may also be better explained through a different mechanism; back stress development during deformation is shown to result in the observed behavior. Lastly, as is well-known, the Taylor formulation, upon which most crystal plasticity models are based, does not adequately predict yield stress behavior in the presence of grain boundaries; once again, an internal stress mechanism matches much better with the experimental results on single and bicrystals. While not all observations could be fully explained by simply adding internal stress generation to a standard crystal plasticity model, this work anticipates further studies to enable more accurate predictive modeling capabilities and increase understanding of the mechanisms driving the fundamental material properties necessary for future progress.