Lateral inhibition

Résumé

In neurobiology, lateral inhibition is the capacity of an excited neuron to reduce the activity of its neighbors. Lateral inhibition disables the spreading of action potentials from excited neurons to neighboring neurons in the lateral direction. This creates a contrast in stimulation that allows increased sensory perception. It is also referred to as lateral antagonism and occurs primarily in visual processes, but also in tactile, auditory, and even olfactory processing. Cells that utilize lateral inhibition appear primarily in the cerebral cortex and thalamus and make up lateral inhibitory networks (LINs). Artificial lateral inhibition has been incorporated into artificial sensory systems, such as vision chips, hearing systems, and optical mice. An often under-appreciated point is that although lateral inhibition is visualised in a spatial sense, it is also thought to exist in what is known as "lateral inhibition across abstract dimensions." This refers to lateral inhibition bet

Source officielle

https://en.wikipedia.org/wiki/Lateral_inhibition

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Sequence and structural determinants of Tau aggregation and seeding capacity: Implications for Neurofibrillary Tangle formation and Tau toxicity in Alzheimer's disease

Nadine Aït Bouziad

Despite decades of research in Alzheimerâs disease (AD), no treatment has been found to efficiently prevent or cure its progression. The microtubule binding protein Tau plays central roles in the pathogenesis of AD and is found, in the form of paired helical filaments (PHFs), as the main component of the neurofibrillary tangles, a major pathological hallmark of AD. Therefore, a better understanding of the molecular and structural determinants of Tau normal and pathological functions is crucial to elucidate the role of Tau in AD. The work presented in this thesis represents our efforts to contribute to addressing this knowledge gap by investigating the sequence, molecular and structural determinants of Tau aggregation, membrane binding, and toxicity and by exploring the interplay between these different properties. In Chapter 1, we assess the effect of manipulating the aggregation conditions on the fibril polymorphism of 4R Tau, the K18 fragment and the four individual repeat peptides within the microtubule binding domain, namely R1, R2, R3 and R4. The fibrilar structures formed by Tau, K18, R2 and R3 are diverse, polymorphic and depend upon the aggregation conditions. This work paves the way to a better understanding of molecular basis underlying Tau fibrils formation and demonstrates the importance of interplay between the different sequence motifs in Tau. In Chapter 2, we describe the discovery of a Tau-derived peptide that forms fibrils with a unique capacity to seed the aggregation of full-length Tau and templates its aggregation into highly ordered twisted fibrils that resemble native PHFs. This has tremendous potential applications in the understanding the biophysical properties of the PHFs, but also provide a powerful platform for designing Tau-specific imaging probes or the screening for small molecule modulators of fibrillization and clearance. In Chapter 3, we investigate the sequence determinants and structural consequences of the interactions of Tau with membranes, and describe for the first time the formation of stable protein/lipid complexes. Using NMR, we determined that the core of these complexes is comprised of short motifs localized in R2 and R3. We designed novel mutants that disrupt Tau interactions with lipids, thus providing powerful tools for investigating the role of membrane interactions in regulating the functions of Tau. Our findings point toward a novel form of Tau complexes that might be part of a membrane-dependent mechanism that regulates Tau oligomerization and toxicity. In Chapter 4, we explore the effect of tyrosine phosphorylation in regulating Tau properties. We report that phosphorylation at Y310, which is located within R3, results in the greatest inhibition of Tau fibril formation. We also identified two novel Tau kinases, Fes and Btk that phosphorylate Tau at positions Y310 and Y394, and developed antibodies specific for pY310 and pY394, thereby providing novel targets and tools that could lead to the discovery of novel mechanisms and pathways involved in regulating Tau functions. In addition to providing several tools to allow further understanding of Tau functions and implications in AD, our work underscores the importance of investigating the individual domains of Tau, especially R2 and R3, as structural determinant of Tau self-assembly and binding to membranes and demonstrates the critical involvement of phosphorylation of the Y310 residue in Tau biophysical and cellular properties.

EPFL2017

Chargement

Surface 3D Micro Free Forms: Multifunctional Microstructured Mesoporous alpha-Alumina by in Situ Slip Casting Using Excimer Laser Ablated Polycarbonate Molds

Paul Bowen, Patrik Hoffmann, Sriharitha Rowthu

Ceramic surface microstructuring is a rapidly growing field with a variety of applications in tribology, wetting, biology, and so on. However, there are limitations to large-area microstructuring and fabrication of three-dimensional (3D) micro free forms. Here, we present a route to obtain intricate surface structures through in situ slip casting using polydimethylsiloxane (PDMS) negative molds which are replicated from excimer laser ablated polycarbonate (PC) master molds. PC sheets are ablated with a nanosecond KrF (lambda = 248 nm) excimer laser mask projection system to obtain micron-scale 3D surface features over a large area of up to 3 m(2). Complex surface structures that include 3D free forms such as 3D topography of Switzerland, shallow structures such as diffractive optical elements (60 nm step) and conical micropillars have been obtained. The samples are defect-free produced with thicknesses of up to 10 mm and 120 mm diameter. The drying process of the slip cast alumina slurry takes place as a one-dimensional process, through surface evaporation and water permeation through the PDMS membrane. This allows homogeneous one-dimensional shrinkage during the drying process, independent of the sample's lateral dimensions. A linear mass diffusion model has been proposed to predict and explain the drying process of these ceramic colloidal suspensions. The calculated drying time is linearly proportional to the height of the slurry and the thickness of the negatively structured PDMS and is validated by the experimental results. An experimentally observed optimum Sylgard PDMS thickness range of similar to 400 mu m to 1 mm has achieved the best quality microstructured green compacts. Further, the model predicts that the drying time is independent of the microstructured areas and was validated using experimental observations carried out with microstructured areas of 300 mm(2), 1200 mm(2), and 120 cm(2). Therefore, in principle, the structures can be further replicated in areas up to 3 m(2) with the same drying time for the same slurry height. The surface-structured ceramics display interesting wetting properties, for example, eicosane-coated mesoporous microstructured alumina shows superhydrophobic behavior. Additionally, ceramic bulk samples could be further used as second-generation very hard and low-wear molds for further microfabrication.

Amer Chemical Soc2015

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Ventral striatal function and trait anxiety have been shown to influence reward-seeking behaviour and social competition in humans. Moreover, social status perceptions have been shown to modulate ventral striatal function. The neurochemical underpinnings of these associations have not been investigated in humans so far. Studies in rodents have previously shown that ventral striatal neurochemistry is associated with these concepts. In humans, objective and perceived social hierarchy position show some links to physical and mental health. Trait anxiety is understood as a predisposing factor underlying neuropsychiatric disorders and is associated with social anxiety. Fear and avoidance of social interactions, both inherent to environmental contexts of direct social competition, are hallmarks of social anxiety. Lost economic productivity due to anxiety and social status associated decrements in physical and mental health renders this scientific topic of high relevance to public health policies. Moving towards a deeper understanding of these associations might constitute an important part in ensuring public health. We combine proton magnetic resonance spectroscopy with personality profiling and an incentivised handgrip motivation task in a socially competitive context to investigate the neurochemical underpinnings of these associations in young adult men. We chose the occipital lobe as a control region. In addition, we have measured the salivary biomarkers cortisol, testosterone and alpha-amylase. We found that trait anxiety is negatively linked to taurine and positively to the excitation-inhibition balance. State anxiety was positively linked to lactate. The salivary biomarker alpha-amylase was found to be associated with both state anxiety and lactate. Social anxiety was positively linked to the excitation-inhibition balance. We also show links between reward-seeking task performance and ventral striatal glutamine, phosphorylethanolamine, GABA, choline, glutathione, myo-inositol, the excitation-inhibition balance and the ratio of glutamine to glutamate. These associations were observed in the ventral striatum but not the occipital lobe. Our methodological approach allowed us to gain a deeper understanding of the neuroscience underlying the links between ventral striatal function, anxiety and motivated behaviour. Thereby, we have extended the literature on the links between personality traits, social status and motivated behaviour in socially competitive contexts and the underlying neurobiology. These new findings pave the way for future experimental investigations to further elucidate the links between neurochemistry, mental health and socially competitive behaviour. A deep understanding of the neuroscience underlying personality traits and performance allow for effective interventions with the goal to ensure public health.

EPFL2017

Chargement

Sequence and structural determinants of Tau aggregation and seeding capacity: Implications for Neurofibrillary Tangle formation and Tau toxicity in Alzheimer's disease

Nadine Aït Bouziad

EPFL2017

Surface 3D Micro Free Forms: Multifunctional Microstructured Mesoporous alpha-Alumina by in Situ Slip Casting Using Excimer Laser Ablated Polycarbonate Molds

Paul Bowen, Patrik Hoffmann, Sriharitha Rowthu

Amer Chemical Soc2015