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Opis: Background: The crucial steps in beta cell stimulus-secretion coupling upon stimulation with glucose are oscillatory changes in metabolism, membrane potential, intracellular calcium concentration, and exocytosis. The changes in membrane potential consist of bursts of spikes, with silent phases between them being dominated by membrane repolarization and absence of spikes. Assessing intra- and intercellular coupling at the multicellular level is possible with ever-increasing detail, but our current ability to simultaneously resolve spikes from many beta cells remains limited to double-impalement electrophysiological recordings. Methods: Since multicellular calcium imaging of spikes would enable a better understanding of coupling between changes in membrane potential and calcium concentration in beta cell collectives, we set out to design an appropriate methodological approach. Results: Combining the acute tissue slice method with ultrafast calcium imaging, we were able to resolve and quantify individual spikes within bursts at a temporal resolution of >150 Hz over prolonged periods, as well as describe their glucose-dependent properties. In addition, by simultaneous patch-clamp recordings we were able to show that calcium spikes closely follow membrane potential changes. Both bursts and spikes coordinate across islets in the form of intercellular waves, with bursts typically displaying global and spikes more local patterns. Conclusions: This method and the associated findings provide additional insight into the complex signaling within beta cell networks. Once extended to tissue from diabetic animals and human donors, this approach could help us better understand the mechanistic basis of diabetes and find new molecular targets.
Ključne besede: beta cell, calcium imaging, calcium oscillations, calcium spikes, physiology
Objavljeno v DKUM: 24.01.2025; Ogledov: 0; Prenosov: 7
Celotno besedilo (9,70 MB)
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Opis: Cholinergic innervation in the pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in detail for endocrine beta cells and exocrine acinar cells separately. Here we describe morphological and functional criteria to separate these two cell types in situ in tissue slices and simultaneously measure their response to ACh stimulation on cytosolic Ca2+ oscillations [Ca2+]c in stimulatory glucose conditions. Our results show that both cell types respond to glucose directly in the concentration range compatible with the glucose transporters they express. The physiological ACh concentration increases the frequency of glucose stimulated [Ca2+]c oscillations in both cell types and synchronizes [Ca2+]c oscillations in acinar cells. The supraphysiological ACh concentration further increases the oscillation frequency on the level of individual beta cells, inhibits the synchronization between these cells, and abolishes oscillatory activity in acinar cells. We discuss possible mechanisms leading to the observed phenomena.
Ključne besede: pancreas tissue slices, acetylcholine, beta cell, acinar cell, Ca2+ oscillations
Objavljeno v DKUM: 14.10.2024; Ogledov: 0; Prenosov: 17
Celotno besedilo (2,41 MB)
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Opis: Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components.How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. In the present work, we combined advanced confocal Ca2+ imaging in fresh mouse pancreas tissue slices with time series analysis and network science approaches to unveil the glucosedependent characteristics of different oscillatory components on both the intra- and inter-cellular level. Our results reveal an interrelationship between the metabolically driven low-frequency component and the electrically driven high-frequency component, with the latter exhibiting the highest bursting rates around the peaks of the slow component and the lowest around the nadirs. Moreover, the activity, as well as the average synchronicity of the fast component, considerably increased with increasing stimulatory glucose concentration, whereas the stimulation level did not affect any of these parameters in the slow component domain. Remarkably, in both dynamical components, the average correlation decreased similarly with intercellular distance, which implies that intercellular communication affects the synchronicity of both types of oscillations. To explore the intra-islet synchronization patterns in more detail, we constructed functional connectivity maps. The subsequent comparison of network characteristics of different oscillatory components showed more locally clustered and segregated networks of fast oscillatory activity, while the slow oscillations were more global, resulting in several long-range connections and a more cohesive structure. Besides the structural differences, we found a relatively weak relationship between the fast and slow network layer, which suggests that different synchronization mechanisms shape the collective cellular activity in islets, a finding which has to be kept in mind in future studies employing different oscillations for constructing networks.
Ključne besede: islets of Langerhans, beta cell network, calcium oscillations, multimodal activity analysis, confocal imaging, functional connectivity, multiplex network
Objavljeno v DKUM: 06.06.2024; Ogledov: 171; Prenosov: 6
Celotno besedilo (9,40 MB)
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Opis: A coordinated functioning of beta cells within pancreatic islets is mediated by oscillatory membrane depolarization and subsequent changes in cytoplasmic calcium concentration. While gap junctions allow for intraislet information exchange, beta cells within islets form complex syncytia that are intrinsically nonlinear and highly heterogeneous. To study spatiotemporal calcium dynamics within these syncytia, we make use of computational modeling and confocal high-speed functional multicellular imaging. We show that model predictions are in good agreement with experimental data, especially if a high degree of heterogeneity in the intercellular coupling term is assumed. In particular, during the first few minutes after stimulation, the probability distribution of calcium wave sizes is characterized by a power law, thus indicating critical behavior. After this period, the dynamics changes qualitatively such that the number of global intercellular calcium events increases to the point where the behavior becomes supercritical. To better mimic normal in vivo conditions, we compare the described behavior during supraphysiological non-oscillatory stimulation with the behavior during exposure to a slightly lower and oscillatory glucose challenge. In the case of this protocol, we observe only critical behavior in both experiment and model. Our results indicate that the loss of oscillatory changes, along with the rise in plasma glucose observed in diabetes, could be associated with a switch to supercritical calcium dynamics and loss of beta cell functionality.
Ključne besede: beta cells, islets of Langerhans, self-organized criticality, intercellular dynamics, calcium waves, glucose oscillations, computational model, confocal calcium imaging
Objavljeno v DKUM: 23.01.2018; Ogledov: 1752; Prenosov: 396
Celotno besedilo (3,43 MB)
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Opis: Chimera states, namely complex spatiotemporal patterns that consist of coexisting domains of spatially coherent and incoherent dynamics, are investigated in a network of coupled identical oscillators. These intriguing spatiotemporal patterns were first reported in nonlocally coupled phase oscillators, and it was shown that such mixed type behavior occurs only for specific initial conditions in nonlocally and globally coupled networks. The influence of initial conditions on chimera states has remained a fundamental problem since their discovery. In this report, we investigate the robustness of chimera states together with incoherent and coherent states in dependence on the initial conditions. For this, we use the basin stability method which is related to the volume of the basin of attraction, and we consider nonlocally and globally coupled time-delayed Mackey-Glass oscillators as example. Previously, it was shown that the existence of chimera states can be characterized by mean phase velocity and a statistical measure, such as the strength of incoherence, by using well prepared initial conditions. Here we show further how the coexistence of different dynamical states can be identified and quantified by means of the basin stability measure over a wide range of the parameter space.
Ključne besede: synchronization, oscillations, symmetry breaking, network
Objavljeno v DKUM: 23.06.2017; Ogledov: 1274; Prenosov: 366
Celotno besedilo (4,46 MB)
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