Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes.

Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface-to-volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+ -induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5-trisphosphate (IP3 ) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage-gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.

The Human Body as a Super Network: Digital Methods to Analyze the Propagation of Aging.

Biological aging is a complex process involving multiple biological processes. These can be understood theoretically though considering them as individual networks-e.g., epigenetic networks, cell-cell networks (such as astroglial networks), and population genetics. Mathematical modeling allows the combination of such networks so that they may be studied in unison, to better understand how the so-called "seven pillars of aging" combine and to generate hypothesis for treating aging as a condition at relatively early biological ages. In this review, we consider how recent progression in mathematical modeling can be utilized to investigate aging, particularly in, but not exclusive to, the context of degenerative neuronal disease. We also consider how the latest techniques for generating biomarker models for disease prediction, such as longitudinal analysis and parenclitic analysis can be applied to as both biomarker platforms for aging, as well as to better understand the inescapable condition. This review is written by a highly diverse and multi-disciplinary team of scientists from across the globe and calls for greater collaboration between diverse fields of research.

Astrocyte as Spatiotemporal Integrating Detector of Neuronal Activity.

The functional role of astrocyte calcium signaling in brain information processing was intensely debated in recent decades. This interest was motivated by high resolution imaging techniques showing highly developed structure of distal astrocyte processes. Another point was the evidence of bi-directional astrocytic regulation of neuronal activity. To analyze the effects of interplay of calcium signals in processes and in soma mediating correlations between local signals and the cell-level response of the astrocyte we proposed spatially extended model of the astrocyte calcium dynamics. Specifically, we investigated how spatiotemporal properties of Ca2+ dynamics in spatially extended astrocyte model can coordinate (e.g., synchronize) networks of neurons and synapses.

A homeostatic model of neuronal firing governed by feedback signals from the extracellular matrix.

Molecules of the extracellular matrix (ECM) can modulate the efficacy of synaptic transmission and neuronal excitability. These mechanisms are crucial for the homeostatic regulation of neuronal firing over extended timescales. In this study, we introduce a simple mathematical model of neuronal spiking balanced by the influence of the ECM. We consider a neuron receiving random synaptic input in the form of Poisson spike trains and the ECM, which is modeled by a phenomenological variable involved in two feedback mechanisms. One feedback mechanism scales the values of the input synaptic conductance to compensate for changes in firing rate. The second feedback accounts for slow fluctuations of the excitation threshold and depends on the ECM concentration. We show that the ECM-mediated feedback acts as a robust mechanism to provide a homeostatic adjustment of the average firing rate. Interestingly, the activation of feedback mechanisms may lead to a bistability in which two different stable levels of average firing rates can coexist in a spiking network. We discuss the mechanisms of the bistability and how they may be related to memory function.