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Modelling of intracellular calcium dynamics

Ca2+ as a universal messenger participates in a great variety of physiological functions and biological events such as cell maturation, chemotaxis or gene expression. These diverse functions are controlled through complex spatio-temporal calcium patterns. To date it is known that these patterns depend on stimuli type and concentration. However, the majority of these observations were from constant or step change stimulation protocols. Under these conditions two leading hypotheses for the stimulus encoding into cytosolic calcium responses were proposed, namely amplitude and frequency modulation. Under physiological conditions, however, cells often experience time dependent stimuli such as transient changes in neurotransmitter or oscillations in hormone concentrations. How cells transduce such dynamic stimuli into an appropriate response is an open question. We exposed HEK293 cells and astrocytes to dynamically varying time courses of carbachol and ATP, respectively, and investigated the corresponding cellular calcium activity. While single cells generally fail to follow the applied stimulation due to their intrinsic stochasticity and heterogeneity, faithful signal reconstruction is observed at the population level. We suggest eight possible population representation measures and using mutual information measure show that the area under the curve and total number of spikes are the most informative ones. Next we provide simple transfer functions that explain how dynamic stimulation is encoded into area under the curve and ensemble calcium spike rates. Cells in a physiological environment often experience diverse stimulation time courses which can be reproduced experimentally. Furthermore, cell populations may differ in the number of cells or exhibit various spatial distributions. In order to understand how these conditions affect population responses, we compute the single cell response to a given dynamic stimulus. Single cell variability and the small number of calcium spikes per cell pose a significant modelling challenge, but we demonstrate that Gaussian processes can successfully describe calcium spike rates in these circumstances and outperform standard tools such as peri-stimulus time histograms and kernel smoothing. Having the single cell response model will allow us to compare responses of various sets of cells to the observed population response and consequently obtain insight into tissue-wide calcium oscillations for heterogeneous cell populations. Finally,in vivo astrocytes respond to a range of hormones and neurotransmitters. Furthermore these agonists can have different characteristics, for example glutamate is a fast excitatory transmitter, while ATP can be an inhibitory transmitter. Despite of this, how (or if at all) astrocytes differentiate between different agonists is still not clear. We hypothesize that astrocytes discriminates between different stimuli by exploiting the spatial-temporal complexity of calcium responses. We show how 2D A Trous wavelet decomposition combined with Bhattacharyya distance measure can be applied to test this hypothesis.
Date January 2018
CreatorsTilūnaitė, Agnė
PublisherUniversity of Nottingham
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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