Integration of calcium signalling mechanisms in neural modelling

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Neurons are a specialised part of the extremely complex structure of the nervous system. They generate electrical signals in response to chemical and other inputs and transmit them to other cells. Over the past hundred years experimental research has accumulated an enormous amount of knowledge about the structure and function of an individual nerve cell as well as neural networks. However, there are still fundamental questions that remain unanswered. Theoretical analysis and computational modelling of neural systems are important tools that help to characterise what neurons do and determine the ways in which they function. It has recently become increasingly clear that calcium plays an important role in controlling a great variety of neuronal processes. Calcium channels activated by voltage (voltage-gated channels) in different neuronal cell types are believed, for example, to regulate components of learning and memory and to be involved in coincidence detection mechanisms. The overall aim of the project is to develop a biophysically realistic and computationally inexpensive model of a nerve cell for better understanding the interaction between electrical and chemical signalling (membrane voltage and calcium concentration). This interaction plays important functional roles in neuronal excitability and synaptic integration and plasticity. Experimental studies demonstrate that calcium channels open in response to membrane depolarisation and in turn cause further depolarisation by generating calcium-dependent action potentials. At the same time the propagation of action potential produces an increase in calcium concentration and generates rich patterns in both space and time, from widespread calcium influx in dendrites to heterogeneous calcium transients in axons. Moreover, the properties of the same voltage-gated calcium channels can be different in somatic and dendritic membranes with substantial variability in channel density. The major objectives of the research are i) to explore the implications of the heterogeneous distribution of calcium channels on amplification or boosting of distal synaptic inputs, ii) to investigate the role of calcium in the induction and maintenance of synaptic plasticity, and iii) to study how calcium waves can generate recently-discovered graded persistent activity in single neurons that may underly working memory. The proposed methodology draws from a number of established principles in different scientific disciplines, predominantly those of nonlinear dynamics, numerical analysis of deterministic and stochastic systems, biophysics, computational neuroscience and molecular signalling. A combination of theoretical analysis, numerical simulations and experimental verification will be used to address important issues of calcium signals underlying vital brain functions. Showing that the persistence of activity in a single neuron can be observed in the presence of calcium may reveal that as a computational system, the single neuron is a far more powerful unit that was previously assumed. Calcium dynamics could thus be the physiological basis for a single-neuron mechanism sub-serving working memory. Also, an understanding of the mechanism of calcium regulation in neurons during brain damage is crucially important, and this might provide the ground for a specific future application of the proposed work. As experiments show, ischemia increases calcium concentration in nerve cells, particularly in their dendrites and synaptic terminals. Due to this large calcium increase, dendritic tissue is very susceptible to damage. This is an area where further research can potentially generate explosive rates of development.