Integration of calcium signalling mechanisms in neural modelling

神经元是神经系统极其复杂结构的一个专门部分。它们响应化学和其他输入产生电信号，并将其传输到其他细胞。在过去的一百年里，实验研究积累了大量关于单个神经细胞和神经网络的结构和功能的知识。然而，仍有一些根本性的问题没有得到解答。神经系统的理论分析和计算建模是重要的工具，有助于解释神经元的作用并确定它们的功能方式。最近越来越清楚的是，钙在控制各种神经过程中起着重要作用。在不同的神经元细胞类型中由电压激活的钙通道（电压门控通道）被认为例如调节学习和记忆的组分并且参与重合检测机制。该项目的总体目标是开发一个生物物理学上现实和计算成本低廉的神经细胞模型，以更好地了解电和化学信号（膜电压和钙浓度）之间的相互作用。这种相互作用在神经元兴奋性、突触整合和可塑性中起着重要的作用。实验研究表明，钙通道响应于膜去极化而打开，并进而通过产生钙依赖性动作电位而引起进一步的去极化。同时，动作电位的传播产生钙浓度的增加，并在空间和时间上产生丰富的模式，从树突中的广泛钙流入到轴突中的异质钙瞬变。此外，相同的电压门控钙通道的特性在体细胞膜和树突细胞膜中可以是不同的，通道密度具有很大的差异。本研究的主要目的是：i）探索钙通道的不均匀分布对远端突触输入放大或增强的影响; ii）研究钙在突触可塑性的诱导和维持中的作用; iii）研究钙波如何在单个神经元中产生最近发现的可能是工作记忆基础的分级持续活动。拟议的方法借鉴了一些既定的原则，在不同的科学学科，主要是那些非线性动力学，确定性和随机系统的数值分析，生物物理学，计算神经科学和分子信号。结合理论分析，数值模拟和实验验证将被用来解决重要的钙信号的重要问题，重要的大脑功能。在钙存在的情况下，可以观察到单个神经元的活动持续存在，这可能表明作为一个计算系统，单个神经元是一个比以前假设的强大得多的单元。因此，钙动力学可能是一个单神经元机制subserving工作记忆的生理基础。此外，了解脑损伤期间神经元中钙调节的机制是至关重要的，这可能为所提出的工作的具体未来应用提供基础。正如实验所示，缺血增加了神经细胞中的钙浓度，特别是在它们的树突和突触末梢中。由于这种大量的钙增加，树突组织非常容易受到损伤。这是一个进一步研究可能产生爆炸性发展速度的领域。

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.