Integration of calcium signalling mechanisms in neural modelling

神经建模中钙信号传导机制的整合

• 批准号: BB/H011900/1
• 负责人: Yulia Timofeeva
• 金额: $ 32.78万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH011900%2F1
• 关键词: Integration; calcium; signalling; mechanisms; neural

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.

神经元是神经系统极其复杂结构的一个特殊部分。它们对化学物质和其他输入产生电信号，并将其传递给其他细胞。在过去的一百年里，实验研究已经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，仍有一些基本问题没有得到解答。神经系统的理论分析和计算建模是重要的工具，有助于描述神经元的功能，并确定它们的功能方式。近来越来越清楚的是，钙在控制多种神经元过程中起着重要作用。例如，在不同类型的神经细胞中，由电压激活的钙通道（电压门控通道）被认为可以调节学习和记忆的组成部分，并参与巧合检测机制。该项目的总体目标是开发一种生物物理上真实且计算成本低廉的神经细胞模型，以便更好地理解电和化学信号（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功能作用。实验研究表明，钙通道在响应膜去极化时打开，并通过产生钙依赖的动作电位导致进一步的去极化。同时，动作电位的传播使钙浓度增加，并在空间和时间上产生丰富的模式，从树突内广泛的钙内流到轴突内不均匀的钙瞬态。此外，相同电压门控钙通道的性质在体细胞膜和树突膜中可能不同，通道密度有很大的差异。本研究的主要目的是：1)探索钙通道的异质分布对远端突触输入的放大或增强的影响；2)研究钙在突触可塑性的诱导和维持中的作用；3)研究钙波如何在单个神经元中产生最近发现的可能在工作记忆基础上的分级持续活动。所提出的方法借鉴了不同科学学科的一些既定原则，主要是非线性动力学、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。理论分析、数值模拟和实验验证的结合将用于解决钙信号在重要脑功能基础上的重要问题。在钙存在的情况下，单个神经元活动的持续性可以被观察到，这可能表明，作为一个计算系统，单个神经元是一个远比之前假设的更强大的单位。因此，钙动力学可能是服务于工作记忆的单神经元机制的生理基础。此外，了解脑损伤期间神经元中钙调节的机制至关重要，这可能为拟议工作的特定未来应用提供基础。实验表明，缺血会增加神经细胞中的钙浓度，特别是在树突和突触末端。由于钙的大量增加，树突组织非常容易受到损伤。在这个领域，进一步的研究可能会产生爆炸性的发展速度。

项目成果

Calmodulin as a major calcium buffer shaping vesicular release and short-term synaptic plasticity: facilitation through buffer dislocation.

• DOI: 10.3389/fncel.2015.00239
• 发表时间: 2015
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Timofeeva Y;Volynski KE
• 通讯作者: Volynski KE

Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels.

• DOI: 10.1038/nn.3563
• 发表时间: 2013-12
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Ermolyuk, Yaroslav S.;Alder, Felicity G.;Surges, Rainer;Pavlov, Ivan Y.;Timofeeva, Yulia;Kullmann, Dimitri M.;Volynski, Kirill E.
• 通讯作者: Volynski, Kirill E.

Computational convergence of the path integral for real dendritic morphologies.

• DOI: 10.1186/2190-8567-2-11
• 发表时间: 2012-11-22
• 期刊: Journal of mathematical neuroscience
• 影响因子: 2.3
• 作者: Caudron Q;Donnelly SR;Brand SP;Timofeeva Y
• 通讯作者: Timofeeva Y

Gap junctions, dendrites and resonances: a recipe for tuning network dynamics.

• DOI: 10.1186/2190-8567-3-15
• 发表时间: 2013-08-14
• 期刊: Journal of mathematical neuroscience
• 影响因子: 2.3
• 作者: Timofeeva Y;Coombes S;Michieletto D
• 通讯作者: Michieletto D