Real Time NEURON Simulation for Experimental Applications

实验应用的实时神经元模拟

• 批准号: 10384810
• 负责人: Mark W Nowak
• 金额: $ 25.66万
• 依托单位: CYTOCYBERNETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384810
• 关键词: Action Potentials; Amplifiers; Behavior; Binding; Biological Assay; Biomedical Technology; Cells; Closure by clamp; Communication; Complex; Computer Models; Computer software; Computers; Coupling; Data; Defect; Development; Diagnosis; Diagnostic tests; Disease; Disease model; Drug Industry; Electrical Engineering; Electrophysiology (science); Engineering; Environment; Explosion; Gap Junctions; Genetic Models; Goals; Innovation Corps; Interneurons; Ion Channel; Kinetics; Link; Medicine; Membrane; Mental disorders; Methodology; Modeling; Molecular Medicine; Monitor; Morphologic artifacts; Mutation; Names; Nervous system structure; Neurons; Neurosciences; Output; Pharmaceutical Preparations; Play; Process; Property; Quality Control; Reporting; Research; Research Personnel; Resistance; Running; Science; Seizures; Software Engineering; Source; Standardization; Stimulus; Synaptic Transmission; System; Technical Expertise; Testing; Time; Training; analog; base; commercial application; computer generated; design; drug discovery; experimental study; fictional works; gain of function; interest; mathematical model; nervous system disorder; operation; parallel computer; patch clamp; prevent; research and development; simulation; simulation software; skills; tool; voltage clamp; Action Potentials; Amplifiers; Behavior; Binding; Biological Assay; Biomedical Technology; Cells; Closure by clamp; Communication; Complex; Computer Models; Computer software; Computers; Coupling; Data; Defect; Development; Diagnosis; Diagnostic tests; Disease; Disease model; Drug Industry; Electrical Engineering; Electrophysiology (science); Engineering; Environment; Explosion; Gap Junctions; Genetic Models; Goals; Innovation Corps; Interneurons; Ion Channel; Kinetics; Link; Medicine; Membrane; Mental disorders; Methodology; Modeling; Molecular Medicine; Monitor; Morphologic artifacts; Mutation; Names; Nervous system structure; Neurons; Neurosciences; Output; Pharmaceutical Preparations; Play; Process; Property; Quality Control; Reporting; Research; Research Personnel; Resistance; Running; Science; Seizures; Software Engineering; Source; Standardization; Stimulus; Synaptic Transmission; System; Technical Expertise; Testing; Time; Training; analog; base; commercial application; computer generated; design; drug discovery; experimental study; fictional works; gain of function; interest; mathematical model; nervous system disorder; operation; parallel computer; patch clamp; prevent; research and development; simulation; simulation software; skills; tool; voltage clamp

The goal of this proposal is to combine the power of the NEURON mathematical modeling software with the Cybercyte “plug and play” dynamic clamp system. Our product will enable all neuronal electrophysiologists to be able to perform sophisticated NEURON model based dynamic clamp experiments, without any requirement for programming, engineering, or mathematical modeling skills. Our product is an integrated package of hardware and software specifically for neuroscience applications, focusing on the specific stability and reliability needed for routine neuronal electrophysiology and the large array of ion channels found in the nervous system. The four aims of this project are: Aim 1. Implement and Test Electronic Expression Mode. In this aim, the patch clamp amplifier is used in current clamp mode to run cell-based action potentials from live cells, augmented with computer models of specific channels. Artificial ion channels generated by computer models are used to inject an equivalent current to mimic the effects of channel mutations, gain of function, state dependent drug binding etc., to reveal their mechanisms of action on the excitability of real neurons. This can be thought of as an inexpensive “short cut” to the painstaking process of generating genetic models of ion channels and other electrophysiological models. Aim 2. Implement and Test Synthetic Cell Mode. In synthetic cell mode, all of the component currents, except for the one of interest, are modelled, along with membrane action potentials. The current of interest is then generated in, for example, an HEK cell expressing the channel of interest and controlled by a voltage-clamp amplifier. The command input to the voltage clamp is the simulated action potential from the dynamic clamp system with the synthetic cell. For example, real drugs can be added to the cloned channel of interest or the consequences of a real kinetic mutation can be analyzed. Aim 3. Implement and Demonstrate Cell Coupling Mode. Cell coupling mode was arguably the first form of dynamic clamp invented. Originally it used analog circuitry to mimic gap junctional resistance between cells. With NEURON, we can implement complex forms of cell to cell coupling, including synaptic transmission and interneurons. Aim 4. Implement and Test Diagnostics and Experimental Safeguards. A major limitation of dynamic clamp applications in research & development, particularly in commercial applications, is the difficulty in maintaining quality control. This aim helps automate the process of quality control to make the system accessible to non- specialist users. Completion of these aims will result in a commercial advanced dynamic clamp system with an interface to NEURON, which is powerful, reliable, but plug and play to install, and simple to use.

该建议的目的是将神经元数学建模软件的力量与 Cyber​​cyte“插件”动态夹具系统。我们的产品将使所有神经元电生理学家能够 可以执行基于复杂的神经元模型的动态夹具实验，而无需任何要求 编程，工程或数学建模技能。我们的产品是一个集成的硬件包装 和专门针对神经科学应用的软件，重点关注所需的特定稳定性和可靠性 用于常规的神经元电生理学和神经系统中发现的大量离子通道。四个 该项目的目的是： AIM 1。实施和测试电子表达模式。在此目标中，使用贴片夹放大器 当前的夹具模式可从活细胞运行基于单元的动作电位，并用计算机模型增强 特定渠道。计算机模型生成的人工离子通道用于注入相等的电流 模仿通道突变，功能增长，状态依赖药物结合等的影响，以揭示其 对真实神经元兴奋的作用机制。这可以认为是廉价的“捷径” 生成离子通道和其他电生理模型的遗传模型的艰苦过程。 AIM 2。实施和测试合成细胞模式。在合成单元模式下，所有组件电流，除了 对于其中一项，将建模，并与膜作用电位一起建模。当前感兴趣的是 例如，在表达感兴趣的通道并通过电压钳控制的HEK单元中生成 放大器。电压夹的命令输入是动态夹的模拟动作电位 具有合成细胞的系统。例如，可以将真实药物添加到感兴趣的克隆通道或 可以分析真正动力学突变的后果。 AIM 3。实现并演示单元耦合模式。细胞耦合模式可以说是一种形式 动态夹具发明。最初，它使用模拟电路来模仿细胞之间的间隙连接抗性。 使用神经元，我们可以实现复杂的细胞形式到细胞偶联，包括突触传播和 中间神经元。 目标4。实施和测试诊断和实验保障。动态夹的主要局限性 研究与开发中的应用，特别是在商业应用中，是维护的困难 质量控制。此目标有助于自动化质量控制的过程，使该系统可访问非 - 专业用户。 这些目标的完成将导致商业高级动态夹具系统，并具有接口 神经元，功能强大，可靠，但要插入插件，可以安装且易于使用。