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

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.

该提案的目标是将 NEURON 数学建模软件的功能与 Cyber​​cyte“即插即用”动态钳系统将使所有神经电生理学家能够成为可能。 能够执行基于复杂神经元模型的动态钳实验，无需任何 我们的产品是一个集成的硬件包。 以及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 用于常规神经元电生理学和神经系统中发现的大量离子通道。 该项目的目标是： 目标 1. 实现并测试电子表达模式 在此目标中，使用膜片钳放大器。 电流钳模式从活细胞运行基于细胞的动作电位，并通过计算机模型进行增强 由计算机模型生成的人工离子通道用于注入等效电流。 模拟通道突变、功能获得、状态依赖性药物结合等的影响，以揭示它们的 这可以被认为是一种廉价的“捷径”。 生成离子通道遗传模型和其他电生理模型的艰苦过程。 目标 2. 实现并测试合成电池模式 在合成电池模式中，所有组件电流（除此之外）。 对于感兴趣的电流，以及膜动作电位进行建模。 例如，在表达感兴趣通道的 HEK 细胞中生成并由电压钳控制 电压钳位放大器的命令输入是来自动态钳位的模拟动作电位。 例如，可以将真正的药物添加到感兴趣的克隆通道或通道中。 可以分析真实动力学突变的后果。 目标 3. 实现并演示单元耦合模式 第一种形式是有争议的。 发明了动态钳位。最初它使用模拟电路来模拟电池之间的间隙连接电阻。 借助 NEURON，我们可以实现复杂形式的细胞间耦合，包括突触传递和 中间神经元。 目标 4. 实施和测试诊断和实验保障措施是动态钳位的主要限制。 研发中的应用，特别是商业应用中，维护的难点是 质量控制这一目标有助于实现质量控制过程的自动化，使系统可供非人员使用。 专业用户。 完成这些目标将产生一个商业化的先进动态夹具系统，该系统具有一个接口 NEURON，功能强大、可靠，但安装即插即用，并且使用简单。