Real Time NEURON Simulation for Experimental Applications

这项提议的目标是将神经元数学建模软件的功能与 Cybercell“即插即用”动态钳位系统。我们的产品将使所有神经元电生理学家 能够执行基于复杂神经元模型的动态钳位实验，无需 具有编程、工程或数学建模技能。我们的产品是一个集成的硬件包装 和专门用于神经科学应用的软件，专注于所需的特定稳定性和可靠性 用于常规神经电生理学和神经系统中发现的大量离子通道。四个 该项目的目标是： 目标1.实现和测试电子表达模式。在这个目的中，膜片钳放大器被用于 电流钳制模式，从活细胞运行基于细胞的动作电位，并通过计算机模型增强 特定的频道。由计算机模型产生的人造离子通道被用来注入等效电流 为了模拟通道突变、功能获得、状态依赖药物结合等的影响，揭示它们的 真实神经元兴奋性的作用机制。这可以被认为是一条廉价的“捷径” 产生离子通道和其他电生理模型的遗传模型的艰苦过程。 目标2.实现和测试合成细胞模式。在合成电池模式下，除 对于感兴趣的一个，与膜动作电位一起被建模。感兴趣的潮流就在那时 例如，在表示感兴趣通道的HEK单元中产生并由电压钳位控制 放大器。电压钳位的命令输入是来自动态钳位的模拟动作电位 使用合成细胞的系统。例如，可以将真正的药物添加到感兴趣的克隆通道或 真正的动力学突变的后果是可以分析的。 目标3.实现和演示单元耦合模式。细胞耦合模式可以说是第一种形式的 发明了动态夹具。最初，它使用模拟电路来模拟电池之间的缝隙连接电阻。 有了神经元，我们可以实现复杂形式的细胞到细胞的耦合，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。动态夹具的一个主要局限性 在研究和开发中的应用，特别是在商业应用中，是维护的困难 质量控制。这一目标有助于使质量控制过程自动化，以使系统可供非 专业用户。 完成这些目标将产生一种商业先进的动态夹具系统，其接口可用于 神经元，这是强大的，可靠的，但即插即用安装，并简单使用。

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.