Automated electrophysiological analysis of neural circuitry using a novel nano-electrode array for intracellular recording of membrane potential

使用新型纳米电极阵列对细胞内膜电位进行自动电生理分析

• 批准号: 9346140
• 负责人: XIN JIANG
• 金额: $ 33.56万
• 依托单位: CYION TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346140
• 关键词: Accelerometer; Alpha Cell; Amplifiers; Appearance; BRAIN initiative; Biological Neural Networks; Brain; Cell Culture Techniques; Cells; Complex; Controlled Environment; Coupling; Data; Development; Disease; Drug Evaluation; Electrodes; Electronics; Electrophysiology (science); Electroporation; Environment; Feedback; Goals; In Vitro; Incubators; Individual; Industrialization; Interneurons; Intracellular Membranes; Investigation; Label; Laboratories; Maps; Measurement; Membrane Potentials; Mental disorders; Methods; Microelectrodes; Monitor; Nanotechnology; Nature; Nervous system structure; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway Analysis; Pharmacological Treatment; Phase; Physiological; Play; Positioning Attribute; Process; Property; Research; Research Personnel; Resolution; Role; Signal Transduction; Small Business Technology Transfer Research; Symptoms; Synaptic Potentials; System; Systems Analysis; Technology; Time; Universities; base; biomaterial compatibility; design; drug development; extracellular; flexibility; high throughput analysis; improved; innovation; millimeter; nano; nanofabrication; neural circuit; neuronal circuitry; neurotoxicity; novel; patch clamp; programs; public health relevance; relating to nervous system; research and development; screening; success

Summary Nervous systems process information by integrating the electrical activity of neurons in complex networks. The alterations in the “flow” of electrical activity through neuronal networks of the brain play a causal role in the pathogenesis and/or the appearance of symptoms of neurodegenerative and psychiatric diseases. A fundamental goal of BRAIN Initiative is therefore to elucidate how the brain's neural circuits are structurally and functionally connected, a prerequisite for hypotheses- guided developments of more effective pharmacological treatments of these diseases. Unfortunately this goal remains elusive at present, largely due to the lack of technology to perform scalable recording and manipulation of neural activity with high S/N ratio, at single-cell level, over long period of time and under physiological conditions. The classic method of electrophysiology requires physical contact and electrical coupling between the recording electrodes and the cells under investigation, which presents different challenges regarding the two primary forms of technologies currently available. Intracellular recording methods by sharp electrode or patch clamping constrains the measurement to one cell at a time, and limits the recording time to several minutes due to the invasive nature of this approach. Extracellular recording with parallel, planar electrode array lacks single cell resolution, and fails to detect subthreshold synaptic potentials. The absence of adequate environmental control for both methods further reduces the physiological relevance of the results. The novel electrophysiology platform proposed in this STTR application aims to provide a powerful solution that bridges the long-standing gap between high-quality, non-scalable intracellular electrophysiology and low-quality, scalable extracellular electrophysiology; so to enable for the first time simultaneous, noninvasive measurement of intracellular membrane potential from many neurons under optimal physiological conditions. Central to this platform is the seamless integration of two innovative approaches: 1) parallel, nano-fabricated biocompatible electrodes, and 2) sensitive, environmentally robust electronics. We also plan to validate the complete system for analyzing neural network, using in vitro culture of cortical neurons. In summary, the ability to monitor the activities of larger neuronal networks simultaneously and non-invasively is a necessary prerequisite to understanding how neuronal networks function at the systems level. Our breakthrough technology is well positioned to provide a significantly improved cellular electrophysiology system for large-scale recording and manipulation of neural activity, with an immediate and positive impact on BRAIN Initiative’s central objective to understand the dynamic activity of neural circuits. This system, with further development, can support recording from even larger number of neurons, of different types, and for other applications such as neurotoxicity evaluation for drug development.

概括 神经系统通过整合复杂神经元的电活动来处理信息 网络。通过大脑神经元网络的电活动“流动”的变化 在神经退行性疾病的发病机制和/或症状的出现中发挥因果作用 和精神疾病。因此，BRAIN Initiative 的一个基本目标是阐明如何 大脑的神经回路在结构和功能上是相互联系的，这是假设的先决条件- 指导开发这些疾病的更有效的药物治疗方法。 不幸的是，这个目标目前仍然难以实现，很大程度上是由于缺乏执行技术 在单细胞水平上以高信噪比可扩展记录和操纵神经活动 长时间且在生理条件下。电生理学的经典方法 需要记录电极和细胞之间的物理接触和电耦合 正在调查中，这对两种主要形式提出了不同的挑战 目前可用的技术。通过锋利电极或贴片进行细胞内记录方法 钳位将一次测量限制为一个细胞，并将记录时间限制为几个 由于这种方法的侵入性，需要几分钟的时间。平行、平面的细胞外记录 电极阵列缺乏单细胞分辨率，无法检测阈下突触电位。 这两种方法缺乏足够的环境控制，进一步降低了 结果的生理相关性。 STTR 应用中提出的新型电生理学平台旨在提供 强大的解决方案，弥补了高质量、不可扩展之间长期存在的差距 细胞内电生理学和低质量、可扩展的细胞外电生理学；所以 首次实现细胞内膜的同步、无创测量 在最佳生理条件下，许多神经元的潜力。这个平台的核心是 两种创新方法的无缝集成：1）并行、纳米制造的生物相容性 电极，以及 2) 敏感、环保的电子设备。我们还计划验证 使用皮层神经元的体外培养来分析神经网络的完整系统。 总之，同时监测更大的神经元网络的活动和 非侵入性是理解神经网络如何发挥作用的必要先决条件 系统级别。我们的突破性技术能够提供显着的 改进的细胞电生理学系统，用于大规模记录和操纵神经 活动，对 BRAIN Initiative 的中心目标产生直接和积极的影响 了解神经回路的动态活动。该系统经过进一步开发，可以 支持记录更多不同类型的神经元以及其他 应用，例如药物开发的神经毒性评估。