Miniaturized silicon neurochemical probe to monitor brain chemistry

项目摘要/摘要 用于监测大脑化学的微型硅神经化学探头。在活体中监测大脑特定部分的局部神经化学物质浓度对于将神经回路功能与行为关联至关重要，因为远程神经调节可以显着改变信息处理。目前检测神经调节剂的方法具有时间和/或空间分辨率有限、灵敏度有限和/或侵入性极强的特点。这笔赠款的目标是开发一种多功能硅技术平台，用于设计和制造可植入的纳米透析探针，使从活的和行为的哺乳动物大脑中快速(1秒)和灵敏(100 Nm)采集多种神经化学物质成为可能。专用集成纳米透析(ASIND)技术允许以时序方式从高化学信息含量的脑细胞外液(ECF)中收集一系列孤立的PL体积分析物。一旦收集并存储在芯片上，这些分析物就会被提供给随后的超灵敏质谱仪(MS)分析，以监控几种重要神经化学物质(从100Da到5 KDa)的时间分布。为了将ASIND技术的适用性扩展到大量不同的神经生物学实验，我们开发、验证和集成了具有附加功能(多路化学采样、本地药物输送、电生理学、电化学、光遗传学和纳米电喷雾)的先进微流控组件，将其集成到硅可植入神经探针上的系统芯片上，其横截面显著减小(&lt；1000微米)，仅相当于几个神经元体。为了对这项技术进行压力测试，并展示其研究化学大脑的先进能力，我们将该平台应用于三个不同的神经生物学实验，以解决用传统方法难以或不可能探索的重要开放问题。这种开发将神经科学各个领域的科学和翻译应用的技术准备水平从基本能力的展示扩展到概念验证这一贡献是重大的，因为仪器平台将允许监测来自精确大脑位置的各种神经调节剂和药物的浓度梯度，与神经活动和行为的记录时间同步，这将使基础系统神经科学的进步以及加快神经系统疾病新疗法的开发。这项拟议的研究具有创新性，因为我们将在硅平台上开发高灵敏度的纳米透析探测器，使我们能够获得前所未有的时间和空间分辨率。开发和验证的ASIND硅平台将大大促进这一可制造技术的广泛传播。

PROJECT SUMMARY/ABSTRACT Miniaturized silicon neurochemical probe to monitor brain chemistry. Monitoring local concentrations of neurochemicals in specific parts of the brain in vivo is critical for correlating neural circuit functionality to behavior as long-range neuromodulation can significantly alter information processing. Current methods for detecting neuromodulators have limited temporal and/or spatial resolution, limited sensitivity, and/or are prohibitively invasive. The objective of this grant is to develop a versatile silicon technology platform for the design and fabrication of implantable nanodialysis probes that enable fast (1sec) and sensitive (100nM) sampling of multiple neurochemicals from the alive and behaving mammalian brain. The Application-Specific Integrated Nano-Dialysis (ASIND) technology allows collection in a time-sequential manner a series of isolated pL-volume analytes from the brain extracellular fluid (ECF) with high chemical information content. Once collected and stored on-chip, these analytes are delivered for subsequent ultra-sensitive mass spectrometry (MS) analysis to monitor temporal profiles of several important neurochemicals (from 100Da up to 5KDa). To extend the applicability of the ASIND technology to a large number of diverse neurobiology experiments, we develop, validate and integrate advanced microfluidic components with add-on functionalities (multiplexed chemical sampling, local drug delivery, electrophysiology, electrochemistry, optogenetics, and nano-electrospray) into a system-on-chip on a silicon implantable neural probe with a significantly reduced cross-section (<1000 µm2) equivalent to just a few neuron bodies across. To stress-test the technology and demonstrate its advanced capabilities to study the chemical brain, we adapt the platform to three different neurobiological experiments to address important open questions that are difficult or impossible to explore with traditional approaches. Such development extends the technology readiness level from a demonstration of basic capabilities to proof-of-concept validation for both scientific and translational applications in various areas of neuroscience This contribution is significant since the instrumental platform will allow monitoring concentration gradients of various neuromodulators and drugs from precise brain locations time-synchronized with recordings of neural activity and behavior that should enable advances in fundamental systems neuroscience as well as accelerate the development of new treatments for neurological diseases. The proposed research is innovative because we will develop highly sensitive nanodialysis probes on a silicon platform that allows us to attain unprecedented temporal and spatial resolution. The developed and verified ASIND silicon platform will significantly facilitate the broad dissemination of this manufacturable technology.