Multiplexed chemical sensing on ultra-narrow electrophysiological neural probes

描述（由申请人提供）：绘制体内的时空电化学反应，特别是在清醒的脊椎动物的大脑中，可以阐明神经调节在大脑活动中的作用。然而，目前的神经科学工具还不足以完成这项任务。在过去的十年中，用于电生理学的多路神经探针技术的进步提高了同时在脑组织内进行电记录的复杂性和空间分辨率。最先进的是我们正在开发的硅基神经纳米探针，它可以同时记录1000个位点的体内电记录。相比之下，能够在体内进行局部电化学传感的探针并没有跟上电生理学的发展步伐。尽管如此，电化学传感器在体内检测单个感兴趣的神经调节剂（如多巴胺和乙酰胆碱）方面已经取得了改进，并且在生理相关水平上的局部传感现在可能具有~400？M和~1秒。我们建议利用我们在电生理学高复用纳米探针工程方面获得的专业知识，并基于最近在体内电化学传感方面的改进，开发新一代高复用、多位点神经纳米探针，用于同时在体内对多个神经调节剂目标进行电化学传感。探头将被制作成长（~5mm），窄(~50？M)证明最适合大脑记录的硅柄；在这些基础上，将集成多种化学传感“三位一体”。每个三元组将包括三个不同的位点，用于神经化学目标的电流感应-例如，多巴胺，乙酰胆碱和胆碱-这些三元组的线性阵列，间距小于100米，将沿着探针柄组装。这些传感器阵列将能够同时检测跨越大脑扩展区域的多个不同神经调节剂目标的时空变化。一个重要的应用是沿着大鼠、小鼠和其他小动物大脑的多个皮层和海马层取样神经调节剂的变化，其中单个层的厚度可达~100 μ m。我们在这项工作中开发的先进的、基于探针的电化学传感技术将为研究分布大脑区域的功能性神经化学异质性的时空演变打开一扇新的窗口。

DESCRIPTION (provided by applicant): Mapping spatiotemporal electrochemical responses in vivo, especially within the brains of awake vertebrates, can elucidate the role of neuromodulation in brain activity. However, present tools in neuroscience are insufficient for the task. In the past decade, advances in the technology of multiplexed neural probes for electrophysiology has improved both the complexity and the spatial resolution of simultaneous electrical recordings that are now possible within brain tissue. The state-of-the-art is represented by silicon-based neural nanoprobes that we are developing to enable simultaneous in vivo electrical recording from 1000 sites. Probes that enable local electrochemical sensing in vivo, by comparison, have not kept apace with these advances in electrophysiology. Nonetheless, improvements have been made to electrochemical sensors for in vivo detection of individual neuromodulators of interest, such as dopamine and acetylcholine -- and local sensing at physiologically relevant levels is now possible with spatial and temporal resolution of ~400?m and ~1 second, respectively. We propose to leverage the expertise we've gained in engineering highly multiplexed nanoprobes for electrophysiology, and to build upon the recent improvements of in vivo electrochemical sensing, to develop a new generation of highly multiplexed, multi-site neural nanoprobes for simultaneous electrochemical sensing of multiple neuromodulator targets in vivo. The probes will be fabricated as long (~5mm), narrow (~50?m) silicon shanks that prove optimal for brain recording; onto these will be integrated a multiplicity of chemical sensing "triads". Each triad will comprise three distinct sites for amperometric sensing of neurochemical targets -- for example, dopamine, acetylcholine, and choline -- and linear arrays of these triads, separated with less than 100¿m pitch, will be assembled along the probe shanks. These sensor arrays will enable simultaneous detection of the spatiotemporal variation of multiple different neuromodulator targets across extended regions in the brain. An important application is sampling neuromodulator variations along the multiple cortical and hippocampal layers of the brains of rats, mice and other small animals, where individual layer thicknesses can be ~100?m. The advanced, probe-based electrochemical sensing technology we will develop in this effort will open a new window into the spatiotemporal evolution of functional neurochemical heterogeneities across distributed brain regions.