Multiplexed chemical sensing on ultra-narrow electrophysiological neural probes

描述(申请人提供)：绘制体内的时空电化学反应图，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，目前神经科学中的工具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电记录的复杂性和空间分辨率，目前在脑组织内进行这种记录是可能的。我们正在开发的硅基神经纳米探针代表了最先进的技术，可以从1000个部位同时进行体内电记录。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这些进步。尽管如此，用于体内检测感兴趣的单个神经调节剂的电化学传感器已经有所改进，如多巴胺和乙酰胆碱--生理相关水平的局部传感现在已经成为可能，空间和时间分辨率分别为~400m和~1s。我们建议利用我们在设计用于电生理学的高度多元化纳米探针方面获得的专业知识，并在体内电化学检测的最新改进的基础上，开发新一代高度多元化、多位点的神经纳米探针，用于同时在体内检测多个神经调节剂靶标。这些探头将被制造成长(~5 mm)、窄(~50？m)的硅小腿，被证明是脑记录的最佳选择；在这些小腿上将集成多种化学传感“三位一体”。每个三联体将包括三个不同的位置，用于神经化学目标的安培传感--例如，多巴胺、乙酰胆碱和胆碱--这些三联体的线性阵列将沿着探头柄组装，间距小于100？m。这些传感器阵列将能够同时检测跨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质和海马层采样神经调节剂的变化，其中单个层的厚度可以达到~100？m。我们将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打开一扇新的窗口，揭示跨分布的大脑区域的功能神经化学异质性的时空演变。

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.