A Wireless, Closed-Loop Neural Probe for Optogenetics, Pharmacology and Neurochemical Monitoring

项目摘要/摘要 新兴的工具和技术，包括光遗传学和药理学，提供了重要的途径 用于神经科学研究。然而，尽管工作强度很大，但实现闭环系统仍然具有挑战性 以一种允许动物自由活动、多模式操作和多路传输的神经调节方式 监测具有高灵敏度、选择性、时空分辨率和细胞特异性的神经化学物质， 同时。我们的长期目标是开发支持这些功能的高级工具和方法 用于对神经系统进行大规模的调节和监测。我们的近期目标是发展无线网络， 用于光遗传学、药理学和神经化学监测的闭环神经探针系统 移动的老鼠和老鼠。我们将通过以下三个具体目标实现这一目标：(一)发展 用于高时空选择性和灵敏监测神经化学物质的软神经探头 分辨率和细胞特异性；(2)开发用于光遗传学的无线、闭环神经探针， 药理和神经化学监测；以及(3)评估和表征效率和 无线闭环神经探头在自由活动的小鼠和大鼠体内的功能。建议数 研究具有创新性有五个关键原因：第一，适体增强型石墨烯-场效应晶体管(AEG- FETS)结合了适体的高选择性和G-FET的高灵敏度，从而使敏感 (毫微微)和选择性(19倍)神经化学物质检测。第二，近乎细胞尺度的维度 (50μm x 50μm)，快速响应时间(~1 S)，以及AEG-FET的位置选择性功能使其成为可能 监测多种神经化学物质，包括多巴胺、5-羟色胺、去甲肾上腺素和神经肽Y 时空分辨率、灵敏度和选择性。第三，结合最先进的基因编码 带有无线多色光度计的荧光传感器使检测多种神经化学物质成为可能 在自由移动的动物的基因定义的神经元中。第四，多式联运和图形化定制 用户界面(GUI)为闭环系统提供强大、易于使用的自动化数据分析和控制界面 光遗传和/或药物操作，从而实现可调节和按需 神经调节。最后，磁共振耦合和无线数据通信允许完全无线， 无电池运行，从而实现轻量化结构并消除对电池寿命的担忧， 充电状态，以及在扩展行为测试期间经常出现的其他问题，同时 允许动物自由活动。这项拟议研究的成功完成将产生无线技术。 具有多项创新功能的一体式闭环式神经探针，用于神经化学监测和 自由活动时的光遗传和/或药物刺激。我们相信这些神经探头 将引起神经科学界对神经科学的基础研究以及研究的极大兴趣 在与大脑主动性相关的各种背景下与疾病相关的过程。

PROJECT SUMMARY/ABSTRACT Emerging tools and technologies, including optogenetics and pharmacology, have provided important avenues for neuroscience research. However, despite intensive work, it is still challenging to achieve closed-loop neuromodulation in a way that allows the free movement of animals, multimodal operation, and multiplexed monitoring of neurochemicals with high sensitivity, selectivity, spatiotemporal resolution, and cellular specificity, simultaneously. Our long-term goal is to develop advanced tools and approaches that support these capabilities for large-scale modulation and monitoring of the nervous system. Our immediate goal is to develop wireless, closed-loop neural probe systems for optogenetics, pharmacology, and neurochemical monitoring in freely moving mice and rats. We will achieve this goal by pursuing the following three specific aims: (1) to develop soft neural probes for the selective and sensitive monitoring of neurochemicals with high spatiotemporal resolution and cellular specificity; (2) to develop wireless, closed-loop neural probes for optogenetics, pharmacology, and neurochemical monitoring; and (3) to evaluate and characterize the efficiency and functionality of the wireless, closed-loop neural probes in vivo in freely moving mice and rats. The proposed research is innovative for five key reasons: First, the aptamer-enhanced graphene-field effect transistors (AeG- FETs) combine the high selectivity of the aptamer with the high sensitivity of G-FETs, thereby enabling sensitive (femtomolar) and selective (> 19-fold) detection of neurochemicals. Second, the nearly cellular-scale dimensions (50 μm x 50 μm), fast response time (~1 s), and site selective functionalization of AeG-FETs make it possible to monitor multiple neurochemicals, including dopamine, serotonin, norepinephrine, and neuropeptide Y, with high spatiotemporal resolution, sensitivity, and selectivity. Third, coupling state-of-the-art genetically encoded fluorescent sensors with a wireless multicolor photometer makes it possible to detect multiple neurochemicals in genetically defined neurons of freely moving animals. Fourth, multimodal operation and a customized graphical user interface (GUI) provide a robust, easy-to-use automated data analysis and control interface for closed-loop optogenetic and/or pharmacological manipulation, thereby enabling adjustable and on-demand neuromodulation. Finally, magnetic resonance coupling and wireless data communication allow fully wireless, battery-free operation, thereby enabling lightweight construction and eliminating concerns about battery life, charging status, and other issues that often arise during extended behavioral tests, while at the same time allowing animals to move freely. The successful completion of the proposed research will yield wireless, “all- in-one” closed-loop neural probes with several innovative features for neurochemical monitoring and optogenetic and/or pharmacological stimulation during freely moving behaviors. We believe these neural probes will be of great interest to the neuroscience community for basic studies in neuroscience as well as for studies of disease-related processes in various contexts relevant to the BRAIN initiative.