Flexible Multielectrode Arrays for Tonic and Phasic Serotonin Electrochemical Detection in the Brain

项目摘要 强直性和相性5-羟色胺(5-羟色胺，5-羟色胺)动态的多点同步测量 对于阐明5-羟色胺在焦虑，抑郁， 以及冲动控制障碍。持续数周的慢性采样对于研究5-羟色胺至关重要 在神经学转变过程中的变化，并了解特定药物治疗的疗效。 尽管它们有价值，但体内多部位慢性测定5-羟色胺受到现有能力的限制。 技术。例如，微透析测量紧张性5-羟色胺水平，时间分辨率慢，而速度快 在碳纤维微电极(CFE)上的扫描循环伏安法(FSCV)只能检测到相性的5-羟色胺释放。 这些实验目前是一次一个部位进行的，而5-羟色胺动力学是复杂的，并且在 不同的大脑区域或同一区域的不同位置，需要高分辨率的多点测量。 此外，据我们所知，没有用这种技术检测慢性5-羟色胺。 在这里，我们建议在超薄柔性衬底上开发一种可植入的碳基多电极阵列 (C-Flex-MEA)用于从不同大脑位置对5-羟色胺动态进行综合时相和紧张性测量。至 实现我们的目标：首先，我们将优化一种允许集成玻璃碳的图案转移技术 (GC)在超薄柔性聚合物衬底上的微电极阵列和互连。由此产生的C-Flex- MEAS将允许对相性5-羟色胺释放进行多部位FSCV检测。第二，我们将合并Poly(3，4- 乙二氧基噻吩改性碳纳米管(PEDOT/CNT) 相同MEAs的微电极，用Square实现多点检测紧张性5-羟色胺浓度 波伏安法。结合了碳电极优异的电化学稳定性和 C-Flex-MEA是一种小型化的薄膜柔性器件，具有良好的生物兼容性 提供了体内神经化学传感的理想特性，用于紧张性和相性5-羟色胺的测量，还 促进无缝组织融合。我们的具体目标1集中在制备和体外优化 C-Flex-MEA，目标是在检测灵敏度、选择性和稳定性方面达到标准。具体目标2 重点研究C-Flex-MEAs在小鼠体内的急性和慢性多部位传感性能 大脑，和植入物的生物相容性。敏锐的测试将指导探头的设计和制造，使其最小化 插入损伤和验证5-羟色胺的感觉。长期实验的完成将使我们能够确定 了解传感器的使用寿命，了解影响传感器稳定性的非生物和生物因素。 该项目的成功完成将产生一个前所未有的平台来研究具体的影响 神经和精神疾病中不同的5-羟色胺动力学。

Project Summary Simultaneous multi-site measurements of tonic and phasic serotonin (5-hydroxytryptamine, 5-HT) dynamics across different brain regions are of utmost importance to clarify the roles that 5-HT plays in anxiety, depression, and impulse control disorders. Chronic sampling across multiple weeks is critical to investigate the 5-HT variations during neurological transitions and to understand the efficacy of specific pharmacological treatments. Despite their values, in vivo multi-site chronic measurements of 5-HT are limited by the capability of the existing technologies. For example, microdialysis measures the tonic 5-HT level with slow temporal resolution, while fast scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes (CFEs) can only detect phasic 5-HT release. These experiments are currently performed one site at a time, while 5-HT dynamics are complex and differ in different brain regions or different loci of the same region, requiring high resolution multisite measurements. Additionally, to the best of our knowledge, no chronic 5-HT detection with such technique have been shown. Here, we propose to develop an implantable carbon-based multielectrode array on ultra-thin flexible substrate (C-Flex-MEA) for integrated phasic and tonic measurements of 5-HT dynamics from different brain locations. To achieve our goal: first, we will optimize a pattern transfer technique that allows for the integration of glassy carbon (GC) microelectrode arrays and interconnections on ultra-thin flexible polymeric substrate. The resulting C-Flex- MEAs will allow for multi-site FSCV detection of phasic 5-HT release. Second, we will incorporate the poly(3,4- ethylenedioxythiophene)/functionalized carbon nanotube (PEDOT/CNT) coating on selected GC microelectrodes of the same MEAs, to achieve multi-site detection of tonic 5-HT concentrations using square wave voltammetry. Combining the superior electrochemical stability of the carbon electrodes and interconnections with the excellent biocompatibility of a miniaturized thin-film flexible device, the C-Flex-MEA presents ideal properties for in vivo neurochemical sensing for both tonic and phasic 5-HT measurements, also promoting seamless tissue integration. Our Specific Aim 1 focuses on fabrication and in vitro optimization of the C-Flex-MEA with the goal of meeting the criteria in detection sensitivity, selectivity, and stability. Specific Aim 2 focuses on acute and chronic in vivo testing of multi-site sensing performance of the C-Flex-MEAs in mouse brain, and implant biocompatibility. The acute testing will guide the probe design and fabrication to minimize insertion injury and validate 5-HT sensing. The completion of the chronic experiments will allow us to determine the sensor’s lifetime and understand the abiotic and biotic factors that affect the stability of the sensor over time. Successful completion of this project will produce an unprecedented platform to study the specific implications of the different 5-HT dynamics in neurological and psychiatric disorders.