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

项目摘要 同时多部位测量强直性和阶段性5-羟色胺（5-HT）动力学 对于阐明5-HT在焦虑，抑郁， 和冲动控制障碍多周的慢性采样对于研究5-HT至关重要。 在神经过渡期间的变化，并了解特定的药物治疗的疗效。 尽管它们的价值，5-HT的体内多部位慢性测量受到现有的生物传感器的能力的限制。 技术.例如，微透析以慢的时间分辨率测量紧张性5-HT水平，而快速的时间分辨率测量紧张性5-HT水平。 在碳纤维微电极上的扫描循环伏安法（FSCV）只能检测阶段性5-HT释放。 这些实验目前是一次一个地点进行的，而5-HT动力学是复杂的，并且在不同的时间点上是不同的。 不同的大脑区域或同一区域的不同位点，需要高分辨率的多位点测量。 此外，据我们所知，没有慢性5-HT检测与这种技术已经显示。 在此，我们提出在超薄柔性基底上开发一种可植入的碳基多电极阵列 （C-Flex-MEA）用于从不同脑位置对5-HT动力学进行综合相位和紧张性测量。到 实现我们的目标：首先，我们将优化图案转移技术，允许玻璃碳的整合 (GC)微电极阵列和互连的超薄柔性聚合物基板上。由此产生的C-Flex- MEA将允许阶段性5-HT释放的多位点FSCV检测。第二，我们将聚（3，4- 乙烯二氧噻吩）/官能化碳纳米管（PEDOT/CNT）涂层 相同MEA的微电极，以实现使用正方形5-HT浓度的多位点检测 波伏安法结合碳电极的上级电化学稳定性和 C-Flex-MEA是一种具有优良生物相容性的小型化薄膜柔性器件， 对于强直性和相位性5-HT测量，呈现出体内神经化学感测的理想特性，还 促进无缝的组织整合。我们的具体目标1侧重于制造和体外优化的 C-Flex-MEA的目标是满足检测灵敏度、选择性和稳定性的标准。具体目标2 侧重于C-Flex-MEA在小鼠中的多部位传感性能的急性和慢性体内测试 大脑和植入物的生物相容性。急性测试将指导探针设计和制造，以最小化 插入损伤和确认5-HT感知。慢性实验的完成将使我们能够确定 传感器的寿命和了解随着时间的推移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，以研究具体的影响 不同的5-羟色胺动力学在神经和精神疾病。

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.