A Closed-Loop Microsystem for Neuromodulation of Reward Circuitry

描述(申请人提供)：用于奖赏回路神经调节的闭环微系统Pedram Mohseni1和Paul A.Garris2 1 Case Western Reserve University 2伊利诺伊州立大学虽然我们对成瘾的基本神经生物学的理解已经取得了长足的进步，但许多悬而未决的问题仍然存在。开发新的治疗方法也是非常必要的，因为目前的选择显示出很高的累犯率。出于很好的理由，人们特别关注多巴胺神经元在强制吸毒和成瘾行为中的作用。一个紧急假设是，滥用物质通过过度激活相多巴胺信号来篡夺奖励处理电路，这会导致突触可塑性改变，并高估预测药物可获得性的线索。驱使追逐 这一潜在的统一假说包括微型传感器、转基因动物和光遗传学方面的最新技术进展。总而言之，这些强大的方法允许对多巴胺神经元及其靶标进行高保真的多巴胺监测和超精细的分子控制。然而，在目前的技术状态下，缺乏动态的、依赖于状态的控制。这种技术将以闭环的方式积极地将神经监测和神经刺激联系起来，以允许现有的神经活动，并通过先验标准确定所需的结果。因此，这项研究的长期目标是实现支持药物滥用研究和治疗成瘾的临床疗法的闭环设备。为此，一位电气工程师/计算机科学家(Pi Mohseni)和一位神经生物学家/分析化学家(Pi Garris)将就目前的尖端基础研究奖(CEBRA)提案进行合作，以开发一种计算和控制集成电路(IC)，用于神经监测和神经刺激的这种联系。该集成电路将集成碳纤维微电极(CFM)的快速扫描循环伏安法(FSCV)，这是一种具有精细时间、空间和化学分辨率的最先进的神经监测技术，以及主成分回归(PCR)，这是一种从复杂的神经化学图谱中分离单一分析物的化学计量学方法。这三个具体目标是：(1)在CFM上开发支持FSCV的传感、计算和控制IC；(2)测试和表征该IC；(3)利用该IC进行基于多巴胺传感的反馈控制试点，以中和激活的相多巴胺信号。我们认为，开发这种集成电路是成瘾研究的变革性步骤，为新型植入式微系统在生物医学研究中的应用奠定了基础，最终为临床领域的智能治疗性神经假体奠定了基础。基于FSCV和PCR询问单个神经元类型的神经化学活动的能力的反馈控制也代表着朝着闭环系统设备发展的重大技术进步。这项研究还具有创新性，因为用于神经化学反馈控制的IC尚未实现，并且所提议的IC将能够调节静态和动态神经化学活动，并容纳在成瘾中重要的广泛的分析物。该项目还将在为期两年的时间里，在电气工程-计算机科学和神经生物学-分析化学领域各培养一名博士生。

DESCRIPTION (provided by applicant): A Closed-Loop Microsystem for Neuromodulation of Reward Circuitry Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University While great strides have been made in our understanding of the basic neurobiology of addiction, many outstanding questions still remain. There is also a grave necessity to develop new treatments, as current options exhibit high recidivism. For good reason, particular attention has focused on the role of dopamine neurons in compulsory drug taking and addictive behavior. One emergent hypothesis is that abused substances usurp reward-processing circuits by hyperactivating phasic dopamine signaling, which leads to altered synaptic plasticity and the overvaluation of cues predicting drug availability. Driving the pursuit of this potentially unifying hypothesis are recent technical advances in microsensors, transgenic animals, and optogenetics. Collectively, these powerful approaches permit high-fidelity dopamine monitoring and ultra-fine molecular control over dopamine neurons and their targets. However, there is a dearth in the current state of technology for dynamic, state-dependent control. Such technology would actively link neuromonitoring and neurostimulation in closed-loop manner to permit extant neural activity and a priori criteria determine the desired outcome. The long-term objective of this research is thus to realize closed-loop devices supporting research in drug abuse and clinical therapies for treating addiction. To this end, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate on the present Cutting-Edge Basic Research Awards (CEBRA) proposal to develop a computation and control integrated circuit (IC) for such linking of neuromonitoring and neurostimulation. This IC will incorporate fast- scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM), a state-of-the-art neuromonitoring technique with exquisite temporal, spatial, and chemical resolution, and principal component regression (PCR), a chemometrics approach for resolving single analytes from complex neurochemical profiles. The three specific aims are to: (1) develop a sensing, computation, and control IC supporting FSCV at a CFM; (2) test and characterize the IC; (3) pilot dopamine-sensing-based feedback control with the IC for neutralizing activated phasic dopamine signaling. We submit that developing this IC is a transformative step for addiction research, by laying the foundation for novel implantable microsystems supporting applications in biomedical research and ultimately for smart therapeutic neuroprostheses in the clinical realm. Feedback control based on the ability of FSCV and PCR to interrogate the neurochemical activity of a single neuron-type also represents a significant technical advance toward the development of closed-loop devices. This research is additionally innovative, because an IC for neurochemical feedback control has not been realized, and the proposed IC will be capable of modulating both static and dynamic neurochemical activity and accommodating a broad repertoire of analytes important in addiction. This project will also train one doctoral student each in the fields of electrical engineering-computer science and neurobiology-analytical chemistry during its two-year duration.