Inhibition of Neural Electrode-mediated Inflammation and Neuronal Cell Death

 描述(申请人提供)：抑制神经电极介导的炎症和神经细胞死亡越来越多的植入式神经电极设备正在开发中，以绘制大脑回路或恢复功能和治疗疾病。这些装置的性能取决于电极-神经组织界面的质量和稳定性。在动物实验中，持续的小胶质细胞激活和血脑屏障破坏、神经胶质瘢痕形成、神经元丢失和变性等不良脑组织反应一直被报道。对于需要与宿主神经元密切接触的电极设备，其性能功能可能会受到这些反应的影响。例如，通过微电极阵列进行的单单位神经记录的产量和质量随着时间的推移而恶化，这是该技术在长期神经科学研究和临床翻译中应用的主要障碍。参与炎症和神经元死亡的分子和途径很多。我们的研究始于caspase-1，因为caspase-1是炎症和程序性细胞死亡的关键介质。在体外和脑缺血、损伤和神经退行性疾病中，caspase-1的激活是神经元凋亡中最早检测到的事件。此外，caspase-1可激活白介素1，一种在植入电极周围组织中高表达的促炎细胞因子，尤其是那些表现出较差电生理结果的组织。IL-1？促发炎性胶质细胞增生症和加重血脑屏障破坏；两者都是慢性记录失败的假想原因。因此，我们假设caspase-1介导了神经植入物周围神经元的死亡和炎症，抑制caspase-1可能会改善神经元的存活，减轻炎症，从而改善电极性能。我们进行了一项初步研究，比较了植入caspase-1基因敲除(KO)小鼠和野生型(WT)小鼠的微电极阵列的神经记录性能。在6个月的时间内，基因敲除动物的单个单位产量和信号质量明显更高，有力地支持了caspase-1在维持电极-组织界面质量方面的关键作用。然而，随着时间的推移，对记录的仔细检查发现了不能用终点组织学解释的动态变化。为了更好地了解caspase-1介导的通路影响记录的机制(S)，我们建议使用双光子活体动物成像来表征细胞和血管对植入的神经探针的反应，并结合神经记录和全面的组织和生化分析。针对caspase-1或炎症/细胞死亡的治疗药物将被评估，以努力改善慢性神经界面。接受测试的药物是caspase 1特异性抑制剂VX765、褪黑素和米诺环素。这项建议使用多学科方法来揭示有助于神经记录性能的分子和细胞机制。这些发现将增加我们对神经植入病理学的科学理解，并指导治疗和/或生物材料策略的发展，以实现稳定和可靠的神经接口。该项目开发的数据和技术也可能有助于研究创伤性脑损伤、中风和神经退行性疾病中的神经元退行性变和炎症。

 DESCRIPTION (provided by applicant): Inhibition of Neural Electrode-mediated Inflammation and Neuronal Cell Death A growing number of implantable neural electrode devices are being developed to map brain circuit or restore function and treat diseases. The performance of these devices hinges on the quality and stability of the electrode-neural tissue interface. Undesirable brain tissue responses, including persistent microglia activation and blood brain barrier breach, glial scarring, neuronal loss and degeneration, have been consistently reported in animal studies. For electrode devices that require intimate contact with host neurons, their performance functionality may be compromised by these responses. As an example, single unit neural recording via microelectrode arrays experiences deterioration in yield and quality over time, which is a major barrier to applications of this technology in long-term neuroscience research and clinical translation. There are many molecules and pathways involved in inflammation and neuronal death. We began our study by focusing on caspase-1, as caspase-1 is a key mediator of both inflammation and programmed cell death. Activation of caspase-1 is the earliest detectable event in neuronal apoptosis in vitro and in brains with ischemic, injury and neurodegenerative conditions. Furthermore, caspase-1 activates interleukin-1 ß (IL-1ß), a pro-inflammatory cytokine highly expressed in the tissue surrounding implanted electrodes, especially those that showed poor electrophysiological outcome. IL-1ß triggers inflammatory gliosis and exacerbates BBB breach; both are hypothesized causes of chronic recording failure. Therefore, we hypothesize that caspase-1 mediates the neuronal death and inflammation around neural implants and inhibiting caspase-1 may improve neuronal survival, reduce inflammation and lead to improved electrode performance. We have performed a preliminary study comparing the neural recording performance of microelectrode arrays implanted in caspase- 1 knockout (KO) vs. wild-type (WT) mice. The single unit yield and signal quality are significantly greater in the knockout animals over the 6 month time period, strongly supporting the critical role for caspase-1 in maintaining the quality of the electrode-tissue interface. However, closer examination of the recording over time revealed dynamic changes that cannot be interpreted with end-point histology. To better understand the mechanism(s) by which caspase-1-mediated pathways affect recording, we propose to use 2-photon live animal imaging to characterize the cellular and vascular responses to implanted neural probes in conjunction with neural recording and comprehensive tissue and biochemical analyses. Therapeutics targeting caspase-1 or the inflammation/cell death in general will be evaluated in an effort to improve the chronic neural interface. The drugs to be tested are caspase 1 specific inhibitor VX765, melatonin and minocycline. This proposal uses a multidisciplinary approach to uncover the molecular and cellular mechanism contributing to neural recording performance. The findings will increase our scientific understanding of neural implant pathology, and guide the development of therapeutic and/or biomaterial strategy for stable and reliable neural interface. Data and technology developed in this project may also contribute to the study of neuronal degeneration and inflammation in traumatic brain injury, stroke and neural degenerative diseases.