Spatial transcriptomics at the interface of implanted electrodes in the brain

大脑植入电极界面的空间转录组学

• 批准号: 10532895
• 负责人: Erin K Purcell
• 金额: $ 15.62万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532895
• 关键词: Acute; Animals; Bar Codes; Basic Science; Benchmarking; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Chemicals; Chromosome Mapping; Chronic; Code; Data; Data Set; Devices; Distal; Electric Stimulation; Electrodes; Elements; Epilepsy; Foreign Bodies; Foundations; Future; Gene Cluster; Gene Combinations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Gliosis; Goals; Gorilla gorilla; Hour; Immunofluorescence Immunologic; Immunohistochemistry; Implant; Implanted Electrodes; Individual; Injury; Interruption; Intractable Epilepsy; Knowledge; Label; Lasers; Longevity; Mental Depression; Methods; Microscopy; Motor Cortex; Nervous System Trauma; Neurons; Neurosciences Research; Obsessive-Compulsive Disorder; Oligonucleotides; Ontology; Parkinson Disease; Pathologic; Pathway Analysis; Patients; Performance; Phase; Principal Component Analysis; Process; Publications; RNA; Rattus; Reporting; Research; Research Personnel; Resolution; Sampling; Seizures; Signal Transduction; Silicon; Slice; Slide; Spatial Distribution; Stains; Synaptic Transmission; Techniques; Time; Tissues; Variant; Writing; astrogliosis; biomaterial compatibility; brain tissue; candidate marker; chronic pain management; clinical application; cohort; conditioning; differential expression; flexibility; implantable device; implantation; improved; insight; interest; nervous system disorder; neuronal excitability; neuroregulation; novel; novel marker; open source; response; response biomarker; spatiotemporal; tissue biomarkers; tool; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Through “read-out” and “write-in” of electrical activity, implanted electrodes in the brain have enabled new discoveries in basic neuroscience research and breakthroughs in the treatment of neurological diseases and injury. However, the biological response to electrodes is widely believed to contribute to variations in recording and stimulation efficacy over time. Despite decades of research, it remains unclear which elements of the tissue response are performance-determining, as traditional metrics of the tissue response have failed to fully explain changes in signal quality, stimulation thresholds, or device longevity. It is our objective to explore new hypotheses and apply new methods to this long-standing issue. In this proposal, we will apply state-of-the-art techniques in spatial transcriptomics to the device-tissue interface. This approach will build upon our recently reported publication, which described spatiotemporal changes in gene expression surrounding devices using a combination of laser capture microscopy and RNA-sequencing. The data revealed 157 differentially expressed (DE) genes in tissue surrounding implanted electrodes in comparison to unimplanted control tissue. However, spatial transcriptomics detects the spatial distribution of transcriptional changes in tissue via barcoded RNA- capture oligonucleotides mounted to slides. The method delivers several advantages over previous approaches: (1) superior spatial resolution, (2) excellent RNA quality, and (3) the ability to assess transcriptional changes in combination with traditional immunohistochemistry labeling within the same tissue slice. Recently, we successfully applied spatial transcriptomics to rat motor cortex tissue following implantation of a single electrode array for a period of one week. The preliminary data revealed superior spatial sampling of transcriptional changes as well as newly unmasked DE genes. The purpose of this R03 application is to collect a more comprehensive pilot data set to explore these changes across multiple animals and time points (2 hours to 6 weeks), while developing analysis techniques to reveal novel gene modules expressed in tissue local to devices. The study includes two aims: Aim 1 will reveal the spatial organization of transcriptional changes surrounding implanted electrodes in the motor cortex of rats across a six-week time course and Aim 2 will develop network analysis techniques to reveal device-induced gene modules and key hub genes localized to the implant interface. We expect the project to deliver a novel data set which will be useful to the field as a stand-alone effort (all data and codes will be publicly accessible), while providing a foundation for future follow-on studies in a larger-scale proposal.

项目摘要 通过电活动的“读出”和“写入”，大脑中的植入电子已启用了新的 基本神经科学研究和神经系统疾病治疗中的突破的发现 受伤。但是，人们普遍认为对电子的生物反应有助于记录的变化 和刺激效率随着时间的流逝。尽管进行了数十年的研究，但尚不清楚组织的哪些要素 响应是性能决定的，因为组织反应的传统指标未能完全解释 信号质量，刺激阈值或设备寿命的变化。我们的目标是探索新的假设 并将新方法应用于这个长期存在的问题。在此提案中，我们将应用最先进的技术 空间转录组学到设备组织接口。这种方法将基于我们最近报道的 出版物，该出版物描述了使用A的基因表达中的时空变化 激光捕获显微镜和RNA测序的组合。数据揭示了157个不同表达的 （DE）与未植入对照组织相比，植入电极周围组织中的基因。然而， 空间转录组学检测通过条形码RNA-组织转录变化的空间分布 捕获安装在幻灯片上的寡核苷酸。该方法比以前的方法具有多种优势： （1）优质的空间分辨率，（2）出色的RNA质量，（3）评估转录变化的能力 结合在同一组织切片中的传统免疫组织化学标记。最近，我们 植入单电极后，成功地将空间转录组学应用于大鼠运动皮层组织 阵列一周。初步数据揭示了转录变化的优质空间采样 以及新的未掩盖的DE基因。该R03应用程序的目的是收集更全面的 试点数据集以探索多种动物和时间点（2小时至6周）的这些变化，而 开发分析技术以揭示在设备本地组织中表达的新基因模块。研究 包括两个目标：AIM 1将揭示围绕植入的转录变化的空间组织 在六周的时间课程中，大鼠运动皮层中的电极和AIM 2将开发网络分析 揭示设备诱导的基因模块和位于植入物界面的关键集线器基因的技术。我们 期望该项目提供一个新颖的数据集，该数据集将作为独立努力（所有数据和 代码将是公开访问的），同时为将来的后续研究提供基础 提议。