Structural and Functional Plasticity Surrounding Implanted Neuroprostheses

植入神经假体周围的结构和功能可塑性

基本信息

批准号：
10083770
负责人：
Erin K Purcell
金额：
$ 37.26万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083770
关键词：
Acute Adult Anti-Inflammatory Agents Astrocytes Autopsy Basic Science Brain Cells Communication Barriers Cues Data Dendritic Spines Detection Development Device Designs Devices Electrodes Electrophysiology (science)Encapsulated Environment Equipment Malfunction Event Excitatory Synapse Exhibits Fluorescent Dyes Gliosis Glutamate Transporter Glutamates Image Immunohistochemistry Implant Implanted Electrodes In Vitro Inflammatory Inflammatory Response Injury Interruption Label Link Measurement Mechanics Mediating Methods Microelectrodes Microglia Microscope Modeling Morphology Motor Cortex N-Methylaspartate Neocortex Nervous System Trauma Neurons Neurotransmitters Noise Outcome Performance Polymers Publishing RNA Interference Radial Rattus Role Scanning Electron Microscopy Shapes Signal Transduction Silicon Slice Source Structure Surface Synapses Synaptic Transmission Synaptic plasticity Testing Thinness Time Time Study Tissues Vertebral column base biomaterial compatibility brain tissue cytokine cytotoxicity density electric impedance excitotoxicity functional plasticity gamma-Aminobutyric Acid implantable device implantation improved in vivo inflammatory marker knock-down microscopic imaging nervous system disorder neuron loss neuroprosthesis neurotoxicity neurotransmission novel preservation response transmission process two-photon vesicular GABA transporter vesicular glutamate transporter 1

项目摘要

PROJECT SUMMARY The development of implantable devices capable of recording or stimulating electrical activity in the brain has created unprecedented opportunities to treat and study neurological diseases and injuries. However, a reactive tissue response typically occurs following implantation which is widely believed to interfere with long-term device performance. Inflammatory microglia and astrocytes encapsulate and isolate devices from neurons, while neuronal signal sources are lost within the recordable radius of the electrode surface. While these observations may contribute to signal instability and recording loss over time, the mechanistic link between specific inflammatory events and changes in signal quality remains unclear. Our group is expanding upon the current basic science understanding of device-tissue integration and recently published a study which showed shifts in subtype-specific markers of synaptic transmission surrounding implanted electrode arrays. Our data indicated an early elevation of markers of excitatory transmission (vesicular glutamate transporter-1, VGLUT1) three days post-implantation that was followed by a subsequent shift to increased expression of labeling for inhibitory neurotransmission (vesicular GABA transporter, VGAT). We hypothesize that structural and functional plasticity of synaptic inputs surrounding devices could contribute to loss of recorded signals. We further hypothesize that the timed elevation of glutamate and GABA release may act as “go” and “stop” cues which mediate the reactive tissue response. In this proposal, we will build upon our initial observations, further investigating the underlying mechanisms and functional consequences of synaptic plasticity on device performance. In Specific Aim 1, we will define the functional impacts of glutamatergic synaptic remodeling at the electrode interface on recorded signal quality and reactive gliosis. We will correlate transporter expression with signal quality and assess the effects of VGLUT1 knockdown on signal quality and tissue response. In Specific Aim 2, we similarly will define the functional impacts of GABAergic synaptic remodeling at the electrode interface on recorded signal quality and reactive gliosis. We hypothesize that while early glutamate release may incite neurotoxicity and reactive gliosis, subsequent GABA release acts in an anti-inflammatory capacity to preserve neuronal viability and mitigate further glial reactivity. In Specific Aim 3, we will reveal structural plasticity in the dendritic arbors of neurons at the electrode interface. For this aim, we will use two photon imaging to assess changes in dendritic spine density and morphology surrounding devices captured in ex vivo brain tissue slices. For all aims, we will test both silicon and polyimide-based arrays to compare results between device designs commonly used in the field. We will inspect impedance measurements and post-mortem scanning electron microscopy images for signs of device failure to strengthen the interpretation of our results. By exploring novel mechanisms of synaptic plasticity surrounding implanted electrode arrays, we expect to open new opportunities to both understand, and improve upon, long-term device function and biocompatibility.

项目摘要能够记录或刺激大脑中电活动的可植入设备的开发具有创造了前所未有的机会来治疗和研究神经系统疾病和伤害。但是，是反应性的组织反应通常是在植入后发生的，这被广泛认为干扰长期装置表现。炎症性小胶质细胞和星形胶质细胞封装和分离神经元的装置，而隔离胶质细胞神经元信号源在电极表面的可记录半径内丢失。而这些观察可能导致信号不稳定性和随着时间的记录损失，特定的机械联系炎症事件和信号质量的变化尚不清楚。我们的小组正在扩展当前基础科学对设备组织整合的理解，并最近发表了一项研究，该研究显示了变化围绕植入电极阵列的突触传输的亚型特异性标记。我们的数据指示兴奋传播标记的早期升高（囊泡谷氨酸转运蛋白1，vglut1）三天植入后植入后，随后转移到标记表达增加的抑制作用神经传递（VESical GABA转运蛋白，VGAT）。我们假设结构和功能性可塑性设备周围的突触输入可能导致记录信号的丢失。我们进一步假设谷氨酸和GABA释放的定时海拔可能充当“ GO”和“停止”线索，可以介导反应性组织反应。在此提案中，我们将基于最初的观察，进一步研究基础突触可塑性对设备性能的机制和功能后果。在特定目标1中，我们将定义谷氨酸能突触重塑在电极接口上的功能影响信号质量和反应性鞠躬。我们将将转运蛋白的表达与信号质量和评估相关联 VGLUT1敲低对信号质量和组织反应的影响。在特定的目标2中，我们同样会定义电极界面处GABA能突触重塑对记录的信号质量的功能影响和反应性神经病。我们假设，尽管早期谷氨酸释放可能会促进神经毒性和反应性神经胶质病，随后的GABA释放具有抗炎能力，可保留神经元的生存力和减轻进一步的神经胶质反应性。在特定的目标3中，我们将在树突状乔木中揭示结构可塑性电极界面处的神经元。为此，我们将使用两种光子成像来评估树突状的变化在离体脑组织切片中捕获的设备周围的脊柱密度和形态。对于所有目标，我们将测试基于硅和聚酰亚胺的阵列，以比较在该设备设计之间常用的设备设计之间的结果场地。我们将检查阻抗测量和验证后电子显微镜图像的迹象设备无法加强我们结果的解释。通过探索突触的新机制围绕植入电极阵列的可塑性，我们期望为理解和改善长期设备功能和生物相容性。