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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：
10548226
负责人：
Erin K Purcell
金额：
$ 34.7万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548226
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 Electric Stimulation 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 Surface Synapses Synaptic Transmission Synaptic plasticity Testing Thinness Time Time Study Tissues Vertebral column biomaterial compatibility brain tissue cytokine cytotoxicity density electric impedance excitotoxicity functional plasticity gamma-Aminobutyric Acid glial activation implantable device implantation improved in vivo inflammatory marker knock-down microscopic imaging neocortical 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.

项目总结能够记录或刺激大脑电活动的植入式设备的发展已经为治疗和研究神经系统疾病和损伤创造了前所未有的机会。然而，一个被动的组织反应通常发生在植入后，人们普遍认为这会干扰长期装置性能。炎性小胶质细胞和星形胶质细胞包裹设备并将其与神经元隔离，而在电极表面可记录的半径内，神经元信号源丢失。虽然这些观察结果随着时间的推移，可能会导致信号不稳定和记录丢失，这是特定的炎症事件和信号质量的变化仍不清楚。我们的集团正在扩大目前的规模对设备-组织整合的基础科学理解，最近发表的一项研究表明，植入电极阵列周围突触传递的亚型特异性标记。我们的数据显示兴奋性传递标志物(囊泡谷氨酸转运体-1，VGLUT1)早期升高3天植入后，随后转变为抑制标记表达增加神经传递(囊泡GABA转运体，VGAT)。我们假设结构和功能的可塑性设备周围的突触输入可能会导致记录信号的丢失。我们进一步假设谷氨酸和GABA释放量的定时升高可能作为“GO”和“STOP”信号，介导反应性组织反应。在这项建议中，我们将以我们最初的观察为基础，进一步调查潜在的突触可塑性对设备性能影响的机制和功能后果。在具体目标1中，我们将确定电极界面谷氨酸能突触重构的功能影响信号质量和反应性胶质细胞增多症。我们将把转运蛋白的表达与信号质量联系起来，并评估 VGLUT1基因敲除对信号质量和组织反应的影响。在具体目标2中，我们同样将界定电极界面GABA能突触重构对记录信号质量的功能影响和反应性胶质细胞增多症。我们假设，虽然早期释放谷氨酸可能会引发神经毒性和反应性胶质增生，随后的GABA释放在抗炎能力中发挥作用，以保持神经元的活性和进一步减轻神经胶质细胞的反应性。在具体目标3中，我们将揭示树枝的结构可塑性。电极交界处的神经元。为此，我们将使用双光子成像来评估树突状细胞的变化在体外脑组织切片中捕捉到的脊柱密度和周围设备的形态。为了所有的目标，我们将测试基于硅和聚酰亚胺的阵列，以比较在菲尔德。我们将检查阻抗测量和尸检扫描电子显微镜图像是否有迹象未能加强对我们结果的解释。通过探索突触的新机制围绕植入电极阵列的可塑性，我们预计将打开新的机会，既了解，也改进，长期的设备功能和生物兼容性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural and functional changes of deep layer pyramidal neurons surrounding microelectrode arrays implanted in rat motor cortex.

植入大鼠运动皮层的微电极阵列周围的深层锥体神经元的结构和功能变化。

DOI：
10.1016/j.actbio.2023.07.027
发表时间：
2023
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Gregory,BronsonA;Thompson,CortH;Salatino,JosephW;Railing,MiaJ;Zimmerman,ArianaF;Gupta,Bhavna;Williams,Kathleen;Beatty,JosephA;Cox,CharlesL;Purcell,ErinK
通讯作者：
Purcell,ErinK

Toward guiding principles for the design of biologically-integrated electrodes for the central nervous system.