Systematic characterization of inhibitory subpopulations activated by spinal cord stimulation using a targeted strategy

项目摘要 脊髓刺激是一种非阿片类药物的神经调节疗法，常用于 治疗顽固性慢性背部和四肢疼痛。有很大的需要 了解SCS的基本生物学机制以提高临床疗效 和结果。事实证明，要描述参与其中的抑制性群体具有挑战性 SCS，因为电生理记录容易受到刺激伪影的干扰 并且只对活跃神经元的稀疏子集进行采样。即早基因(c-fos)的表达 研究一直是模棱两可的，没有区分兴奋性和抑制性人群。 因此，目前尚不清楚SCS是否驱动不同抑制亚群的激活 以依赖于刺激幅度和频率的方式。一款创新的鼠标模型将是 用于标记长期植入的SCS期间激活的神经元 微型双极电极。一系列与临床相关的SCS波形将被 使用，激活的神经元将通过分子表型和原位可视化 多重RNA杂交。针对特定分子标记的探针将用于分类 不同抑制簇中的神经元，并将开发统计模型来表征影响 刺激参数对神经元簇的影响。该项目将在空间和分子上识别 由临床相关的SCS波形的全谱激活的抑制亚群。 这些信息将极大地提高针对特定脊柱设计波形的能力 电源线电路，并具有直接的翻译相关性，为合理实施打开了大门 针对不同临床病理的SCS。

Project Summary Spinal cord stimulation is an opioid-sparing neuromodulation therapy commonly used for the treatment of intractable chronic pain of the back and limbs. There is a substantial need to understand the fundamental biological mechanisms of SCS in order to improve clinical delivery and outcomes. It has proven challenging to characterize the inhibitory populations engaged by SCS, as electrophysiological recordings are vulnerable to interference from stimulation artifacts and only sample a sparse subset of active neurons. Immediate-early gene (c-fos) expression studies have been equivocal and did not distinguish excitatory and inhibitory populations. Therefore, it remains unknown whether SCS drives activation of distinct inhibitory subpopulations in a stimulation amplitude- and frequency-dependent manner. An innovative mouse model will be used to tag activated neurons during prolonged SCS delivered via chronically implanted miniaturized bipolar electrodes. A wide range of clinically-relevant SCS waveforms will be employed, and activated neurons will be molecularly phenotyped and visualized in situ via multiplexed RNA hybridization. Probes against specific molecular markers will be used to classify neurons in distinct inhibitory clusters, and statistical models will developed to characterize effects of stimulation parameters on neuronal clusters. This project will spatially and molecularly identify the inhibitory subpopulations activated by the full spectrum of clinically-relevant SCS waveforms. This information will dramatically improve the ability to design waveforms targeting specific spinal cord circuits, and have direct translational relevance, opening the door to rational implementation of SCS for distinct clinical pathologies.