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

项目摘要 脊髓刺激是一种阿片类药物保留的神经调节疗法，通常用于 治疗顽固性慢性背部和四肢疼痛。非常需要 了解SCS的基本生物学机制，以改善临床交付 和结果。已经证明，表征由以下物质参与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 并且仅对活跃神经元的稀疏子集进行采样。即刻早期基因（c-fos）表达 研究是模棱两可的，没有区分兴奋性和抑制性群体。 因此，SCS是否驱动不同抑制性亚群的激活仍然是未知的。 以依赖于刺激幅度和频率的方式。一种创新的小鼠模型将 用于在通过长期植入的植入物输送的长时间SCS期间标记激活的神经元 微型双极电极。将提供广泛的临床相关SCS波形 使用，激活的神经元将被分子表型化，并通过 多重RNA杂交。针对特定分子标记的探针将用于分类 神经元在不同的抑制集群，统计模型将开发的特点影响 神经元簇的刺激参数。这个项目将从空间和分子上识别 由临床相关SCS波形的全谱激活的抑制性亚群。 这些信息将极大地提高设计针对特定脊柱的波形的能力。 软电线电路，并有直接的翻译相关性，打开大门，合理实施 SCS用于不同的临床病理。

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.