Investigating the Neural Circuits of Spinal Cord Stimulation

脊髓刺激(SCS)是一种用于治疗难治性神经病的微创疗法 疼痛。据认为，脊髓通过电刺激A-β纤维(A-β-ES)来介导疼痛缓解，但详细的 对它的生物学基础缺乏了解，尤其是关于它如何参与脊髓伤害性感受。 小路。这项建议的长期目标是描述SCS诱导的脊髓机制。 旨在优化其在慢性疼痛治疗中的临床应用。总体目标 本应用的目的是剖析β-ES对已定义的神经元微电路的影响，并测试其作用 Aβ-ES止痛作用的关键候选亚群。中心假设是Aβ-es 通过诱导驻留在脑内的特定脊髓神经元群体的动态变化来实现镇痛 浅背角(SDH)。这一假设将通过追求三个具体目标来检验：1)确定 背根Aβ-ES的条件反射对高阈值(C-纤维)诱发活动的调节程度 幼稚和神经损伤脊髓制备过程中SDH的兴奋性和抑制性神经元 老鼠。2)使用活体成像来确定背柱Aβ-ES的条件性训练的程度 减弱幼稚时浅背角兴奋性和抑制性神经元的外周诱发活动 和神经损伤的小鼠。3)确定A背柱β-ES内生长抑素表达神经元的作用 中介止痛。所提出的方法利用了最先进的体外和体内双光子 成像结合光遗传学方法描绘β-ES对特定神经元群体的影响 实时的。这项拟议的研究意义重大，因为对β-ES如何参与 后角将为强化SCS治疗提供一个直接的生物靶点，具有健全的机制 基础。因此，这项工作将具有直接的翻译相关性，因为它可能有助于优化脊髓刺激 计划，并改善患者的预后。 Andrei Sdrulla博士是一名医学博士/博士临床医生兼科学家，他的职业目标是成为一名成功的、独立的 资助疼痛研究人员和神经调节领域的临床领先者。斯德鲁拉博士将与他的 全面的指导团队，开发活体神经元群体定量成像方面的专业知识 成像、慢性疼痛的小鼠模型和行为中神经元群体的光遗传操作 动物。这项培训将主要通过在他的监督下进行实验来完成 教师培训，以及由教学、面授和研讨会组成的结构化培训。斯德鲁拉博士 将在俄勒冈健康与科学大学麻醉学系进行研究 实验室，建立在共享资源和核心基础上的独特协作环境 卓越，这是早期职业调查员的理想选择。

Spinal cord stimulation (SCS) is a minimally invasive therapy used for the treatment of refractory neuropathic pain. It is believed that SCS mediates pain relief by electrical stimulation of Aβ fibers (Aβ-ES), however a detailed understanding of its biological basis is lacking, particularly concerning how it engages spinal cord nociceptive pathways. The long-term goals of this proposal are to delineate the spinal mechanisms of SCS-induced analgesia in an effort to optimize its clinical implementation for the treatment of chronic pain. The overall objective of the present application is to dissect the influence of Aβ-ES on defined neuronal microcircuits, and test the role of a critical candidate subpopulation for the analgesic effects of Aβ-ES. The central hypothesis is that Aβ-ES achieves analgesia by inducing dynamic changes in specific populations of spinal cord neurons residing in the superficial dorsal horn (SDH). This hypothesis will be tested by pursuing three specific aims: 1) Determine the extent to which a conditioning train of dorsal root Aβ-ES modulates high-threshold (C-fiber) evoked activity of excitatory and inhibitory neurons in the SDH in an en bloc spinal cord preparation from naïve and nerve-injured mice. 2) Use in vivo imaging to determine the extent to which a conditioning train of dorsal column Aβ-ES attenuates peripherally evoked activity of excitatory and inhibitory neurons, in the superficial dorsal horn, in naïve and nerve-injured mice. 3) Determine the role of somatostatin expressing neurons in dorsal column Aβ-ES mediated analgesia. The proposed approach takes advantage of state-of-the-art ex vivo and in vivo two-photon imaging coupled with optogenetic approaches to delineate the effects of Aβ-ES on defined neuronal populations in real time. The proposed research is significant because a detailed understanding of how Aβ-ES engages the dorsal horn will provide a direct biological target for enhancements to SCS therapies with a sound mechanistic basis. This work will thus have direct translational relevance, as it may help optimize spinal cord stimulation programs and improve patient outcomes. Dr. Andrei Sdrulla is a MD/PhD clinician-scientist whose career goals are to become a successful, independently funded pain researcher and a clinical leader in the field of neuromodulation. Dr. Sdrulla will work closely with his comprehensive mentorship team to develop expertise in quantitative imaging of neuronal populations, in vivo imaging, mouse models of chronic pain and optogenetic manipulation of neuronal populations in behaving animals. This training will be accomplished primarily via performing experiments under supervision from his mentors, as well as structured training consisting of didactics, face-to-face instruction and seminars. Dr. Sdrulla will be conducting his research within Oregon Health & Science University’s Department of Anesthesiology Laboratories, a uniquely collaborative environment constructed on a foundation of shared resources and core excellence, which is ideal for an early career investigator.