Investigating the Neural Circuits of Spinal Cord Stimulation

脊髓电刺激（SCS）是一种微创治疗方法，用于治疗难治性神经病变 痛苦据信SCS通过电刺激Aβ纤维（Aβ-ES）介导疼痛缓解，然而， 对它的生物学基础缺乏了解，特别是关于它如何参与脊髓伤害性感受 途径。这项建议的长期目标是阐明脊髓脊髓损伤的机制， 镇痛，以努力优化其用于治疗慢性疼痛的临床实施。总体目标 本申请的目的是剖析Aβ-ES对限定的神经元微回路的影响，并测试Aβ-ES在神经元微回路中的作用。 Aβ-ES镇痛作用的关键候选亚群。核心假设是Aβ-ES 通过诱导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的条件训练调节高阈值（C纤维）诱发的活动的程度 未处理和神经损伤的完整脊髓标本中SDH中的兴奋性和抑制性神经元 小鼠2)使用体内成像来确定背柱Aβ-ES的条件化训练的程度 减弱外周诱发的兴奋性和抑制性神经元的活动，在浅背角，在幼稚 和神经损伤的小鼠。3)确定背柱Aβ-ES中生长抑素表达神经元的作用 介导镇痛所提出的方法利用了最先进的离体和体内双光子 成像结合光遗传学方法描述Aβ-ES对确定的神经元群体的影响 在真实的时间里。这项拟议的研究是重要的，因为详细了解Aβ-ES如何参与 背角将提供直接的生物靶点，用于增强SCS治疗， 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 计划和改善患者的结果。 博士Andrei Sdrulla是一名医学博士/博士临床科学家，他的职业目标是成为一名成功的独立 他是一位疼痛研究者，也是神经调节领域的临床领导者。斯德鲁拉博士将与他的 全面的指导团队，以发展体内神经元群体定量成像的专业知识 慢性疼痛的小鼠模型和行为神经元群体的光遗传学操纵 动物这项培训将主要通过在他的监督下进行实验来完成。 此外，还提供了由教学法、面对面指导和研讨会组成的结构化培训。斯德鲁拉博士 他将在俄勒冈州健康与科学大学的麻醉学系进行研究 实验室，一个独特的协作环境，建立在共享资源和核心的基础上， 卓越，这是理想的早期职业调查员。

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.