Harnessing T-junction filtering; bidirectional control of sensory neuron impulse traffic

利用 T 形接头过滤；

• 批准号: 9419475
• 负责人: Quinn H Hogan
• 金额: $ 47.1万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9419475
• 关键词: Absence of pain sensation; Action Potentials; Acute Pain; Afferent Neurons; Anatomy; Animal Disease Models; Animals; Axon; Behavioral; Brain imaging; Clinical; Complement; Control Animal; Data; Degenerative polyarthritis; Disease; Electrophysiology (science); Esthesia; FDA approved; Female; Foundations; Functional Magnetic Resonance Imaging; Ganglia; Generations; Goals; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Joints; Measures; Mechanoreceptors; Membrane; Modality; Modeling; Molecular; Neuraxis; Neurogenic Inflammation; Neurons; Neuropathy; Neurostimulation procedures of spinal cord tissue; Nociceptors; Optics; Organ; Pain; Pain management; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral Nervous System; Pharmacology; Physiological; Population; Preparation; Process; Production; Property; Rattus; Reflex action; Regulation; Rheumatoid Arthritis; Role; Sensory; Signal Transduction; Spinal Ganglia; System; Testing; Therapeutic; Tissues; Training; behavior test; calmodulin-dependent protein kinase II; chronic pain; clinical application; designer receptors exclusively activated by designer drugs; dorsal column; dorsal horn; experimental study; in vivo; male; neuronal cell body; neuroregulation; novel; optogenetics; preference; prevent; receptive field; sensory system; spinal nerve posterior root; transmission process

Sensory neurons naturally adapt to ongoing stimulation, but harnessing this inherent plasticity for therapeutic purposes has not been explored. The recent clinical observation that dorsal root ganglion field stimulation (GFS) blocks pain, provides a clue that an unrecognized process regulates conduction of impulses through the DRG since exactly the opposite, i.e. production of pain, would be expected. The paradoxical phenomenon of GFS analgesia indicates that our current understanding of peripheral neuron signal transmission is fundamentally insufficient, and that a novel, clinically applicable modality of use-dependent neuronal manipulation awaits discovery. That is the goal of this proposal. Sensory neurons also convey retrograde impulses from the dorsal horn to peripheral tissues, where they trigger inflammation and tissue damage, for instance in rheumatoid arthritis. We will therefore explore bidirectional GFS modulation of both afferent and efferent signal transmission through the DRG. In three Aims, we will test the overall hypothesis that GFS, by triggering action potentials (APs) in the somata of sensory neurons, reduces the intrinsic excitability of their T-junction, which reduces bidirectional propagation of APs through the DRG, and can thereby produce analgesia and block neurogenic inflammation. In Aim 1, we will first develop a rat model in order to lay the groundwork for mechanistic exploration. GFS analgesia will be tested in the setting of neuropathy, and osteoarthritis. To test GFS blockade of retrograde impulses, we will identify GFS effects on joint changes in a model of rheumatoid arthritis. For these experiments, examination will be by behavioral tests and functional magnetic resonance imaging (fMRI) of the brain, examining both male and female rats. In Aim 2, to identify the exact neuronal targets of GFS, we will test GFS activation of sensory neuron somata, and determine which DRG neuronal subtypes are modulated by GFS and at which component (axon vs. soma) this takes place. Aim 3 will employ electrophysiological approaches to directly measure the effects of GFS on functional properties of DRG neurons, in order to identify the mechanism of GFS impulse regulation. Additionally, we will explore the role of CaMKII, and we will compare GFS effects between the various sensory neuron subpopulations. Together, our proposed experiments will establish a mechanistic foundation for a novel regulatory process that governs impulse train transmission in the peripheral nervous system. As molecular and electrical neuromodulatory therapies move forward in the clinical setting, understanding this new regulatory node will have direct translational utility for harnessing an inherent impulse regulating system and applying it to control sensory and peripheral inflammatory disorders.

感觉神经元自然地适应持续的刺激，但利用这种固有的可塑性进行治疗 目的尚未探讨。背根神经节场刺激（GFS）的最新临床观察 阻止疼痛，提供了一个线索，表明一个未被识别的过程通过 DRG 调节冲动的传导 因为预期会发生完全相反的情况，即产生疼痛。 GFS的悖论现象 镇痛表明我们目前对周围神经元信号传递的理解从根本上来说是 不足，并且等待一种新颖的、临床适用的依赖于使用的神经元操作方式 发现。这就是本提案的目标。感觉神经元还传递来自背侧的逆行冲动 角向周围组织，引发炎症和组织损伤，例如类风湿病 关节炎。因此，我们将探索传入和传出信号传输的双向 GFS 调制 通过 DRG。在三个目标中，我们将通过触发动作电位（AP）来测试 GFS 的总体假设 在感觉神经元的体细胞中，降低其 T 形接头的内在兴奋性，从而降低双向性 AP 通过 DRG 传播，从而产生镇痛并阻断神经源性炎症。 在目标1中，我们将首先开发大鼠模型，为机制探索奠定基础。政府财政司司长 将在神经病和骨关节炎的情况下测试镇痛效果。测试 GFS 逆行阻断 脉冲，我们将确定 GFS 对类风湿关节炎模型关节变化的影响。对于这些实验， 检查将通过行为测试和大脑功能磁共振成像（fMRI）进行，检查 雄性和雌性大鼠。在目标 2 中，为了确定 GFS 的确切神经元目标，我们将测试 GFS 激活 感觉神经元体细胞，并确定哪些 DRG 神经元亚型受 GFS 调节，以及哪些 DRG 神经元亚型受 GFS 调节 组件（轴突与体细胞）发生这种情况。目标 3 将采用电生理学方法直接 测量 GFS 对 DRG 神经元功能特性的影响，以确定 GFS 的机制 冲动调节。此外，我们将探讨 CaMKII 的作用，并将比较 GFS 的效果 各种感觉神经元亚群。 总之，我们提出的实验将为新颖的监管过程奠定机械基础， 控制周围神经系统的脉冲序列传输。作为分子和电 神经调节疗法在临床环境中取得进展，了解这个新的调节节点将有 直接转化效用，用于利用固有的脉冲调节系统并将其应用于控制感官 和外周炎症性疾病。