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， 目的尚未探索。背根神经节电场刺激（GFS）的近期临床观察 阻断疼痛，提供了一个线索，即一个未被识别的过程调节通过DRG的冲动传导 因为恰恰相反，即疼痛的产生是可以预期的。GFS的悖论现象 镇痛表明，我们目前对外周神经元信号传递的理解从根本上是 这是不够的，一种新的，临床上可应用的使用依赖性神经元操纵模式正在等待 的发现这就是本提案的目标。感觉神经元也从背侧传递逆行冲动 角到外周组织，在那里它们触发炎症和组织损伤，例如在类风湿性关节炎中， 关节炎因此，我们将探讨传入和传出信号传递的双向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。 在感觉神经元的胞体中，降低了其T连接的内在兴奋性，从而降低了双向 在一些实施方案中，药物可以抑制AP通过DRG的传播，并且由此可以产生镇痛和阻断神经源性炎症。 在目标1中，我们将首先开发大鼠模型，以便为机制探索奠定基础。GFS 将在神经病和骨关节炎的情况下测试镇痛作用。测试GFS对逆行 脉冲，我们将确定GFS对类风湿性关节炎模型中关节变化的影响。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），检查 雄性和雌性大鼠。在目标2中，为了确定GFS的确切神经元靶点，我们将测试GFS对神经元的激活。 感觉神经元胞体，并确定哪些DRG神经元亚型由GFS调节，以及在哪些位置 这发生在轴突与索马之间。目标3将采用电生理方法直接 检测GFS对DRG神经元功能特性的影响，以探讨GFS的作用机制 脉冲调节此外，我们将探讨CaMKII的作用，我们将比较GFS的影响， 各种感觉神经元亚群。 总之，我们提出的实验将为一种新的调节过程建立一个机制基础， 控制着周围神经系统中的脉冲序列传输。作为分子和电子 神经调节疗法在临床环境中向前发展，了解这个新的调节节点将有 利用固有的脉冲调节系统并将其应用于控制感觉的直接转化效用 和外周炎性疾病。