Glial regulation of neuronal physiology in response to local injury

神经胶质对局部损伤的神经生理学调节

• 批准号: 10040377
• 负责人: Taylor Reagan Jay
• 金额: $ 6.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-17 至 2022-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040377
• 关键词: ANXA5 gene; Acute; Address; Affect; Anterior; Axon; Axonal Transport; Axotomy; Cells; Chronic; Development; Distant; Drosophila genus; Exhibits; Fellowship; Focal Brain Injuries; Genetic Transcription; Goals; Impaired cognition; Impairment; Individual; Injury; Label; Laboratories; Lead; Length; Mediating; Mediator of activation protein; Mentorship; Modeling; Molecular; Mutation; Nerve; Nervous system structure; Neurobiology; Neuroglia; Neuronal Injury; Neurons; Pathway interactions; Peripheral Nervous System Diseases; Physiological; Physiology; Population; Process; Receptor Activation; Recovery; Regulation; Research; Research Personnel; Sensory; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Spinal nerve structure; Stimulus; Structure; System; Technical Expertise; Testing; Time; Training Activity; Traumatic Brain Injury; Visualization; Wing; Work; axon injury; axonal degeneration; base; chronic pain; cognitive change; fly; improved; in vivo; injured; insight; knock-down; nerve injury; neuronal circuitry; neurophysiology; neurotransmission; novel strategies; painful neuropathy; prevent; programs; receptor; response; response to injury; sensory stimulus; skills; success; targeted treatment; therapeutic target; tool

Localized damage to the nervous system can lead to far-reaching alterations in neurophysiology, even in uninjured neurons distant from the site of injury. Surprisingly, it is these changes in the physiology of uninjured neurons, rather than damage to injured neurons themselves, that is responsible for the chronic pain associated with peripheral neuropathy after nerve injury. These changes have also been observed in uninjured neurons following traumatic brain injury, and it has been posited that physiological changes in uninjured neurons could be responsible for the widespread cognitive changes that result from even focal brain injuries. Despite their involvement in these important processes, the mechanisms by which injury signals spread across the nervous system are poorly defined. We have recently developed a model in which neurons within a single nerve can be sparsely labeled and individual injured and uninjured neurons definitively identified after axotomy. Using this model of axotomy in the anterior nerve of the Drosophila wing, we found that uninjured neurons within the nerve undergo stalling of axon transport and exhibit reduced activity in response to sensory stimuli. Interestingly, we found that these effects require glial signaling, demonstrating that glia act as mediators between injured and uninjured neurons to drive changes in physiology. This proposal will focus on understanding how glia sense that neurons have been injured, and how and why these cells then change the physiology of surrounding neurons. In Aim 1, I will assess what type of injury glia recognize as sufficient to modulate neuronal physiology and will test whether these signaling pathways are distinct from those required for injured axon degeneration. We have already identified that the Draper receptor is required in glia to sense injury. In Aim 2, I will perform a structure function analysis of the Draper receptor to determine which functional domains are required for signaling downstream of receptor activation and test whether the associated signaling molecules are required for glial modulation of uninjured neuron signaling. In Aim 3, I will determine why glia might cause these change in uninjured neurons by blocking uninjured neuron signaling and assessing long-term recovery of neuronal physiology and survival within the nerve. Together, these studies will provide insight into the mechanisms by which injury signals spread across the nervous system and identify the cellular and molecular pathways responsible for this unknown but important phenomenon. These mechanisms could then be targeted therapeutically to maintain beneficial responses of glia in clearing axonal debris after injury, but prevent signaling that leads to detrimental changes in uninjured neuronal physiology. This would be a completely novel approach to targeting neuropathic pain and cognitive dysfunction after injury. In addition, performing this work will allow me to develop the new technical skills and intellectual approaches I will need to use Drosophila to address fundamental neurobiological questions in my own laboratory. The additional training activities proposed in this fellowship will also enhance my quantitative and analytical skills, improve my ability to communicate my work, and engage in mentorship, preparing me for success as an independent investigator.

对神经系统的局部损伤可导致神经生理学的深远改变，甚至在远离损伤部位的未受伤神经元中也是如此。令人惊讶的是，正是这些未受伤神经元的生理变化，而不是对受伤神经元本身的损害，导致了神经损伤后与周围神经病变相关的慢性疼痛。在创伤性脑损伤后未受伤的神经元中也观察到这些变化，并且已经假定未受伤神经元中的生理变化可能是由甚至局灶性脑损伤引起的广泛认知变化的原因。尽管它们参与了这些重要的过程，但损伤信号在神经系统中传播的机制还很不清楚。我们最近开发了一种模型，在该模型中，单个神经内的神经元可以稀疏地标记，并且在轴突切断后明确地识别出单个损伤和未损伤的神经元。使用这个模型的轴突切断在前神经的果蝇翅膀，我们发现，未受伤的神经元内的轴突运输停滞，并表现出减少的活动，在响应感官刺激。有趣的是，我们发现这些效应需要胶质细胞信号传导，这表明胶质细胞作为受损和未受损神经元之间的介质来驱动生理变化。这项提案将集中在理解神经胶质细胞如何感知神经元受损，以及这些细胞如何以及为什么改变周围神经元的生理机能。在目标1中，我将评估哪种类型的损伤胶质细胞识别为足以调节神经元生理学，并将测试这些信号通路是否与损伤轴突变性所需的信号通路不同。我们已经确定德雷珀受体是神经胶质细胞感受损伤所必需的。在目标2中，我将进行德雷珀受体的结构功能分析，以确定哪些功能域是受体激活下游信号传导所需的，并测试相关的信号传导分子是否是未受损神经元信号传导的胶质细胞调节所需的。在目标3中，我将通过阻断未受伤的神经元信号传导和评估神经元生理学和神经内存活的长期恢复来确定为什么胶质细胞可能导致未受伤的神经元发生这些变化。总之，这些研究将深入了解损伤信号在神经系统中传播的机制，并确定负责这种未知但重要现象的细胞和分子途径。然后，这些机制可以在治疗上被靶向，以维持胶质细胞在损伤后清除轴突碎片的有益反应，但防止导致未损伤神经元生理学有害变化的信号传导。这将是一种针对损伤后神经性疼痛和认知功能障碍的全新方法。此外，从事这项工作将使我能够发展新的技术技能和智力方法，我将需要使用果蝇来解决我自己的实验室中的基本神经生物学问题。该奖学金中提议的其他培训活动也将提高我的定量和分析技能，提高我沟通工作的能力，并参与指导，为我作为独立调查员的成功做好准备。