Glial Regulation of Neuronal Physiology in Response to Local Injury

项目摘要 神经系统的局部损伤会导致神经生理学的深远改变，即使是在未受伤的情况下。 远离损伤部位的神经元。令人惊讶的是，正是这些未受伤神经元的生理变化，而不是 损伤神经元本身，这是负责慢性疼痛与周围神经病变 神经损伤后。在创伤性脑损伤后未受伤的神经元中也观察到了这些变化， 已经假设，未受伤神经元的生理变化可能是造成广泛认知障碍的原因。 即使是局部脑损伤也会引起变化。尽管他们参与了这些重要的进程， 损伤信号在神经系统中传播的机制尚不清楚。 我们最近开发了一种模型，其中神经内的神经元可以被稀疏地标记，并且个体受伤， 未受伤的神经元明确确定后轴突切断。使用这种模型的轴突切断在前神经的 果蝇翅膀，我们发现神经内未受伤的神经元经历轴突运输停滞， 对刺激的反应减少。有趣的是，这些作用被证明需要神经胶质信号传导， 神经胶质是受损神经元和未受损神经元之间所需的介质，其中生理改变。这 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受伤， 改变周围神经元的生理机能。 在目标1中，我将评估胶质细胞识别哪种类型的损伤足以在回路内广泛调节信号。我会 也测试这些信号通路是否不同于受损轴突变性所需的信号通路。我们有 已经确定德雷珀受体是神经胶质细胞感受这些损伤反应所必需的。在目标2中，我将执行 德雷珀受体的结构功能分析，以确定哪些功能域是信号传导所需的 受体激活的下游，并测试这些结构域下游的信号传导组分是否 这是神经胶质细胞调节未受损神经元信号传导所必需的。TRAPseq对损伤后神经胶质细胞的作用将用于识别 神经胶质用来与未受伤的神经元交流的其他因素。在目标3中，我将确定为什么胶质细胞可能导致 通过阻断未损伤神经元信号传导和评估神经元的长期恢复， 生理学和神经内的存活。 总之，这些研究将提供深入了解损伤信号在神经系统中传播的机制。 系统，并确定负责这一未知但重要的现象的细胞和分子途径。 这些机制可以在治疗上靶向维持胶质细胞在清除轴突中的有益反应 损伤后的碎片，但防止信号，导致未受伤的神经元生理的有害变化。这将 是一种全新的方法，针对神经性疼痛和认知功能障碍的伤害后。

Project Summary Localized damage to the nervous system can lead to far-reaching alterations in neurophysiology, even in uninjured neurons far 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 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 stimuli. Interestingly, these effects were shown to require glial signaling, demonstrating that glia are required mediators between injured neurons and the uninjured neurons in which physiology is altered. 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 signaling broadly within the circuit. I will also 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 these injury responses. 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 signaling components downstream of those domains are required for glial modulation of uninjured neuron signaling. TRAPseq on glia after injury will be used to identify additional factors that glia use to communicate with uninjured neurons. 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.