Glial Regulation of Neuronal Physiology in Response to Local Injury

点击翻译按钮获取中文摘要

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.