Glial regulation of neuronal physiology in response to local injury

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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.