Mechanisms of Dendrite Regeneration after Injury

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At the most straightforward level, a neuron receives information along dendrites, and sends information down an axon to synaptic contacts. Dendrites are injured by traumatic brain injury, stroke, and many forms of neurodegeneration, yet while factors that control axon regeneration after injury have been extensively studied, we know almost nothing about dendrite regeneration. My long term research goal is to understand the cellular mechanisms of dendrite regeneration after injury. During my graduate training with Dr Joshua Kaplan at Harvard, I used quantitative imaging, behavior, and C. elegans genetics to examine a key step in neuronal circuit development. For my postdoctoral training with Dr Yuh Nung Jan at UCSF, I have transitioned to studying the response to neurons to dendrite injury in Drosophila. I have found that the da sensory neurons in the Drosophila peripheral nervous system exhibit robust regeneration of dendrites after injury and am using this system to explore fundamental features of dendrite regeneration. I have observed that regenerated dendrites are identical to uninjured dendrites in many ways, like the trafficking of sensory ion channels and the expression of cell-type specific transcription factors. However the morphology and patterning of injury-induced dendrites are significantly defective compared to uninjured dendrites. Moreover, manipulations that alter the excitability of neurons specifically alter the regrowth of neurons after injury without affecting uninjured neurons, suggesting that dendrite regeneration is an activity-dependent process. I propose that developing a research program to deepen our knowledge about dendrite regeneration will create a new framework for understanding how neurons recover from injury. My short term research goals for the K99 mentored phase are to gain additional experimental skills to test the function of regenerated dendrites. These skills will facilitate the research proposed here: to investigate the activity dependence of dendrite regeneration; to examine the cell biological changes that underlie the alterations in regenerated dendrite morphology and their functional consequences; and explore the relationship between dendrite arbor maintenance and dendrite regeneration after injury. The proposed experimental training and the planned career development activities will prepare me to transition to leading an independent and productive research program as a tenure-track faculty member at a research institution.