Cellular and molecular mechanisms of neuronal remodeling in healthy tissue

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PROJECT SUMMARY/ABSTRACT In the adult nervous system, peripheral sensory neurons maintain appropriate innervation patterns despite continual turnover of the target epithelia they innervate. The goal of this research is to elucidate fundamental neuronal mechanisms that govern plasticity of peripheral neurons in healthy tissue. The project focuses on Merkel cell-neurite complexes, which are high acuity touch receptors composed of epidermal Merkel cells innervated by myelinated (Aβ) sensory afferents. These discriminative touch receptors are enriched in fingertips, whisker follicles and touch domes in hairy skin. In mice, skin goes through marked changes in thickness and stiffness during the hair growth cycle, which repeats throughout adulthood. These target-organ changes are accompanied by rapid plasticity in the complexity of peripheral axonal arbors of Merkel-cell afferents. This application's central hypothesis is that the intrinsic pathways that dictate neuronal remodeling after injury also govern structural plasticity in healthy tissue, which causes behaviorally relevant changes across sensory modalities. The hypothesis will be tested using a combination of transgenic mouse models, quantitative neuroanatomy and three-dimensional neuronal tracing, in vivo, live-cell imaging and sensory behavioral tests. Aim 1 will test whether pathways that mediate axonal degeneration and regrowth after axonal injury are involved in afferent remodeling in healthy tissue. This aim will evaluate differences in neuronal morphology at defined hair cycle stages in transgenic mice lacking genes that interfere with injury-induced signaling pathways. Aim 2 will use mouse behavioral assays to test whether somatosensory afferents that mediate distinct sensory modalities remodel in parallel. These studies will define the functional consequences of neuronal remodeling in healthy tissue as well as cellular and molecular mechanisms that mediate structural plasticity.