A versatile reporter for visualization of myelin plasticity in the genetically modified rat

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Abstract Myelin structure is a critical regulator of nerve conduction and an essential factor in axon development and homeostasis. In recent years, a number of seminal observations have dispelled a long-standing dogma that myelin is a static, inflexible structure. Advances in imaging techniques as well as in the methods used to label myelin have revealed that myelin plasticity occurs at the level of wrap number and sheath length during post- natal development, aging, and regeneration after injury. Observations of myelin plasticity indicate a more profound role of myelin axon function, and thereby highlight a critical need for better tools to investigate the mechanisms of myelin formation and remodeling. Here, we propose that the limited availability of tools for myelin reporting has significantly hindered our understanding of myelin biology. Illuminating the mechanisms of myelin plasticity will dramatically impact our understanding of the function of myelin in the nervous system and how myelin contributes to aging, injury, and disease. Our lab and others have developed myelin reporter systems in the mouse, but many of the behavioral and physiological studies that could inform myelin function are better modeled in the rat. The rat nervous system is unique from the mouse in terms of critical elements of behavior, endocrine function, epigenetics, and neurogenesis. Rats are also considered superior for modeling and translating regenerative therapies. We propose to develop a versatile myelin membrane reporter system in the rat capable of discriminating between new and old myelin in the nervous system with spatial and temporal precision. To generate the first myelin reporter rat system, we propose: Aim 1: Develop a rat myelin reporter system and Aim 2: Test the specificity and efficiency of myelin promoters in the rat reporter system. Results from this research will produce a myelin tagging system that will have unique functional advantages for the study of myelin development, myelin regeneration, and myelin in aging.