The long term goal of this work is to better define the emergence of pattern in the developing brain as well as the changes in these patterns with the progress of development, of aging and pathology. The goal of the proposed project is to develop and apply the tools needed tot image cells and axons within the intact brain as it develops. Because no one imaging technique offers the combination of field of view, depth of penetration and resolution, imaging neural development will require combination multiple imaging modalities at multiple resolutions. Our approach is based upon our previous successes in labeling cells with fluorescent dyes so that their movements and the navigation of their labeled axons can be followed with light microscopy. It is also based upon recent advances both in MRI microscopy and in contrast agents that permit labeled cells to be followed in both the MRI and fluorescence microscopes. Together, these advances offer the promise of following changes in the nervous system as they take place within individual animals by combining data obtained at multiple resolutions and multiple imaging modalities. This approach poses several challenges, ranging from the labeling of the cells and acquisitions of the individual images to the registration of the multiple images into a single rendering and the databasing of the findings. Preliminary experiments and test computer programs suggest that this combined approach is feasible. The proposed project will combine the talents of a computational biology laboratory and a biological imaging laboratory to develop the needed experimental and computer tools. In particular the project will: . Develop the tools for acquiring, aligning and merging 3-D data sets from confocal and 2-photon light microscopes. . Develop the tools for acquiring, aligning and merging 3-D data sets from light and MRI microscopes. . Utilize these tools for examining the refinement of patterned neuronal projects and the migrations of neuronal precursors within living animals. The approach offers a new paradigm for following dynamic changes in the nervous system at resolutions spanning brain areas to individual synapses.

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California Institute of Technology
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