High-content light sheet microscopy of cleared tissue for mental health research

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Investigators at the Broad Institute are actively developing ever more precise molecular and genetic tools for psychiatric research, harnessing powerful human model systems to understand the neurobiological results of genetic risk factors; and developing new computational and experimental approaches for unbiased mapping of mammalian brains. Large scale volumetric imaging of brain tissue would help achieve all these goals by enabling rapid evaluation of the performance of new tool compounds, and unbiased investigation of brain-wide cell type distributions and projection patterns. The ideal imaging technology for these experiments is selective plane illumination microscopy, or light-sheet microscopy, which, when performed in cleared brain tissue can avoid photobleaching of thick samples while achieving high volumetric scan rates. Large field-of-view light sheet microscopes have been developed, but, despite the potential advantage of this technology, Broad Institute investigators do not have access to such an instrument either at the Broad or at surrounding imaging facilities. To address this need, an ultra large field-of-view light sheet microscope, the mesoSPIM, will be built in the Broad Institute’s new Optical Profiling Platform according to clearly established specifications published by its inventors (Voigt, et al. 2019). The instrument will be accompanied by tissue clearing accessories permitting mental health researchers to clear, label, and image brain tissue in a highly automated and robust fashion. The OPP’s role at the Broad Institute is specifically to support such custom-built, cutting-edge technology for the broader research community. This is accomplished by a team of automation engineers, professional optics staff, computational biologists, and academic trainees who work together to both develop the next generation of tools and support existing technologies. This experienced team will build and manage the mesoSPIM for the benefit of the Broad mental health research community at minimal cost to users. Implemented in this way, the mesoSPIM will rapidly provide results characterizing the location and anatomical structure of newly identified cell types in the mouse and non-human primate brains; and will provide large-scale cell type catalogs and distributions across the mammalian brain.