In-utero characterization of embryonic mouse brain development and injury with MRI

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Project summary: We propose to establish an integrated imaging platform for in-utero monitoring of the embryonic mouse brain development and injury. We will investigate a mouse model of intrauterine inflammatory injury in this project, which induces well-defined phenotypes of fetal neuronal injury. In-utero MRI will be useful to non-invasively detect the injury and monitor the injury progression, in addition to conventional histological examination. We will develop novel techniques to overcome the challenges for in-utero MRI, such as the fetal and maternal motion. A localized imaging technique will be used to focus the imaging field-of-view on selected mouse embryo instead of the entire abdomen, which leads to accelerated acquisition and reduced exposure to motion, as we previously demonstrated. Fast imaging sequences and motion correction techniques will be integrated to achieve 3D high-resolution MRI to resolve the miniature structures in the embryonic mouse brain. The technique will be extended for simultaneous imaging of multiple embryos to improve the throughput. Based on these innovations, multi-modality MRI including T1- and T2-weighted imaging, diffusion-weighted and diffusion tensor imaging will be achieved collectively to characterize the brain morphology and microstructural organization. We will first perform in-utero examination of the normal embryonic mouse brain development from embryonic day 14 to 18. The brain volumetric changes will be quantified from high-resolution T1/T2 images, and the microstructural changes, such as cortical and white matter development will be characterized with diffusion MRI. Using the multi-contrast in-utero MRI tools, and the baseline information from normal brain development, we will examine a mouse model of inflammatory fetal brain injury, induced by intrauterine injection of lipopolysaccharide. Acute edema will be captured from T2- and diffusion-weighted contrasts; while changes in brain morphology, damages in major white matter and cortical structures will be followed with anatomical images and diffusion MRI metrics. The spatiotemporal patterns of injury progression will be characterized by comparing the time courses of the MRI measurements in the injured and sham groups. We will also investigate two time windows of the injury onset at the middle and late gestation stages in order to understand the impacts of the timing of injury. The underlying pathology of the MRI findings will be examined with an array of immune-histological markers, and the MRI-histopathology correlations will be pursued. If the measurements are successful, we will establish multi- contrast MRI markers of the inflammatory fetal brain injury, and demonstrate their pathological implications. The proposed pioneer work will be one of the first studies to achieve in-utero monitoring of embryonic mouse brain development and injury. The findings would contribute important knowledge to human fetal MRI studies as it may reveal the link between MRI and histology markers. The proposed imaging platform will also be useful to evaluate intervention strategies and monitor treatment responses in small animal models, and the techniques are translatable to clinical scanners for safe examination of human fetal brains.