A fundamental goal of neuroscience research is to understand the genetic and molecular basis for the development of brain structure and function. The most widely used model organism for studying developmental genetics of the mammalian brain is the mouse, offering a complete genomic database and a wide variety of transgenic, gene targeting and mutagenesis approaches. As a result, there now exist large numbers of genetically-engineered mouse models with altered neural development, providing essential animal models of human developmental brain diseases. In particular, many mutant mice have been generated with defects in midbrain and cerebellum development that can serve as an increasingly important resource for understanding a range of neuro-developmental diseases, including numerous cerebellar displasias and autism spectral disorders. To effectively analyze altered development and disease in these mouse models, we are developing in vivo ultrasound biomicroscopy (UBM) and magnetic resonance micro-imaging (micro-MRI) approaches for imaging the embryonic and neonatal mouse brain. The broad goals of this project are to further develop these noninvasive imaging tools for 3D anatomical, functional and molecular analysis, from embryonic to adult stages of brain development. The developing mouse mid-hindbrain (MHB) will be used as the model system for our in vivo micro-imaging studies. There are four specific aims: 1) To develop and apply 3D UBM methods for in utero anatomical analysis of early embryonic MHB;2) To develop and apply 3D micro-MRI methods for in vivo anatomical and functional analysis of late embryonic to adult stages of midbrain and cerebellum;3) To analyze anatomical and functional phenotypes in three selected groups of mutant mice with distinct MHB defects;and 4) To develop and test a manganese-based genetic reporter system for in vivo molecular MRI in the developing mouse MHB. The combination of genetic engineering approaches in the mouse with advanced ultrasound and MR micro-imaging technology will provide powerful new tools for analyzing mouse developmental neurobiology, and leading to new insights into mammalian brain development and human neuro-developmental diseases.
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