This application addresses the broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-AA-107: Refinements of Procedures for Diffusion Tensor Imaging (DTI) in Rodent Models of Alcohol Dependence. As set forth for this Challenge, the proposed effort is designed to rapidly advance DTI technology and its application to discovery and documentation of alcohol's deleterious effects on the pre-and postnatal rodent brain. A major focus will be on achieving faster imaging times than are currently possible. This will allow the extension of DTI analyses from ex vivo to in vivo specimens. To complement the advances in imaging, new methodologies including tools and software for data management and analyses will also be developed and applied to our analyses of the fetal and postnatal mouse brain. These techniques will be utilized to extend this laboratory's current investigation of fetal alcohol spectrum disorders (FASD) in a mouse model and to address the hypothesis that maternal alcohol (ethanol) administration limited to very early stages of prenatal development (corresponding to week 3 of human development) results in permanent central nervous system damage. Preliminary work from our laboratory utilizing DTI has shown significant alterations in fiber tract morphology in the mouse fetus following acute alcohol exposure. The proposed effort will allow faster imaging times than previously possible and will facilitate extension of our imaging analyses into the postnatal period. To this end, the following specific Aims will be addressed:
Aim # 1 is to develop new DTI methodologies that will allow faster imaging times than are currently feasible. This will be accomplished by the use of active staining techniques, 3D radial keyhole imaging, and a novel cryogenic radiofrequency coil applied to DTI.
Aim #2 is to rapidly develop a software framework for a new, automated mouse brain data analysis based on an unbiased atlas generation. This analysis method will be used for voxel-wise analysis of DTI properties and connectivity patterns, as well as DTI fiber tractography-specific analysis.
Aim #3 is to apply the methodologies advanced in the previous Aims to the examination of alcohol's effect on the pre- and postnatal mouse brain. For this, the brains of control mice and those exposed to alcohol on their 7th day of gestation, will be examined on their 17th prenatal day (GD 17), or their 45th or 90th postnatal day (PND 45, PND 90) for fiber tract morphology (including microstructural integrity). In addition to ex vivo imaging of the GD 17 and PND 45 and 90 brains, a subset of the PND 45 animals will be imaged in vivo. Since prenatal alcohol exposure is reportedly related to subsequent alcohol dependence in humans and also increases alcohol self administration and preference in animals, prior to imaging, the postnatal animals will be examined in a number of behavioral batteries designed to assess their reactions to acute alcohol challenge. Promise for the successful completion of these Aims is provided by the expertise of the investigators in their respective fields (G.A Johnson in imaging technology development;M.A. Styner in image analysis software development;and K.K. Sulik in FASD research) and their previously productive collaborative efforts. It is expected that in addition to rapidly providing tools and approaches that can be directly applied to other rodent models and research questions, the proposed Challenge effort will provide important new information regarding the biological (both structural and functional) consequences of prenatal alcohol exposure.
The proposed work addresses the broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-AA-107: Refinements of Procedures for Diffusion Tensor Imaging (DTI) in Rodent Models of Alcohol Dependence. As set forth for this Challenge, the proposed effort is designed to rapidly advance DTI technology and its application to discovery and documentation of alcohol's deleterious effects on the pre-and postnatal rodent brain. A major focus will be on achieving faster imaging times than are currently possible. This will allow the extension of DTI analyses from fixed to live specimens. To complement the advances in imaging, new methodologies including tools and software for data management and analyses will also be developed and applied to our study of alcohol-induced brain abnormalities.
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