This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Huntingtons Disease (HD) is an untreatable inherited neurodegenerative disease causing motor and cognitive dysfunction and premature death, due to loss of specific neurons in the basal ganglia. Having access to the first transgenic rat model of HD, this project will provide the 1st in-depth survey of neural network changes in the brains of pre-symptomatic and symptomatic rats. Expertise from neuroanatomy, genetics, and high-resolution tomographic imaging will be employed to address questions about how HD affects the neural circuitry of the basal ganglia. We will first localize and quantify major structural brain changes occurring in conjunction with observed behavioral alterations, using contrast-enhanced in vitro high-resolution magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) in combination with immunocytochemistry and histological analysis. Secondly, we will characterize alterations occurring in the basal ganglia neural circuits using combined anterograde and retrograde axonal tracing techniques. Third, we will evaluate DWI as a diagnostic tool for detecting loss of axonal projections in this HD rat model. To facilitate comparison of multi-modal data across animals and experiments, a local coordinate system for the basal ganglia will be constructed. This coordinate system will serve to normalize and co-register all data in a common framework, suitable for future sharing of data in a 3D brain atlas environment. The project will provide valuable anatomical data relevant for subsequent investigations of HD pathophysiology and evaluation of potential therapeutic interventions.
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