David C. Reutens, M.D. - US grants

DESCRIPTION (provided by applicant): Genetically modified animal models, such as the zebrafish, are frequently employed to understand the development, genetics, and biological processes associated with human diseases. To decipher the complex genotype-phenotype relationships underlying inherited neurological disorders, the structure of the central nervous system in a transgenic model must be compared with that of wild-type animals. Anatomical methods that rely on transparency of the zebrafish are restricted to embryonic and larval animals but cannot be applied to older animals (>6 days post fertilization), which have become opaque. Moreover, results obtained with this immature age group may not be applicable for neurodegenerative diseases with a mid- to late-life onset. Consequently, there is a growing interest in the use of mature-aged (juvenile and adult) zebrafish in studies of neurodegenerative diseases. However, a complete anatomical characterization of the mature zebrafish brain and a quantitative voxel-based probabilistic map of brain structures are needed to compare disease models with wild-type zebrafish. Recent technological developments in magnetic resonance imaging (MRI) now enable non-invasive and three-dimensional imaging of the juvenile and adult zebrafish brain. Specifically, with high- resolution T2*-weighted and super-resolution track density imaging, delineations of gross brain regions and white matter tracts are now possible at resolutions better than 105m isotropically. Therefore we propose (1) to develop a probabilistic atlas of the wild-type (AB) zebrafish brain with high resolution T2*-weighted and super- resolution track density imaging (TDI);(2) to reconstruct histological specimens of the brain into three- dimensional volumes and to co-register these with the MR images allowing cross-referencing across modalities;(3) to create a tractographic atlas using seed points within brain regions segmented in Aim 1. PUBLIC HEALTH RELEVANCE: This study will produce the first three-dimensional anatomical characterization of an important animal model of disorders such as Alzheimer's disease that are major contributors to the global burden of disease. A population-based atlas of structures and fibre bundles in the wild-type zebrafish brain with normative values for parameters of tissue density and diffusion will endow future studies with the essential capability to perform voxel-based comparisons between model and wild type animals. This will allow a more comprehensive account of the effects of genetic and/or environmental manipulation on brain structure.