Studies of mouse models of human disease helped by NCMIR’s large-scale imaging expertise
Scientists studying the nervous system have long struggled to understand how higher order structures, such as cellular networks, are assembled out of finer building blocks, such as dendritic and axonal architectures. Mapping the entire neural structure is the key to elucidating brain function. In a forthcoming issue of Neuroinformatics, a team of NCMIR researchers report on their progress towards this central goal by describing new procedures to study brain architecture and to characterize pathological changes in transgenic mice, spanning millimeter- to nanometer-sized structures. In a complementary paper in press for the Journal of Microscopy, the team details the development of an automated ultra-large field light microscope with in-depth discussion of key technical problems of image acquisition, normalization, and alignment (Chow et al).
Diana Price, Sunny Chow, Hiro Hakozaki and their NCMIR colleagues describe how to acquire and systematically link thousands of high resolution fluorescent micrographs of mouse brain tissue to form large-scale mosaicked digital image datasets. The resulting datasets permit detailed examination of cellular and subcellular structure and reveal macromolecular distributions in a larger context. The NCMIR researchers applied these techniques to reveal the wide-spread distribution of the α-synuclein protein across brain regions in a transgenic mouse modified to over-express the a-synuclein protein. Alpha-synuclein is a neuronal protein that has been associated with several neurodegenerative diseases and typically manifests itself in aggregated proteinaceous inclusions called Lewy bodies.
This work represents an important step in characterizing a preclinical mouse model of parkinsonian disorders (PD). “Thorough characterization of preclinical animal models are a prerequisite to proper evaluation of putative therapeutics in animal models,” notes Diana Price, co-author on this study. In collaboration with UCSD’s Dr. Eliezer Masliah, the NCMIR research team has noted PD-like alterations in the alpha-synuclein transgenic mouse. According to Price, this indicates, “the animal model is potentially a good model for preclinical studies, providing us with some insights into the mechanisms of the disease”.
In order to share the massive amount of mouse data with other scientists investigating mouse models to characterize brain structures, the NCMIR team has placed the data into a shared informatics environment for online viewing and analysis. In this way, the brain maps will provide a persistent digital archive of potentially valuable specimens. In addition, such mosaicked datasets provide a bridge between whole brain MRI imaging techniques and electron microscopic analysis.
By developing techniques to digitally characterize mouse brain tissue across a large scale, the NCMIR researchers have demonstrated a persistent and powerful means to easily compare phenotypes among animal models. Digital archives of the cerebellum and hippocampus mouse brain datasets are available for online viewing and download through the Cell Centered Database and the Biomedical Informatics Research Network (BIRN). The Cell Centered Database is an online resource for 3d Light and electron microscopic data.
Price DL, Chow SK, MacLean NAB, Hakozaki H, Peltier S, Martone ME and Ellisman MH, (In Press) High-Resolution Large-Scale Mosaic Imaging using Multiphoton Microscopy to Characterize Transgenic Mouse Models of Human Neurological Disorders, Invited Manuscript. Neuroinformatics.
Chow SK, Hakozaki H, Price DL, MacLean NAB, Deerinck T, Bouwer J, Martone ME, Peltier S, Ellisman, MH (In Press) Automated Microscopy System for Mosaic Acquisition and Processing. Journal of Microscopy.