2005 All Hands Meeting Science of the Mouse models of human neurodegenerative disease

Mouse BIRN Data Integration Framework 2. Create conceptual links to a shared ontology 1. Create multimodal databases 3. Situate the data in a common spatial framework 4. Use mediator to navigate and query across data sources

Mouse models of neurological disease  Allow us to better understand the disease mechanism and potential therapies of related human neurological disorders Use of single strain (essentially “clones”):  Different imaging modalities  Different ages or progression  Gene manipulation: strain is it’s own control  Different therapies Multiple strains and crossbreeding:  Genetics and environment  Therapeutic interactions

Mouse BIRN models  Parkinson’s  Multiple Sclerosis  Alzheimer’s

Parkinson’s Disease (  -synuclein model)  Lewy Bodies  Alpha-synuclein protein (  -SYN) aggregates  Found in several brain areas in PD  Mouse model overexpressing  -SYN PD like pathology Motor deficits  Link expression of  -SYN to behavior and structure

 -synuclein Results slide Assessment of cognitive and motor function Genetic analyses (Web QTL) Ultrastructural studies using EM Correlation of large-scale mapping of immunolabeling and MRI studies

Multiple Sclerosis (EAE model)  Inflammatory autoimmune demyelinating diseases Demyelination and axonal degeneration Limb weakness and paralysis  Experimental Autoimmune Encephalomyelitis (EAE): Induced inflammatory autoimmune disease Chronic progressive disability Differential susceptibility across strains and antigens  Examine disease progression and severity in relation to structure

EAE Results slide

Alzheimer’s Disease  Several mouse models over-express APP (A  precursor protein)  These accumulate amyloid-  (A  ) protein Aggregates into extracellular lesions (amyloid plaques) Found throughout the hippocampus and cortex Accumulation of plaques similar to human  New collaborator’s model: turn on/off mutant APP production Examine if there is recovery Time course of recovery  Great place for integration with Morph testbed

Situate data in a common spatial framework Image Processing Registration Reconstruction Coregistered Data

Designing this Framework BAMS WebQTL Spatially Coregistered Images in Database Coregistered Atlas Modules Web Based Resources Ontologies MOUSE BIRN VIEWING TOOL

Multiple Ways of Querying Data Brain Cerebellum Purkinje Cell Layer Purkinje cell neuron has a is a Spatial (Atlases) Transformations Ontologies

Progress on interoperative atlasing interface SmartAtlas SHIVA Neuroterrain Individual Mouse BIRN Atlas Tools Mouse BIRN Integrated Tool Mouse Orientation and Registration Tool (MORT)

In the last year  Cyr M, Caron MG, Johnson GA, Laakso A, (2005) Magnetic resonance imaging at microscopic resolution reveals subtle morphological changes in a mouse model of dopaminergic hyperfunction, NeuroImage, 26:83-90  Anjum A. Ali, Anders M. Dale, Alexandra Badea, G. Allan Johnson (2005) Automated Segmentation of Neuroanatomical Structures in Multispectral MR Microscopy of the Mouse Brain. NeuroImage, 27:  Price DL, Chow SK, MacLean NAB, Hakozaki H, Peltier S, Martone ME, Ellisman MH (In Press) High-Resolution Large-Scale Mosaic Imaging using Multiphoton Microscopy to Characterize Transgenic Mouse Models of Human Neurological Disorders. Neuroinformatics.  Erh-Fang L, Jacobs RE, Dinov I, Leow A, Toga A, (In Press) Standard Atlas Space for C57BL/6 Neonatal Mouse Brain. Anatomy and Embryology  MacKenzie-Graham A, Tinsley M, Shah KP, Aguilar C, Strickland LV, Boline J, Martin M, Morales L, Shattuck DW, Jacobs RE, Voskuhl RR, Toga AW, (In Progress) Cerebellar Cortical Atrophy in C57BL/6J Mice with Experimental Autoimmune Encephalomyelitis.  D.L. Price, E. Rockenstein, N.A.B. MacLean, M. Mante, V. Phung, D. Askay, E. Masliah, and M.H. Ellisman (In preparation) Increased mGluR5 immunoreactivity and behavioral deficits in transgenic mice overexpressing alpha- synuclein PUBLICATIONS IN PRESS IN PREPARATION

Summary  Create powerful intuitive infrastructure to incorporate, visualize, manage, search, analyze, and compare data  Use these tools to help characterize mouse models of neurodegenerative disease, with the goal of better understanding the disease mechanism and potential therapies  Share these technologies with the scientific community