title: Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model.
abstract: Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100 μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across time is essential for gaining a real understanding of disease processes in-vivo. MTR increases in healthy mice throughout adolescence and adulthood were observed, illustrating the need for appropriate age-matched controls. Elucidating the unique and site-specific demyelination in the cuprizone model may offer new insights into in mechanisms of both damage and repair in human demyelinating diseases.
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.|Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Tagge
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Audrey
authors.initials: A
authors.lastname: O'Connor
authors.affiliation: Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Jim
authors.initials: J
authors.lastname: Pollaro
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Berlow
authors.affiliation: Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Chalupsky
authors.affiliation: Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.|Portland VA Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, United States of America.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
authors.affiliation: Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: Randy
authors.initials: R
authors.lastname: Woltjer
authors.affiliation: Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA 02210, United States of America.
authors.forename: Mac
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.|Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.|Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Rooney
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced*; D004195:Disease Models, Animal; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism; D059467:Transcriptome
chemical_list: D003471:Cuprizone