Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model
Open accessAbstract
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.
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In contrast to EAE, where lesion formation happens stochastically/sporadically in the spinal cord, cuprizone lesions are confined to certain topographical areas in the brain, increasing reproducibility.
“In contrast to the EAE model where lesion formation happens stochastically/sporadically in the spinal cord, the lesions are confined to these certain topographical areas in the brain – increasing the reproducibility [189, 190].”
From Insights and challenges on animal models for progressive multiple sclerosis (2026) · cites this paper as [189]
The Introduction says cuprizone reliably produces demyelination in the murine brain, and the Discussion (‘Regional heterogeneity may hold the key to understanding the model’; page unavailable) describes site-specific patterns in the corpus callosum. These passages support the cuprizone portion, but they do not establish that EAE spinal-cord lesions form sporadically or that the spatial pattern itself increases reproducibility. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe cuprizone mouse model is a well-established demyelination model.
“The cuprizone mouse model is a well-established demyelination model, and MRI studies demonstrated that various MRI techniques can detect white matter abnormality noninvasively (Thiessen et al. 2013; Tagge et al. 2016).”
From Neurite orientation dispersion and density imaging of mouse brain microstructure (2019) · cites this paper as Tagge et al. 2016
Various MRI techniques can detect white matter abnormality noninvasively.
“The cuprizone mouse model is a well-established demyelination model, and MRI studies demonstrated that various MRI techniques can detect white matter abnormality noninvasively (Thiessen et al. 2013; Tagge et al. 2016).”
From Neurite orientation dispersion and density imaging of mouse brain microstructure (2019) · cites this paper as Tagge et al. 2016
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- Authors
- Tagge, I., O’Connor, A., Chaudhary, P., Pollaro, J., Berlow, Y., Chalupsky, M., Bourdette, D., Woltjer, R., Johnson, M., & Rooney, W.
- Affiliations
- Oregon Health & Science University (US)
- Vertex Pharmaceuticals (United States) (US)
- Corresponding author
- Tagge, Ian
- O’Connor, Audrey
- Chaudhary, Priya
- Pollaro, Jim
- Berlow, Yosef
- Chalupsky, Megan
- Bourdette, Dennis
- Woltjer, Randy
- Johnson, Mac
- Rooney, William
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-04-07
- Volume
- 11
- Issue
- 4
- Pages
- e0152480
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4824475
- OpenAlex
- W2315326168
- Cited by
- 81
- References
- 60
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 3 · 2020: 4 · 2019: 14 · 2018: 7 · 2017: 7 · 2016: 7
- FWCI
- 10.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Vertex Pharmaceuticals
- National Institutes of Health (1s10od018224-01, 1s10rr027694-01)
- National Institute on Aging (AG008017, P30AG008017)
- National Institute of Neurological Disorders and Stroke (P30NS061800)
- National Center for Research Resources (S10 RR027694)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- cuprizone, demyelination, remyelination, multiple sclerosis model, corpus callosum, magnetization transfer ratio, spatiotemporal patterns, oligodendrocyte precursor cells, myelin basic protein, C57BL/6 mice
- MeSH terms
- Animals, Body Weight, Brain, Corpus Callosum, Cuprizone, Demyelinating Diseases, Disease Models, Animal, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mice, Inbred C57BL, Myelin Sheath, Transcriptome
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