Myelin replacement triggered by single-cell demyelination in mouse cortex
Open accessAbstract
Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex demyelination as subtle as the loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown. This results in reliable reestablishment of the original myelin pattern along continuously myelinated axons, while in parallel, patchy isolated internodes emerge on previously unmyelinated axons. Therefore, in mammalian cortex, internodes along partially myelinated cortical axons are typically not reestablished, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, myelin sheaths forming continuous patterns show remarkable homeostatic resilience and remyelinate with single axon precision.
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The efficacy of remyelination depends on multiple factors such as age, disease duration and lesion location.
“The efficacy of remyelination has been shown to depend on multiple factors such as, age, disease duration and lesion location.”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [10]
The Results section (‘Remyelination is instructed by pre-ablation myelin pattern’; page not provided) shows that cortical remyelination efficiency varies with the pre-existing myelin pattern in mice. It does not show that efficiency depends on age, disease duration, or lesion location, the factors named in the claim. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPrevious experimental and human work suggests that g-ratios are higher and internodes shorter in demyelinated cortex than in normal cortex, without directly associating newly formed internodes to BCAS1 expression.
“Previous experimental and human work on demyelinated cortex suggests that g-ratios are indeed higher and internodes shorter than in NC, however, without directly associating newly formed internodes to the expression of BCAS1.10,17”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [10]
In Results (page unavailable), newly formed internodes in the mouse cortex had thinner myelin and higher g-ratios than pre-existing internodes. The Discussion (page unavailable) says spontaneously added internodes appeared shorter than pre-existing ones, but Results also says restored internodes were longer than de novo internodes. This paper does not establish the human comparison or directly associate internodes with BCAS1 expression. (LLM, conf=0.85)
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Periods of synchronized myelin changes shape brain function and plasticity
de Faria, O., Pivoňková, H., Varga, B. V., Timmler, S., Evans, K. A., & Káradóttir, R. T. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00917-2 · Cited by 193 · see citing works
The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases
Zang, X., Chen, S., Zhu, J., Ma, J., & Zhai, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.872134 · Cited by 139 · see citing works
Oligodendrocyte–axon metabolic coupling is mediated by extracellular K+ and maintains axonal health
Looser, Z. J., Faik, Z., Ravotto, L., Zanker, H. S., Jung, R. B., Werner, H. B., Ruhwedel, T., Möbius, W., Bergles, D. E., Barros, L. F., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-023-01558-3 · Cited by 120 · see citing works
Motor learning drives dynamic patterns of intermittent myelination on learning-activated axons
Bacmeister, C. M., Huang, R., Osso, L. A., Thornton, M. A., Conant, L., Chavez, A. R., Poleg-Polsky, A., & Hughes, E. G. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01169-4 · Cited by 113 · see citing works
Remyelination alters the pattern of myelin in the cerebral cortex
Orthmann-Murphy, J., Call, C. L., Molina-Castro, G. C., Hsieh, Y. C., Rasband, M. N., Calabresi, P. A., & Bergles, D. E. (2020) · eLife · doi:10.7554/elife.56621 · Cited by 111 · see citing works
The aging mouse brain: cognition, connectivity and calcium
Radulescu, C. I., Cerar, V., Haslehurst, P., Kopanitsa, M. V., & Barnes, S. J. (2021) · Cell Calcium · doi:10.1016/j.ceca.2021.102358 · Cited by 105 · see citing works
Cheng, Y.-J., Wang, F., Feng, J., Yu, B., Wang, B., Gao, Q. C., Wang, T.-Y., Hu, B., Gao, X., Chen, J., et al. (2024) · Brain · doi:10.1093/brain/awae029 · Cited by 102 · see citing works
Call, C. L., & Bergles, D. E. (2021) · Nature Communications · doi:10.1038/s41467-021-25035-2 · Cited by 96 · see citing works
Oligodendrogenesis and myelination regulate cortical development, plasticity and circuit function
Fletcher, J. L., Makowiecki, K., Cullen, C. L., & Young, K. M. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.03.017 · Cited by 76 · see citing works
Osso, L. A., & Hughes, E. G. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01642-2 · Cited by 80 · see citing works
Bretheau, F., Castellanos-Molina, A., Bélanger, D., Kusik, M., Mailhot, B., Boisvert, A., Vallières, N., Lessard, M., Gunzer, M., Liu, X., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33463-x · Cited by 67 · see citing works
Chapman, T. W., Olveda, G. E., Bame, X., Pereira, E., & Hill, R. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01271-1 · Cited by 65 · see citing works
Remyelination by surviving oligodendrocytes is inefficient in the inflamed mammalian cortex
Mezydlo, A., Treiber, N., Ullrich Gavilanes, E. M., Eichenseer, K., Ancău, M., Wens, A., Ares Carral, C., Schifferer, M., Snaidero, N., Misgeld, T., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.03.031 · Cited by 63 · see citing works
Self-citationHeterogeneity and regulation of oligodendrocyte morphology
Osanai, Y., Yamazaki, R., Shinohara, Y., & Ohno, N. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1030486 · Cited by 45 · see citing works
Thornton, M. A., Futia, G. L., Stockton, M. E., Budoff, S. A., Ramirez, A. N., Ozbay, B. N., Tzang, O., Kilborn, K., Poleg-Polsky, A., Restrepo, D., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01613-7 · Cited by 41 · see citing works
Oligodendrocytes and myelin: Active players in neurodegenerative brains?
Chen, J., Wang, F., Huang, N., Xiao, L., & Mei, F. (2022) · Developmental Neurobiology · doi:10.1002/dneu.22867 · Cited by 34 · see citing works
Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination
Chapman, T. W., Kamen, Y., Piedra, E. T., & Hill, R. A. (2024) · The Journal of Neuroscience · doi:10.1523/jneurosci.1794-23.2024 · Cited by 33 · see citing works
Lipid metabolism alterations in peripheral neuropathies
Silva, A., Prior, R. C., D’Antonio, M., Swinnen, J. V., & Bosch, L. V. D. (2025) · Neuron · doi:10.1016/j.neuron.2025.04.006 · Cited by 33 · see citing works
Palhol, J. S. C., Balia, M., Terán, F. S.-R., Labarchède, M., Gontier, É., & Battefeld, A. (2023) · Fluids and Barriers of the CNS · doi:10.1186/s12987-023-00425-4 · Cited by 30 · see citing works
Cai, Y., Pinheiro‐de‐Sousa, I., Slobodyanyuk, M., Chen, F., Huynh, T., Kanyo, J. E., Tang, P., Fuentes, L. A., Braker, A., Welch, R., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01973-8 · Cited by 32 · see citing works
Myelin is repaired by constitutive differentiation of oligodendrocyte progenitors
Mironova, Y. A., Dang, B., Heo, D., Xu, Y. K. T., Hsu, A. T.-W., von Bernhardi, J. E., Molina-Castro, G. C., Kim, A. A., LIN, J., Reich, D. S., et al. (2026) · Science · doi:10.1126/science.adu2896 · Cited by 26 · see citing works
Kislinger, G., Niemann, C., Rodriguez, L., Jiang, H., Fard, M. K., Snaidero, N., Schumacher, A.-M., Kerschensteiner, M., Misgeld, T., & Schifferer, M. (2023) · Methods in cell biology · doi:10.1016/bs.mcb.2023.01.012 · Cited by 20 · see citing works
Self-citationDella-Flora Nunes, G., Osso, L. A., Haynes, J. A., Conant, L., Thornton, M. A., Stockton, M. E., Brassell, K. A., Morris, A., Mancha Corchado, Y. I., Gaynes, J. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56092-6 · Cited by 19 · see citing works
Reconstructing neural circuits using multiresolution correlated light and electron microscopy
Friedrichsen, K. A., Ramakrishna, P., Hsiang, J.-C., Valkova, K., Kerschensteiner, D., & Morgan, J. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2022.753496 · Cited by 17 · see citing works
BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis
Bergner, C. G., van der Meer, F., Franz, J., Vakrakou, A., Würfel, T., Nessler, S., Schäfer, L., Nau-Gietz, C., Winkler, A., Lagumersindez-Denis, N., et al. (2025) · Brain · doi:10.1093/brain/awae293 · Cited by 16 · see citing works
“10,17 In summary, in combined work on MS patient tissues and experimental models of demyelination, we provide evidence that the cerebral cortex harbours a population of BCAS1+ pre-differentiated oligodendrocytes ready to myelinate in case of a demyelinating insult, such as occurs in MS.”
Clinical Applications of Myelin Plasticity for Remyelinating Therapies in Multiple Sclerosis
Pan, S., & Chan, J. R. (2021) · Annals of Neurology · doi:10.1002/ana.26196 · Cited by 16 · see citing works
Myelin sheaths in the central nervous system can withstand damage and dynamically remodel
Arafa, D., van de Korput, J., Braaker, P. N., Higgins, K. P., Meijns, N., Marshall-Phelps, K. L., Meng, J., Soong, D. Y. H., Scalia, E., Lathem, K., et al. (2026) · Science · doi:10.1126/science.adr4661 · Cited by 12 · see citing works
Schifferer, M., Snaidero, N., Djannatian, M., Kerschensteiner, M., & Misgeld, T. (2021) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2021.732506 · Cited by 12 · see citing works
Self-citationPaired vagus nerve stimulation drives precise remyelination and motor recovery after myelin loss
Huang, R., Carter, E., Hughes, E. G., & Welle, C. G. (2024) · Neuromodec journal. · doi:10.31641/nmj-fdgu6868 · Cited by 9 · see citing works
Lee, J. Y., Donato, S., Mack, A. F., Mattheus, U., Tromba, G., Longo, E., D’Amico, L., Mueller, S., Shiozawa, T., Bause, J., et al. (2024) · Frontiers in Physics · doi:10.3389/fphy.2023.1335285 · Cited by 8 · see citing works
Flower, G., Vorthmann, S., Fulton, D. J., & Hamilton, N. B. (2025) · Advances in neurobiology · doi:10.1007/978-3-031-87919-7_8 · Cited by 9 · see citing works
Pantazou, V., Roux, T., Moreira, V. O., Lubetzki, C., & Desmazières, A. (2021) · Life · doi:10.3390/life11030231 · Cited by 5 · see citing works
Chondroitin Sulphate Proteoglycan Axonal Coats in the Human Mediodorsal Thalamic Nucleus
Pantazopoulos, H., Hossain, N. M., Chelini, G., Durning, P. T., Barbas, H., Zikopoulos, B., & Berretta, S. (2022) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2022.934764 · Cited by 5 · see citing works
Label-free and fluorescence imaging of oligodendrocytes and myelin
Kamen, Y., Doty, M. E., Ciolkowski, M. E., Bame, X., Pietramale, A. N., Schain, A. J., Grutzendler, J., & Hill, R. (2025) · npj Imaging · doi:10.1038/s44303-025-00098-8 · Cited by 5 · see citing works
Kislinger, G., Fabig, G., Wehn, A. C., Rodriguez, L., Jiang, H., Niemann, C., Klymchenko, A. S., Plesnila, N., Misgeld, T., Müller‐Reichert, T., et al. (2024) · eLife · doi:10.7554/elife.90565.3 · Cited by 4 · see citing works
Self-citationKislinger, G., Fabig, G., Wehn, A. C., Rodriguez, L., Jiang, H., Niemann, C., Klymchenko, A. S., Plesnila, N., Misgeld, T., Müller‐Reichert, T., et al. (2023) · eLife · doi:10.7554/elife.90565.1 · Cited by 4 · see citing works
Self-citationRemyelination restores myelin content on distinct neuronal subtypes in the cerebral cortexPreprint
Call, C. L., & Bergles, D. E. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.17.431685 · Cited by 3 · see citing works
Bretheau, F., Castellanos-Molina, A., Mailhot, B., Kusik, M., Belanger, D., Lessard, M., Vallières, N., Liu, X., Quan, N., & Lacroix, S. (2021) · Research Square · doi:10.21203/rs.3.rs-580331/v1 · Cited by 2 · see citing works
Cortical and white matter myelination proceed in concert during early infancyPreprint
Zika, S., Chang, K., Orhon, A., Kruper, J., Tyagi, C., Yan, X., Tung, S. S., Kalanit Grill-spector, A., Rokem, A., & Grotheer, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.07.663449 · Cited by 2 · see citing works
Dying oligodendrocytes persist without mitochondriaPreprint
Bame, X., Gilani, S. Z., Kamen, Y., & Hill, R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.19.699752 · Cited by 2 · see citing works
Kislinger, G., Fabig, G., Wehn, A. C., Rodriguez, L., Jiang, H., Niemann, C., Klymchenko, A. S., Plesnila, N., Misgeld, T., Müller‐Reichert, T., et al. (2023) · eLife · doi:10.7554/elife.90565 · Cited by 1 · see citing works
Self-citationMartin, E., Aigrot, M., Frère, N., Lepaulmier, R., Stankoff, B., Boschert, U., Lubetzki, C., & Zalc, B. (2025) · Multiple Sclerosis Journal - Experimental Translational and Clinical · doi:10.1177/20552173251326913 · Cited by 1 · see citing works
Self-citationWobbly hedgehog syndrome- a progressive neurodegenerative disease
Doss, G. A., Radecki, D. Z., Kethireddy, A., Reilly, M. J., Pohly, A. E., August, B. K., Duncan, I. D., & Samanta, J. (2023) · Experimental Neurology · doi:10.1016/j.expneurol.2023.114520 · Cited by 1 · see citing works
Sun, F., Huang, X., Wang, H., Lin, B., Li, H., Wang, X., & Liu, Q. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155788 · Cited by 1 · see citing works
Kislinger, G., Fabig, G., Wehn, A. C., Rodriguez, L., Jiang, H., Niemann, C., Klymchenko, A. S., Plesnila, N., Misgeld, T., Müller‐Reichert, T., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.12.547497 · Cited by 1 · see citing works
Self-citationCheng, G. W., Ma, I. W.-T., Huang, J., Yeung, S. H., Ho, P., Chen, Z., Mak, H. K., Herrup, K., Chan, K. W. Y., & Tse, K. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.24.547147 · Cited by 1 · see citing works
Ronzano, R., Perrot, C., Mazuir, E., Thétiot, M., Aigrot, M., Stheneur, P., Lejeune, F., Stankoff, B., Lubetzki, C., Sol‐Foulon, N., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.16.585168 · Cited by 1 · see citing works
Späte, E., Higgins, K. P., Kim, Y., Mangana, C., Komarek, L., Teymouri, M., Gerwig, U. C., Melzer, S., Sadowski, B., Ruhwedel, T., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.05.692364 · Cited by 1 · see citing works
An organotypic neocortical slice culture for studying neuroglial interactionsPreprint
Higgins, K. P., Naqib, V. A. B. A., Mayo, P., Lodder, B., Masuda, T., Amann, L., Prinz, M., & Kole, M. H. P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.15.725074 · Cited by 1 · see citing works
Age and axon-specific forms of cortical remyelination by divergent populations of NG2-gliaPreprint
Chapman, T. W., Olveda, G. E., Pereira, E., & Hill, R. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.12.09.414755
Ajanović, Z., Dervišević, L., Hasanbegović, I., Dervišević, A., Lujinović, A., Šahinović, M., Biščević-Tokić, J., Jesenković, D. A., & Dervišević, E. (2024) · World Congress on Medical Physics and Biomedical Engineering, September 7 - 12, 2009, Munich, Germany · doi:10.1007/978-3-031-49068-2_1
Kislinger, G., Fabig, G., Wehn, A. C., Rodriguez, L., Jiang, H., Niemann, C., Klymchenko, A. S., Plesnila, N., Misgeld, T., Müller‐Reichert, T., et al. (2024) · eLife · doi:10.7554/elife.90565.2
Self-citationKislinger, G., Fabig, G., Wehn, A. C., Rodriguez, L., Jiang, H., Niemann, C., Klymchenko, A. S., Plesnila, N., Misgeld, T., Müller‐Reichert, T., et al. (2024) · eLife · doi:10.7554/elife.90565.2.sa0
Self-citationYuan, Y., Zhu, L., Wang, M., Fu, P., Zhang, H., Chu, B., Yang, F., Zhao, X., Zhang, Z., & Wang, X. (2025) · ACS Photonics · doi:10.1021/acsphotonics.5c01095
Integration of Peripheral and Central Immune Alteration in Neurodegeneration
Wali, Z., Pinky, Neha, & Parvez, S. (2026) · Springer eBooks · doi:10.1007/978-981-95-5088-3_4
Zi, H., Goldbrunner, A., Askari, S., Eichenseer, K., Misgeld, T., & Snaidero, N. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.15.705957
Self-citationLocal demyelination rekindles oligodendrocyte precursor dynamics and remyelination in old agePreprint
Eichenseer, K., Askari, S., Shkurti, L., Misgeld, T., & Snaidero, N. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.15.705983
Self-citationEarly demyelination by off-target complement injury in a mouse model of neuromyelitis opticaPreprint
Kenet, S., Herwerth, M., Askari, S., Eichenseer, K., Dornmair, K., Qin, X., Stadelmann, C., Bennett, J. L., Hemmer, B., & Misgeld, T. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.13.711636
Self-citationRight on cue—Neuronal signals guide myelination in the developing cortex
Zhang, A., & Chan, J. R. (2026) · Developmental Cell · doi:10.1016/j.devcel.2026.05.009
Cortical and white matter myelination proceed in concert during early infancy
Zika, S., Chang, K., Orhon, A., Kruper, J., Tyagi, C., Yan, X., Tung, S. S., Kalanit Grill-spector, A., Rokem, A., & Grotheer, M. (2026) · Nature Communications · doi:10.1038/s41467-026-73366-9 · Cited by 2 · see citing works
- Authors
- Snaidero, N., Schifferer, M., Mezydlo, A., Zalc, B., Kerschensteiner, M., & Misgeld, T.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Centre National de la Recherche Scientifique (FR)
- Munich Cluster for Systems Neurology (DE)
- Corresponding author
- Snaidero, Nicolas
- Venue
- Nature Communications
- Published
- 2020-09-29
- Volume
- 11
- Issue
- 1
- Pages
- 4901-4901
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7525521
- OpenAlex
- W3091095424
- Cited by
- 63
- References
- 83
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 17 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 2
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion, other-oa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- European Commission (390857198, 2007–2013, HORIZON2020, 825759, 408885537, FP/2007/2013)
- Deutsche Forschungsgemeinschaft (FOR2879, 426715780, TRR274/1 2020, EXC 2145, CRC 870, FP/2007-2013, TRR-274, and Z01, EXC114, 774/5‐1, 390857198, TRR128, Ke 774/5-1/Mi 694/7-1, Mi694/7‐1, 825759, projects B02, CIPSM EXC114, Project Z01, 408885537, Mi 694/8-1)
- Agence Nationale de la Recherche (CRC870, FP/2007-2013, ANR-11-INBS-0011, ANR-18-CE92-0004)
- Bundesministerium für Bildung und Forschung (825759, EXC 114)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Deutschen Multiple Sklerose Gesellschaft
- FP7 Ideas: European Research Council (616791, 310932)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- remyelination, demyelination, oligodendrocytes, cortical axons, internodes, circuit plasticity, mouse cortex
- MeSH terms
- Remyelination, Animals, Axons, Cerebral Cortex, Female, Male, Mice, Inbred C57BL, Myelin Sheath, Oligodendroglia, Mice
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