Remyelination alters the pattern of myelin in the cerebral cortex
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Abstract
Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can be restored by regenerating oligodendrocytes from resident progenitors; however, it is not known whether regeneration restores the complex myelination patterns in cortical circuits. Here, we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. These longitudinal studies revealed that the pattern of myelination in cortex changed dramatically after regeneration, as new oligodendrocytes were formed in different locations and new sheaths were often established along axon segments previously lacking myelin. Despite the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired in deeper cortical layers that experienced higher gliosis. Repeated reorganization of myelin patterns in MS may alter circuit function and contribute to cognitive decline.
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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 [8]
The Results section (‘Layer specific differences in cortical remyelination’; page unavailable) reports that responses to demyelination vary across cortical depths and may affect recovery, supporting a limited role for location. But the Discussion (‘Implications for myelin repair and cognitive function’; page unavailable) says the study examined only the somatosensory cortex of young adult mice and does not know whether replacement varies with age or in other cortical regions. The paper does not establish disease duration as a determinant of remyelination efficacy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThere are no significant changes in OPC number in the deep cortex following cuprizone or recovery.
“Similar to our prior study (Orthmann‐Murphy et al. 2020), we found no significant changes in OPC number in the deep cortex (Figure 1G, also see Figure S1C).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
In Results, under “Layer specific differences in cortical remyelination” (page unavailable), the paper reports no evidence of persistent OPC depletion during recovery in deeper cortical layers (p=0.086). That supports the recovery portion, but the passage does not establish that OPC number was unchanged immediately following cuprizone treatment. (LLM, conf=0.82)
Experimental — accuracy not yet measuredBCAS1 + GFP+ oligodendrocytes represent a relatively more mature differentiating oligodendrocyte state than BCAS1 + GFP- cells.
“BCAS1 + GFP+ oligodendrocytes should represent a relatively more mature differentiating oligodendrocyte state than BCAS1 + GFP‐ cells (Chapman et al. 2024; Hughes et al. 2018; Orthmann‐Murphy et al. 2020).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
The Materials and methods section describes Mobp-EGFP imaging as following newly formed mature oligodendrocytes, supporting the use of GFP expression as an indicator of maturity in this mouse model. Our copy does not address BCAS1 or compare BCAS1+ GFP+ cells with BCAS1+ GFP− cells, so it does not establish the claimed relative differentiation state. (LLM, conf=0.82)
Experimental — accuracy not yet measuredNew oligodendrocytes formed after cessation of the cuprizone-supplemented diet, with a peak rate of formation at 2 weeks post-cuprizone.
“We found that new oligodendrocytes formed after cessation of the cuprizone‐supplemented diet, with a peak rate of formation at 2 weeks post‐cuprizone (“early” recovery).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
The Results sections on inefficient regeneration and layer-specific remyelination report that new oligodendrocytes appeared rapidly after cuprizone cessation and that replacement peaked during the first two weeks of recovery. They do not establish that the peak rate occurred specifically at the two-week time point. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA blinded observer quantified the number of NG2+, GFAP+, Iba1+, ASPA+, BCAS1+, and GFP+ cells within each region.
“For cell counts, a blinded observer quantified the number of NG2+, GFAP+, Iba1+, ASPA+, BCAS1+, and GFP+ cells within each 500 μm × 750 μm region using a custom counting macro in FIJI/ImageJ (Orthmann‐Murphy et al. 2020).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
The Immunohistochemistry methods (page unavailable) report that a blinded observer counted NG2+, GFAP+, and EGFP+ cells, supporting the core counting procedure. They specify 425 μm × 500 μm regions, not 500 μm × 750 μm regions, and do not report blinded counts of Iba1+, ASPA+, or BCAS1+ cells. The Image processing and analysis methods mention FIJI/ImageJ, but not a custom counting macro for these counts. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Even in the presence of Csf1r inhibitor, deep cortical reactive astrocytes persistently upregulate GFAP.
“Similar to our previous findings (Orthmann‐Murphy et al. 2020), even in the presence of Csf1r inhibitor, deep cortical reactive astrocytes persistently upregulate GFAP (Figure S5B).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
The Results section, “Layer specific differences in cortical remyelination” (page unavailable), reports that GFAP expression in deeper cortical astrocytes remained elevated throughout recovery and that the cells retained a reactive morphology. It does not report this finding in the presence of a Csf1r inhibitor, so the inhibitor condition is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDeep cortical oligodendrogenesis was selectively impaired, with only ~55% of the baseline oligodendrocyte population replaced after 9 weeks of recovery in the deepest cortical zone examined (200-300 μm).
“In our prior in vivo imaging study, however, we showed that deep cortical oligodendrogenesis was selectively impaired, with only ~55% of the baseline oligodendrocyte population replaced after 9 weeks of recovery in the deepest cortical zone examined (200–300 μm; Orthmann‐Murphy et al. 2020).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
Oligodendrocyte regeneration in the somatosensory cortex is incomplete, driven primarily by inefficient oligodendrocyte replacement in deep cortical regions.
“We found that oligodendrocyte regeneration in the somatosensory cortex is incomplete, and this is driven primarily by inefficient oligodendrocyte replacement in deep cortical regions.”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
Nearly all oligodendrocytes present at 5 weeks recovery were newly formed.
“Nearly all oligodendrocytes present at 5 weeks (“late”) recovery were newly formed.”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
Deep cortical astrocytes persistently upregulate GFAP following cuprizone administration.
“We previously showed that deep cortical astrocytes persistently upregulate GFAP following cuprizone administration (Orthmann‐Murphy et al. 2020);”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
Loss and formation of oligodendrocytes overlapped in early recovery.
“Due to the exquisite spatial and temporal resolution of in vivo imaging, we also showed that the loss and formation of oligodendrocytes overlapped in early recovery, a finding that is difficult to appreciate by immunostaining alone.”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
Many of the early recovery BCAS1+ cells formed in PLX-treated mice become stably incorporated into the late recovery cortex.
“Given that deep cortical ASPA+ oligodendrocytes recovered to baseline levels at late recovery only in PLX‐treated mice, but not cuprizone‐only treated mice (Figure 5), and late recovery oligodendrocytes are predominantly represented by newly formed cells (Orthmann‐Murphy et al. 2020), we suspect that many of these early recovery BCAS1+ cells formed in PLX‐treated mice become stably incorporated in”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
Deep cortical astrocytes also become persistently reactive.
“In addition, deep cortical astrocytes also become persistently reactive (Figure S4; Orthmann‐Murphy et al. 2020) and likely influence deep cortical reactive microglia function (Liddelow and Barres 2017).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
There are likely overlapping pathogenic roles of cortical reactive microglia, especially at early recovery.
“In fact, there are likely overlapping pathogenic roles of cortical reactive microglia, especially at early recovery (Orthmann‐Murphy et al. 2020).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Orthmann‐Murphy et al. 2020
The Results section on layer-specific cortical remyelination discusses reactive astrocytes during recovery, not reactive microglia. The Discussion on cortical OPC regeneration considers possible effects of inflammation but does not assign overlapping pathogenic roles to microglia, particularly in early recovery. Searches for reactive microglia and early-recovery inflammation found no passage addressing that claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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Periods of synchronized myelin changes shape brain function and plasticity
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FAST: Fast, Free, Consistent, and Unsupervised Oligodendrocyte Segmentation and Tracking System
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- Authors
- Orthmann-Murphy, J., Call, C. L., Molina-Castro, G. C., Hsieh, Y. C., Rasband, M. N., Calabresi, P. A., & Bergles, D. E.
- Affiliations
- The Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, United States
- Johns Hopkins University (US)
- Baylor College of Medicine (US)
- Corresponding author
- Bergles, Dwight E
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-05-27
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7292648
- OpenAlex
- W3029244827
- Cited by
- 111
- References
- 85
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 20 · 2023: 22 · 2022: 15 · 2021: 20 · 2020: 6
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Conrad N. Hilton Foundation
- National Multiple Sclerosis Society
- National Science Foundation (Graduate Research Fellowship)
- National Institutes of Health (NS051509, NS050274, NS080153)
- Dr. Miriam and Sheldon G Adelson Medical Research Foundation
- 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, oligodendrogenesis, cerebral cortex, somatosensory cortex, multiple sclerosis, gliosis, cortical layers, cognitive decline, in vivo two-photon imaging
- MeSH terms
- Remyelination, Animals, Axons, Female, Humans, Kinetics, Male, Mice, Inbred C57BL, Multiple Sclerosis, Myelin Sheath, Oligodendroglia, Somatosensory Cortex, Mice
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