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Cortical neurons exhibit diverse myelination patterns that scale between mouse brain regions and regenerate after demyelination

Call, Cody L., Bergles, Dwight E.·2021·Nature Communications
DOI 10.1038/s41467-021-25035-2PMC PMC8346564
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Abstract

Axons in the cerebral cortex show a broad range of myelin coverage. Oligodendrocytes establish this pattern by selecting a cohort of axons for myelination; however, the distribution of myelin on distinct neurons and extent of internode replacement after demyelination remain to be defined. Here we show that myelination patterns of seven distinct neuron subtypes in somatosensory cortex are influenced by both axon diameter and neuronal identity. Preference for myelination of parvalbumin interneurons was preserved between cortical areas with varying myelin density, suggesting that regional differences in myelin abundance arises through local control of oligodendrogenesis. By imaging loss and regeneration of myelin sheaths in vivo we show that myelin distribution on individual axons was altered but overall myelin content on distinct neuron subtypes was restored. Our findings suggest that local changes in myelination are tolerated, allowing regenerated oligodendrocytes to restore myelin content on distinct neurons through opportunistic selection of axons.

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Figures

Fig. 1 High-resolution tracing of distinct axon populations reveals discontinuous myelination patterns. a Schematic of the cortex indicating the sources of axons from the distinct neuronal populations investigated. Note that the axons depicted may not necessarily be the primary projection of each neuron. b A horizontal section of the entire cortical flatmount and schematic representing approximate cortical areas. N = 4 mice per neuron subtype. c Schematic of experimental design. Traces (black dotted line) of fluorescently labeled axons (red) were used to trace corresponding MBP-immunostained myelin sheaths (cyan). d–I Full reconstructions of traced PV (d), RBP4 (g), and VM (j) axons within cortical layer I and their associated dimensions (PLM, percent length myelinated). Black myelin sheaths are overlaid on colored axons. Labeled rectangles highlight example myelinated segments of PV (e, f), RBP4 (h, i), and VM (k, l) axons. Yellow arrowheads indicate the ends of myelin segments (MBP immunoreactivity). n = 60 (PV), 62 (VM), 60 (SOM), 61 (PO), 60 (NXPH4), 78 (RBP4), 60 (NTSR1) axons. Scale bars, b, 1 mm; d, g, j: 100 μm; e, f, h, i, k, l: 10 μm. OB olfactory bulb, lot lateral olfactory tract, MOp/MOs primary/secondary motor, ACA anterior cingulate area, GU/VISC gustatory/visceral, SSp/SSs primary/secondary somatosensory, PTLp posterior parietal association, AUD auditory, RSP retrosplenial, VISp primary visual, ECT/PERI ectorhinal/perirhinal, TEa temporal association.
Fig. 1 High-resolution tracing of distinct axon populations reveals discontinuous myelination patterns. a Schematic of the cortex indicating the sources of axons from the distinct neuronal populations investigated. Note that the axons depicted may not necessarily be the primary projection of each neuron. b A horizontal section of the entire cortical flatmount and schematic representing approximate cortical areas. N = 4 mice per neuron subtype. c Schematic of experimental design. Traces (black dotted line) of fluorescently labeled axons (red) were used to trace corresponding MBP-immunostained myelin sheaths (cyan). d–I Full reconstructions of traced PV (d), RBP4 (g), and VM (j) axons within cortical layer I and their associated dimensions (PLM, percent length myelinated). Black myelin sheaths are overlaid on colored axons. Labeled rectangles highlight example myelinated segments of PV (e, f), RBP4 (h, i), and VM (k, l) axons. Yellow arrowheads indicate the ends of myelin segments (MBP immunoreactivity). n = 60 (PV), 62 (VM), 60 (SOM), 61 (PO), 60 (NXPH4), 78 (RBP4), 60 (NTSR1) axons. Scale bars, b, 1 mm; d, g, j: 100 μm; e, f, h, i, k, l: 10 μm. OB olfactory bulb, lot lateral olfactory tract, MOp/MOs primary/secondary motor, ACA anterior cingulate area, GU/VISC gustatory/visceral, SSp/SSs primary/secondary somatosensory, PTLp posterior parietal association, AUD auditory, RSP retrosplenial, VISp primary visual, ECT/PERI ectorhinal/perirhinal, TEa temporal association.CC BY · PubMed Central
Fig. 2 Different neuronal subtypes exhibit diverse myelination profiles. a Myelination profiles for the six neuronal subtypes examined in this study with myelinated axons. Each plot is a histogram of pooled data across four animals for each subtype representing the proportion of axons with different percent length myelinated in 10% bins (n = 60 (PV), 62 (VM), 60 (SOM), 61 (PO), 60 (NXPH4), 78 (RBP4), 60 (NTSR1) axons). See Table 2 for statistical comparisons. b Cumulative distribution plot of data in (a), showing three distinct classes of myelination patterns. c Proportions of axons myelinated per neuronal subtype (N = 4 mice for each subtype) ****p < 0.0001. d Lengths for each axon traced (same Ns as in (a)). e Average internode lengths per axon for each neuronal subtype (n = 38 (PV), 41 (VM), 18 (SOM), 14 (PO), 6 (NXPH4), 2 (NTSR1) axons) (ns, not significant, p = 0.514, one-way ANOVA). f Violin plots of the lengths of unmyelinated axon segments (axonal distance between two consecutive MBP segments) for the top four most strongly myelinated neuronal subtypes. Unmyelinated segments of <5 μm (typical maximum length of nodes of Ranvier) are most common, while unmyelinated segments between 5 and 150 μm distributed broadly. g Cumulative distribution plot of all non-nodal (>5 μm) unmyelinated segments from data in f. All error bars represent the standard error of the mean. Source data and statistical tests are provided as a Source Data file.
Fig. 2 Different neuronal subtypes exhibit diverse myelination profiles. a Myelination profiles for the six neuronal subtypes examined in this study with myelinated axons. Each plot is a histogram of pooled data across four animals for each subtype representing the proportion of axons with different percent length myelinated in 10% bins (n = 60 (PV), 62 (VM), 60 (SOM), 61 (PO), 60 (NXPH4), 78 (RBP4), 60 (NTSR1) axons). See Table 2 for statistical comparisons. b Cumulative distribution plot of data in (a), showing three distinct classes of myelination patterns. c Proportions of axons myelinated per neuronal subtype (N = 4 mice for each subtype) ****p < 0.0001. d Lengths for each axon traced (same Ns as in (a)). e Average internode lengths per axon for each neuronal subtype (n = 38 (PV), 41 (VM), 18 (SOM), 14 (PO), 6 (NXPH4), 2 (NTSR1) axons) (ns, not significant, p = 0.514, one-way ANOVA). f Violin plots of the lengths of unmyelinated axon segments (axonal distance between two consecutive MBP segments) for the top four most strongly myelinated neuronal subtypes. Unmyelinated segments of <5 μm (typical maximum length of nodes of Ranvier) are most common, while unmyelinated segments between 5 and 150 μm distributed broadly. g Cumulative distribution plot of all non-nodal (>5 μm) unmyelinated segments from data in f. All error bars represent the standard error of the mean. Source data and statistical tests are provided as a Source Data file.CC BY · PubMed Central
Fig. 3 PV axon myelination patterns are consistent across cortical regions. a Representative binarized images of MBP immunostaining from all cortical regions analyzed (SS somatosensory, AUD auditory, VIS visual, MOs secondary motor, TEa temporal association area). Scale bars, 50 μm. b Example axon and myelin traces from each cortical region analyzed from a single PV-Cre; Ai9 flatmount. Red, axons; white, myelin. Scale bars, 50 μm. c Cumulative distribution plot of PLM from all axons traced in each region in a (SS, n = 60 axons from 4 mice; VIS, n = 60 axons from 4 mice; AUD, n = 59 axons from 4 mice; MOs, N = 30 axons from 2 mice; TEa, N = 37 axons from 3 mice). See Table 3 for PLM distribution statistics. d Scaled prevalence (MBP intensity/proportion of axons myelinated) of PV axon myelination across all regions analyzed (same Ns as in c) (ns not significant, p = 0.24, Kruskal–Wallis ANOVA). Error bars represent the standard error of the mean. Source data and statistical tests are provided as a Source Data file.
Fig. 3 PV axon myelination patterns are consistent across cortical regions. a Representative binarized images of MBP immunostaining from all cortical regions analyzed (SS somatosensory, AUD auditory, VIS visual, MOs secondary motor, TEa temporal association area). Scale bars, 50 μm. b Example axon and myelin traces from each cortical region analyzed from a single PV-Cre; Ai9 flatmount. Red, axons; white, myelin. Scale bars, 50 μm. c Cumulative distribution plot of PLM from all axons traced in each region in a (SS, n = 60 axons from 4 mice; VIS, n = 60 axons from 4 mice; AUD, n = 59 axons from 4 mice; MOs, N = 30 axons from 2 mice; TEa, N = 37 axons from 3 mice). See Table 3 for PLM distribution statistics. d Scaled prevalence (MBP intensity/proportion of axons myelinated) of PV axon myelination across all regions analyzed (same Ns as in c) (ns not significant, p = 0.24, Kruskal–Wallis ANOVA). Error bars represent the standard error of the mean. Source data and statistical tests are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 A combination of diameter and neuronal subtype predicts myelination status. a Example segment of an axon imaged at high resolution for diameter analysis and corresponding MBP immunostaining. A small rectangle was used to plot a profile of the average gray value intensity profile across a few μm of the axon (result shown in (b)) to determine its diameter by the full width at half maximum (FWHM). Scale bar, 2 μm. b Plot of the average profile across the axon in (a). Each point represents the average gray value of a single pixel across the representative lines in (a), top panel. c Histograms of the proportions of axons myelinated (colored bars) or unmyelinated (gray bars) for different axon diameters. Note the color of overlapping bars is additive. d As in (c), pooled across all neuronal subtypes. e Probability distributions for the myelination probability of each neuronal subtype given a certain diameter. Points are individual axons myelinated. Intermediate probabilities (not 1 or 0) represent the average myelination status across at least three positions along the axon surveyed to calculate the average diameter. See text for details on probability functions. Source data and statistical tests are provided as a Source Data file.
Fig. 4 A combination of diameter and neuronal subtype predicts myelination status. a Example segment of an axon imaged at high resolution for diameter analysis and corresponding MBP immunostaining. A small rectangle was used to plot a profile of the average gray value intensity profile across a few μm of the axon (result shown in (b)) to determine its diameter by the full width at half maximum (FWHM). Scale bar, 2 μm. b Plot of the average profile across the axon in (a). Each point represents the average gray value of a single pixel across the representative lines in (a), top panel. c Histograms of the proportions of axons myelinated (colored bars) or unmyelinated (gray bars) for different axon diameters. Note the color of overlapping bars is additive. d As in (c), pooled across all neuronal subtypes. e Probability distributions for the myelination probability of each neuronal subtype given a certain diameter. Points are individual axons myelinated. Intermediate probabilities (not 1 or 0) represent the average myelination status across at least three positions along the axon surveyed to calculate the average diameter. See text for details on probability functions. Source data and statistical tests are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 Overall subtype-specific myelination patterns are restored despite remodeling of individual axons. a Experimental timeline. b Example image from a PV-Cre; Ai9 mouse injected with AAV-EGFP into thalamic VM. SCoRe signal from the same region is overlaid on top of the fluorescent dual-colored image acquired with two-photon microscopy. Right panel shows a few myelinated axons of both neuronal subtypes extracted from the left panel. Scale bar, 30 μm. c Axon traces from an example 3-week cuprizone timecourse. Left panel shows PV axon traces (white) and the associated myelin segments traced from the corresponding SCoRe image (magenta). Right panel shows same region with the surviving baseline axon traces overlaid with the positions of SCoRe segments traced at 5 weeks of recovery (green). Yellow arrowhead indicates example axon that had a net loss in length myelinated, while the cyan arrowhead indicates a portion of axon which gained myelination. Scale bar, 100 μm. d, Pooled data from remyelinated PV and VM axons showing the net change in PLM between baseline and 5 weeks recovery where –100% represents an axon going from fully myelinated to fully unmyelinated, and +100% represents an axon that went from unmyelinated to fully myelinated. Dashed lines bordering 0% (solid line) reflect the tracing error as calculated by the average negative ΔPLM from axons of the respective subtype traced in control animals (Supplemental Fig. 2, see text for additional details). e and f Scatter plots showing the relationship between the PLM of an axon at baseline and its PLM at five weeks recovery from cuprizone for PV axons (e) and VM axons (f). The solid red line (y = x) is the identity line (no change between baseline and 5 weeks recovery) and the red dashed lines are the error based on control traces (as in (d)). The black line is the best fit found by regression and the black dotted lines are the 95% confidence bounds. g and h Data as plotted in (e, f) readjusted to include the ΔPLM of each axon in the linear model (adjusted formula: PLM at 5 weeks recovery ~ 1 + baseline PLM + baseline PLM: ΔPLM; g, PV axons; h VM axons). The solid line is the fit and dotted lines are the 95% confidence bounds. Source data and statistical tests are provided as a Source Data file.
Fig. 5 Overall subtype-specific myelination patterns are restored despite remodeling of individual axons. a Experimental timeline. b Example image from a PV-Cre; Ai9 mouse injected with AAV-EGFP into thalamic VM. SCoRe signal from the same region is overlaid on top of the fluorescent dual-colored image acquired with two-photon microscopy. Right panel shows a few myelinated axons of both neuronal subtypes extracted from the left panel. Scale bar, 30 μm. c Axon traces from an example 3-week cuprizone timecourse. Left panel shows PV axon traces (white) and the associated myelin segments traced from the corresponding SCoRe image (magenta). Right panel shows same region with the surviving baseline axon traces overlaid with the positions of SCoRe segments traced at 5 weeks of recovery (green). Yellow arrowhead indicates example axon that had a net loss in length myelinated, while the cyan arrowhead indicates a portion of axon which gained myelination. Scale bar, 100 μm. d, Pooled data from remyelinated PV and VM axons showing the net change in PLM between baseline and 5 weeks recovery where –100% represents an axon going from fully myelinated to fully unmyelinated, and +100% represents an axon that went from unmyelinated to fully myelinated. Dashed lines bordering 0% (solid line) reflect the tracing error as calculated by the average negative ΔPLM from axons of the respective subtype traced in control animals (Supplemental Fig. 2, see text for additional details). e and f Scatter plots showing the relationship between the PLM of an axon at baseline and its PLM at five weeks recovery from cuprizone for PV axons (e) and VM axons (f). The solid red line (y = x) is the identity line (no change between baseline and 5 weeks recovery) and the red dashed lines are the error based on control traces (as in (d)). The black line is the best fit found by regression and the black dotted lines are the 95% confidence bounds. g and h Data as plotted in (e, f) readjusted to include the ΔPLM of each axon in the linear model (adjusted formula: PLM at 5 weeks recovery ~ 1 + baseline PLM + baseline PLM: ΔPLM; g, PV axons; h VM axons). The solid line is the fit and dotted lines are the 95% confidence bounds. Source data and statistical tests are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 PV axons are not preferentially remyelinated in regions with reduced oligodendrogenesis. a In vivo image of layer II/III somatosensory cortex acquired from a Mobp-EGFP; PV-Cre; Ai9 mouse. Yellow arrowheads identify example sheaths surrounding PV axons, while magenta arrowheads identify sheaths surrounding non-PV axons (“other”). Scale bar, 10 μm. b Example maximum XZ projection of an ROI (100 μm × 100 μm × 100 μm) from layer II/III showing all traced internodes within the volume at baseline (left) and at 5 weeks recovery from cuprizone (right). Red, sheaths surrounding PV axons; black, sheaths surrounding “other” axons. Scale bar, 20 μm. c Total number of internodes within an ROI at baseline vs. 5 weeks recovery (n = 10 ROIs (up to 2 ROIs from 2 imaged regions across 3 mice)) (**p = 0.003, paired two-tailed t-test). d Percent of traced sheaths surrounding PV axons within an ROI at baseline vs. 5 weeks recovery, same Ns as in c (ns, not significant, p = 0.068, paired two-tailed t-test). All error bars represent standard error of the mean. Source data and statistical tests are provided as a Source Data file.
Fig. 6 PV axons are not preferentially remyelinated in regions with reduced oligodendrogenesis. a In vivo image of layer II/III somatosensory cortex acquired from a Mobp-EGFP; PV-Cre; Ai9 mouse. Yellow arrowheads identify example sheaths surrounding PV axons, while magenta arrowheads identify sheaths surrounding non-PV axons (“other”). Scale bar, 10 μm. b Example maximum XZ projection of an ROI (100 μm × 100 μm × 100 μm) from layer II/III showing all traced internodes within the volume at baseline (left) and at 5 weeks recovery from cuprizone (right). Red, sheaths surrounding PV axons; black, sheaths surrounding “other” axons. Scale bar, 20 μm. c Total number of internodes within an ROI at baseline vs. 5 weeks recovery (n = 10 ROIs (up to 2 ROIs from 2 imaged regions across 3 mice)) (**p = 0.003, paired two-tailed t-test). d Percent of traced sheaths surrounding PV axons within an ROI at baseline vs. 5 weeks recovery, same Ns as in c (ns, not significant, p = 0.068, paired two-tailed t-test). All error bars represent standard error of the mean. Source data and statistical tests are provided as a Source Data file.CC BY · PubMed Central

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Metadata

Authors
Call, C. L., & Bergles, D. E.
ORCID
Bergles, Dwight E.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-08-06
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-25035-2
PMC
PMC8346564
Cited by
95
References
12
Language
en
Licence
Funders
Dr. Miriam and Sheldon G Adelson Medical Research Foundation

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CoChat. (2026). Citation check: Cortical neurons exhibit diverse myelination patterns that scale between mouse brain regions and regenerate after demyelination. https://app.cochat.ai/papers/10.1038/s41467-021-25035-2
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Call, C. L., & Bergles, D. E. (2021). Cortical neurons exhibit diverse myelination patterns that scale between mouse brain regions and regenerate after demyelination. Nature Communications. https://doi.org/10.1038/s41467-021-25035-2