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Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain

Abstract

Axonal myelin increases neural processing speed and efficiency. It is unknown whether patterns of myelin distribution are fixed or whether myelinating oligodendrocytes are continually generated in adulthood and maintain the capacity for structural remodeling. Using high-resolution, intravital label-free and fluorescence optical imaging in mouse cortex, we demonstrate lifelong oligodendrocyte generation occurring in parallel with structural plasticity of individual myelin internodes. Continuous internode formation occurred on both partially myelinated and unmyelinated axons, and the total myelin coverage along individual axons progressed up to two years of age. After peak myelination, gradual oligodendrocyte death and myelin degeneration in aging were associated with pronounced internode loss and myelin debris accumulation within microglia. Thus, cortical myelin remodeling is protracted throughout life, potentially playing critical roles in neuronal network homeostasis. The gradual loss of internodes and myelin degeneration in aging could contribute significantly to brain pathogenesis.

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Fig. 1: SCoRe microscopy for label-free myelin imaging.
Fig. 2: Lifelong changes in cortical myelin and oligodendrocyte density.
Fig. 3: Protracted addition of new internodes and long-term myelin sheath plasticity.
Fig. 4: Evidence of myelin plasticity through internode remodeling.
Fig. 5: Lifelong changes in myelin coverage along single cortical axons.
Fig. 6: Continuous myelin deposition along partially myelinated axons.
Fig. 7: Oligodendrocyte and myelin degeneration in advanced aging.
Fig. 8: Myelin debris accumulate in microglia in advanced aging.

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Acknowledgements

We thank A. Nishiyama (University of Connecticut) and F. Kirchhoff (University of Saarland) for sharing PLP-DsRed transgenic mice. This work was supported by the following grants from the National Institutes of Health: R21NS087511, R21NS088411 and R01NS089734 to J.G.; T32NS007224 andT32GM007205 to A.M.L.; and F32NS090820 and K99NS099469 to R.A.H. This work was also supported in part by a research grant from the National Multiple Sclerosis Society (#RR-1602-07686) to J.G. and a New Vision Award through the Donors Cure Foundation to R.A.H.

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R.A.H. and J.G. conceived of and designed all experiments. R.A.H. performed all in vivo imaging and data analysis. A.M.L. performed immunostaining and some fixed-tissue imaging. R.A.H. and J.G. wrote the manuscript.

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Correspondence to Robert A. Hill or Jaime Grutzendler.

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Integrated supplementary information

Supplementary Figure 1 Spectral confocal reflection (SCoRe) microscopy allows label-free myelin imaging in vivo and in fixed tissues.

(a) In vivo image captured from layer I of the mouse somatosensory cortex showing the separated reflective wavelengths of single myelin fibers using SCoRe microscopy. All other SCoRe images were combined into a single color. (b) In vivo image of an oligodendrocyte in the cortex of a transgenic mouse with DsRed fluorescent protein expressed exclusively in mature oligodendrocytes (Plp-DsRed) showing the specificity of the SCoRe signal for portions of the oligodendrocyte forming compact myelin (arrows) and not the proximal processes extending from the oligodendrocyte cell body (arrowheads). (c) Confocal images in fixed brain slices showing the overlap of SCoRe signal with that of immunofluorescence for myelin basic protein (MBP). (d) Confocal images showing the beginning portion of myelination at the axon initial segment (AIS) visualized with SCoRe microscopy and with MBP staining in the top image (arrow) as well as a break in myelination at a node of Ranvier in the bottom image (arrowhead). Each image is representative of at least three locations in at least three animals.

Supplementary Figure 2 Overlap between fluorescent and SCoRe signals for in vivo detection of myelin.

(a) In vivo image captured from layer I of the somatosensory cortex in a transgenic mouse with membrane tethered EGFP expressed exclusively in mature oligodendrocytes (Cnp-mEGFP) showing the overlap between fluorescence and SCoRe. Single oligodendrocyte cell soma can be seen in the fluorescence (yellow arrowheads) but not the SCoRe image due to the specificity of SCoRe for myelin. (b) The number of myelin segments intersecting the yellow line can be quantified as a proxy for equivalent myelin detection between mEGFP and SCoRe as shown in Fig. 1g. (c) Reliable detection of myelin segment borders (arrowheads) using both fluorescence and SCoRe as shown in Fig. 1g. (d) Classification of myelin segments as paired or unpaired for quantification of internode plasticity as shown in Fig. 3h-i. Each image is representative of at least three locations in at least three animals.

Supplementary Figure 3 Lifelong changes in layer I oligodendrocyte and myelin density.

(a) Oligodendrocyte (Plp-DsRed) and SCoRe imaging captured in vivo from the somatosensory cortex at the ages indicated showing significant changes in both oligodendrocyte cell soma and myelin fiber density. Each image is representative of at least three locations in at least three animals.

Supplementary Figure 4 Lifelong changes in layer I myelination.

(a) Images of oligodendrocyte specific CNPase staining captured from the somatosensory cortex showing age-dependent changes in the upper layers of the cortex. (b) Examples of single oligodendrocyte cell soma (arrows) revealed by CNPase staining in layer I of the cortex. Each image is representative of at least three locations in at least three animals.

Supplementary Figure 5 Evidence of myelin plasticity through internode remodeling.

(a) In vivo time-lapse SCoRe images showing addition of single myelin internodes (yellow arrows) and extension of a single myelin internode (yellow arrowhead) over 68 days (b) In vivo two-photon fluorescence images of a single oligodendrocyte (red arrow) imaged over 60 days in a transgenic mouse (Plp-creER:mT/mG) with membrane tethered GFP expressed specifically in mature oligodendrocytes and membrane tethered Tomato (mTomato) expressed predominantly in cerebral blood vessels. (c-d) In vivo time-lapse images showing extension of single internodes (blue arrowheads) and stability of other internodes from the same oligodendrocyte (red arrowheads). Each image is representative of at least three locations in at least three animals.

Supplementary Figure 6 In vivo imaging of myelin distribution along single cortical axons.

(a) In vivo images captured from the cortex of a P60 Thy1-YFP transgenic mouse showing a partially myelinated axon with arrowheads designating myelin segments and arrows pointing to unmyelinated regions. (b) Image captured from the cortex of a P640 mouse showing an unmyelinated region along a single axon in late adulthood. (c) Representative traced axons from mice at the ages indicated showing age-dependent increase in myelin coverage along single axons. Each image is representative of at least three locations in at least three animals.

Supplementary Figure 7 Myelin degeneration and debris accumulation in microglia in advanced aging.

(a-b) In vivo images captured from the cortex of a 910-day old mouse with mature oligodendrocytes labeled with DsRed (Plp-DsRed) showing examples of myelin pathology detected in aged mice revealed by SCoRe and DsRed fluorescence. Myelin spheroids (yellow arrowheads) can be detected using SCoRe and are only found in aged mice. Myelin debris (yellow arrows) can also be detected using SCoRe and the vast majority were found to have accumulation of DsRed fluorescent protein in the Plp-DsRed transgenic mice. Myelin debris and oligodendrocyte cell bodies (white arrows) can be distinguished due to the lack of SCoRe signals in addition to the proximal processes extending from the cell body. (c) In vivo image captured from the cortex of a Cx3cr1-GFP:Plp-DsRed transgenic mouse showing accumulation of reflective and DsRed labeled myelin debris within microglia (yellow arrows). (d) High resolution in vivo image of a single myelin debris accumulation engulfed within a microglia process (eg) In vivo images showing examples of myelin debris engulfed by microglia (yellow arrows) with no preferential microglial association with myelin spheroids (yellow arrowheads). Each image is representative of at least three locations in at least three animals.

Supplementary Figure 8 In vivo imaging of myelin, oligodendrocytes and microglia.

Low magnification in vivo image captured from the cortex of a Cx3cr1-GFP:Plp-DsRed transgenic mouse showing the capabilities of imaging myelination (SCoRe), oligodendrocytes (Plp-DsRed) and microglia (Cx3cr1-GFP) in an 810 day old mouse. This image is representative of at least three locations in at least three animals.

Supplementary Figure 9 Myelin debris accumulation in microglia in advanced aging.

(a) Image captured of a tissue section stained with nuclear dye from an 860-day old Cx3cr1-GFP:Plp-DsRed transgenic mouse showing myelin debris accumulation (white arrows) within a single microglia. These debris are characterized by bright DsRed and SCoRe labeling and no nuclear dye labeling. Two oligodendrocyte cell soma are shown in the lower portion of the image characterized by DsRed expression with nuclear dye labeling. (b) Images from 860-day old Cx3cr1-GFP:Plp-DsRed mice showing the presence of myelin debris within microglia in the cerebral cortex, corpus callosum, and the hippocampus suggesting myelin degeneration is a wide spread phenomenon in the aging brain. Each image is representative of at least three locations in at least three animals.

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Supplementary Text and Figures

Supplementary Figures 1–9

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Supplementary Table 1

Descriptive statistics for all data

Supplementary Video 1 – Overlap between fluorescent and SCoRe signals for in vivo detection of myelin

Video shows a confocal Z stack taken through a cranial window of an anesthetized transgenic mouse with membrane tethered EGFP expressed exclusively in mature oligodendrocytes (Cnp-mEGFP) overlaid with sequentially acquired SCoRe signals. White arrow indicates a mEGFP labeled cell body and yellow arrows indicate the location of a presumptive node of Ranvier as evidenced by the break in both fluorescence and SCoRe signals. Depth from the pial surface is indicated in the upper right corner. This video is representative of at least three locations in at least three animals.

Supplementary Video 2 – Microglia surveillance in advanced aging

Video shows two time-lapse sequences of microglia process surveillance in an 810 day old Cx3cr1-GFP:Plp-DsRed transgenic mouse. Time is indicated in the upper right corner. This video is representative of at least three locations in at least three animals.

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Hill, R.A., Li, A.M. & Grutzendler, J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat Neurosci 21, 683–695 (2018). https://doi.org/10.1038/s41593-018-0120-6

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