Remyelination alters the pattern of myelin in the cerebral cortex

Abstract

37Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters 38 neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can 39 be restored by regenerating oligodendrocytes from resident progenitors; however, it is not 40 known whether regeneration restores the complex myelination patterns in cortical circuits. Here 41 we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to 42 define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. 43These longitudinal studies revealed that the pattern of myelination in cortex changed 44 dramatically after regeneration, as new oligodendrocytes were formed in different locations and 45 new sheaths were often established along axon segments previously lacking myelin. Despite 46 the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired 47 in deeper cortical layers that experienced higher gliosis. The repeated reorganization of myelin 48 patterns in MS may alter circuit function and contribute to cognitive decline. 49 50 51 INTRODUCTION 52 53 Oligodendrocytes form concentric sheets of membrane around axons that enhance the speed of 54 action potential propagation, provide metabolic support and control neuronal excitability through 55 ion homeostasis. Consequently, loss of oligodendrocytes and myelin can alter the firing 56 behavior of neurons and impair their survival, leading to profound disability in diseases such as 57 multiple sclerosis (MS), in which the immune system inappropriately targets myelin for 58 destruction. In both relapsing-remitting forms of MS and the cuprizone model of demyelination in 59 mouse, the CNS is capable of spontaneous remyelination through mobilization of 60 oligodendrocyte precursor cells (OPCs) (Baxi et al., 2017; Chang, Nishiyama, Peterson,

Myelin replacement triggered by single-cell demyelination in mouse cortex

“…These could result in addition, but also in retraction of internodes, which appear to be relatively common in specific settings 61,71 . On the time-scale of our follow-up (on average 81.1 ± 1.1 days), however pruning of fully differentiated internodes was rather rare (about 1.9 ± 0.4 segments per area), in line with other reports from mice 5,18,49 . This indicates that it is uncommon for cortical myelin to undergo remodeling at the level of single internodes.…”

“…Our imaging technique allowed us to achieve single internode resolution in vivo for cortical volumes exceeding the typical territory of a single OL (Supplementary Movie 1) and to track internode fate after single OL ablation ( Fig. 2a) or during spontaneous sheath loss or OL addition in control areas 5,18,49 (Fig. 2b, c).…”

“…Can such prior patterns in principle be re-established by endogenous or therapeutically supported remyelination, and if so, how precisely? Answering this question is not easy in injury paradigms where most OLs are damaged, as axon loss, glial scaring and local inflammation can obscure remyelination patterns 48,49,[59][60][61] .…”

“…Statistical analysis. Sample sizes were chosen according to previous in vivo imaging studies 5,18,49,61…”

Age and axon-specific forms of cortical remyelination by divergent populations of NG2-glia

“…It remains to be determined, however, whether the same axons would also have an increased tendency to be remyelinated following degenerative events. Recent intravital imaging experiments do suggest that both sensory experience 27 and developmental myelin patterning 28,29 are important for remyelination success, lending credence to the idea that remyelination proceeds through similar checkpoints used during development.…”