Myelin, the multilayered membrane surrounding many axons in the nervous system, increases the speed by which electrical signals travel along axons and facilitates neuronal communication between distant regions of the nervous system. However, how neuronal signals influence the myelinating process in the CNS is still largely unclear. Recent studies have significantly advanced this understanding, identifying important roles for neuronal activity in controlling oligodendrocyte development and their capacity of producing myelin in both developing and mature CNS. Here, we review these recent advances, and discuss potential mechanisms underpinning activity-dependent myelination and how remyelination may be stimulated via manipulating axonal activity, raising new questions for future research.
Oligodendrocyte production and myelination continues lifelong in the central nervous system (CNS), and all stages of this process can be adaptively regulated by neuronal activity. While artificial exogenous stimulation of neuronal circuits greatly enhances oligodendrocyte progenitor cell (OPC) production and increases myelination during development, the extent to which physiological stimuli replicates this is unclear, particularly in the adult CNS when the rate of new myelin addition slows. Here, we used environmental enrichment (EE) to physiologically stimulate neuronal activity for 6 weeks in 9-week-old C57BL/six male and female mice and found no increase in compact myelin in the corpus callosum or somatosensory cortex. Instead, we observed a global increase in callosal axon diameter with thicker myelin sheaths, elongated paranodes and shortened nodes of Ranvier. These findings indicate that EE induced the dynamic structural remodelling of myelinated axons. Additionally, we observed a global increase in the differentiation of OPCs and premyelinating oligodendroglia in the corpus callosum and somatosensory cortex.Our findings of structural remodelling of myelinated axons in response to physiological neural stimuli during young adulthood provide important insights in understanding experience-dependent myelin plasticity throughout the lifespan and provide a platform to investigate axon-myelin interactions in a physiologically relevant context.
The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2 ΔO/ΔO ). At 6 weeks of age, normal-appearing myelin had formed in CerS2 ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2 ΔO/ΔO mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2 ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2 ΔO/ΔO mice. By 16 weeks, CerS2 ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2 ΔO/ΔO mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases.
JX conceived the study; MN performed the experiments and analyzed data; RW, DG and JF assisted the experiments and data analysis; AH contributed to experimental design; JX and SM supervised the study; MN and JX wrote the manuscript. Scholarship and the University of Melbourne STRAPA Scholarship to M.N. Confocal Microscopy was performed at the Biological Optical Microscopy Platform, The University of Melbourne (www.microscopy.unimelb.edu.au). AbstractNeuronal activity influences oligodendrocyte production and myelination during brain development. While it is known that the myelinating process continues across the lifespan, the extent to which neuronal activity influences oligodendrocyte production and myelin acquisition during adulthood is not fully understood. Here, we find that using environmental enrichment (EE) to physiologically upregulate neuronal activity for 6-weeks during young adulthood in C57Bl/6 mice results in increased axon diameter in the corpus callosum, with a corresponding increased thickness of pre-existing myelin sheaths. Furthermore, EE uniformly promotes the differentiation of pre-existing oligodendroglia in both corpus callosum and cerebral somatosensory cortex, while differentially altering new OPC production in these regions. Together, results of this study suggest that neuronal activity induced by EE exerts a pronounced influence on adult myelination, promoting the remodeling of pre-existing myelinated axons and accelerating the differentiation of preexisting oligodendroglia. Importantly, we show that these effects are independent of the addition of new myelin or contributions by newly-generated oligodendroglia. This impact on pre-existing oligodendroglia and pre-existing myelin sheaths is a previously undescribed form of adaptive myelination that potentially contributes to neuronal circuit maturation in the young adult central nervous system.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.