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Yakugaku Zasshi : Journal of the... 2022Myelin is a multilamellar membrane structure formed by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). It... (Review)
Review
Myelin is a multilamellar membrane structure formed by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). It has been recognized as an insulator that is essential for the rapid and efficient propagation of action potentials by saltatory conduction. However, recently many studies have shown that myelin and myelin-forming cells interact with axons and regulate the nervous system far more actively than previously thought. For example, myelination changes axons dynamically and divides them into four distinct functional domains: node of Ranvier, paranode, juxtaparanode, and internode. Voltage-gated Na channels are clustered at the node, while K channels are at the juxtaparanode, and segregation of these channels by paranodal axoglial junction is necessary for proper axonal function. My research experience began at the neurology ward of the Niigata University Medical Hospital, where I saw a patient with peripheral neuropathy of unknown etiology more than 37 years ago. In the patient's serum, we found an autoantibody against a glycolipid enriched in the PNS. Since then, I have been interested in myelin because of its beautiful structure and unique roles in the nervous system. In this review, our recent studies related to CNS and PNS myelin are presented.
Topics: Autoantibodies; Axons; Central Nervous System; Humans; Myelin Sheath; Ranvier's Nodes; Schwann Cells
PubMed: 35908945
DOI: 10.1248/yakushi.21-00224 -
Nature Communications Oct 2023Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the...
Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.
Topics: Humans; Mice; Animals; Male; Memory, Short-Term; Cognitive Training; Oligodendroglia; Mice, Knockout; Cognition; Myelin Sheath
PubMed: 37838794
DOI: 10.1038/s41467-023-42293-4 -
Current Opinion in Neurobiology Dec 2017Myelin sheaths in the vertebrate nervous system enable faster impulse propagation, while myelinating glia provide vital support to axons. Once considered a static... (Review)
Review
Myelin sheaths in the vertebrate nervous system enable faster impulse propagation, while myelinating glia provide vital support to axons. Once considered a static insulator, converging evidence now suggests that myelin in the central nervous system can be dynamically regulated by neuronal activity and continues to participate in nervous system plasticity beyond development. While the link between experience and myelination gains increased recognition, it is still unclear what role such adaptive myelination plays in facilitating and shaping behaviour. Additionally, fundamental mechanisms and principles underlying myelin remodelling remain poorly understood. In this review, we will discuss new insights into the link between myelin plasticity and behaviour, as well as mechanistic aspects of myelin remodelling that may help to elucidate this intriguing process.
Topics: Animals; Brain; Humans; Learning; Myelin Sheath; Neuronal Plasticity; White Matter
PubMed: 29054040
DOI: 10.1016/j.conb.2017.09.014 -
Developmental Neurobiology Feb 2018Human central nervous system myelin development extends well into the fourth decade of life, and this protracted period underscores the potential for experience to... (Review)
Review
Human central nervous system myelin development extends well into the fourth decade of life, and this protracted period underscores the potential for experience to modulate myelination. The concept of myelin plasticity implies adaptability in myelin structure and function in response to experiences during development and beyond. Mounting evidence supports this concept of neuronal activity-regulated changes in myelin-forming cells, including oligodendrocyte precursor cell proliferation, oligodendrogenesis and modulation of myelin microstructure. In healthy individuals, myelin plasticity in associative white matter structures of the brain is implicated in learning and motor function in both rodents and humans. Activity-dependent changes in myelin-forming cells may influence the function of neural networks that depend on the convergence of numerous neural signals on both a temporal and spatial scale. However, dysregulation of myelin plasticity can disadvantageously alter myelin microstructure and result in aberrant circuit function or contribute to pathological cell proliferation. Emerging roles for myelin plasticity in normal neurological function and in disease are discussed. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 123-135, 2018.
Topics: Animals; Epilepsy; Humans; Mental Disorders; Multiple Sclerosis; Myelin Sheath; Neoplasms; Neuronal Plasticity
PubMed: 28986960
DOI: 10.1002/dneu.22541 -
Nature Neuroscience Oct 2022Myelin plasticity occurs when newly formed and pre-existing oligodendrocytes remodel existing patterns of myelination. Myelin remodeling occurs in response to changes in...
Myelin plasticity occurs when newly formed and pre-existing oligodendrocytes remodel existing patterns of myelination. Myelin remodeling occurs in response to changes in neuronal activity and is required for learning and memory. However, the link between behavior-induced neuronal activity and circuit-specific changes in myelination remains unclear. Using longitudinal in vivo two-photon imaging and targeted labeling of learning-activated neurons in mice, we explore how the pattern of intermittent myelination is altered on individual cortical axons during learning of a dexterous reach task. We show that behavior-induced myelin plasticity is targeted to learning-activated axons and occurs in a staged response across cortical layers in the mouse primary motor cortex. During learning, myelin sheaths retract, which results in lengthening of nodes of Ranvier. Following motor learning, addition of newly formed myelin sheaths increases the number of continuous stretches of myelination. Computational modeling suggests that motor learning-induced myelin plasticity initially slows and subsequently increases axonal conduction speed. Finally, we show that both the magnitude and timing of nodal and myelin dynamics correlate with improvement of behavioral performance during motor learning. Thus, learning-induced and circuit-specific myelination changes may contribute to information encoding in neural circuits during motor learning.
Topics: Animals; Axons; Learning; Mice; Myelin Sheath; Neurons; Oligodendroglia
PubMed: 36180791
DOI: 10.1038/s41593-022-01169-4 -
Journal of Neurochemistry Aug 2022Oligodendrocytes are the glial cells responsible for the formation of myelin around axons of the central nervous system (CNS). Myelin is an insulating layer that allows... (Review)
Review
Oligodendrocytes are the glial cells responsible for the formation of myelin around axons of the central nervous system (CNS). Myelin is an insulating layer that allows electrical impulses to transmit quickly and efficiently along neurons. If myelin is damaged, as in chronic demyelinating disorders such as multiple sclerosis (MS), these impulses slow down. Remyelination by oligodendrocytes is often ineffective in MS, in part because of the failure of oligodendrocyte precursor cells (OPCs) to differentiate into mature, myelinating oligodendrocytes. The process of oligodendrocyte differentiation is tightly controlled by several regulatory networks involving transcription factors, intracellular signaling pathways, and extrinsic cues. Understanding the factors that regulate oligodendrocyte development is essential for the discovery of new therapeutic strategies capable of enhancing remyelination. Over the past decade, microRNAs (miRNAs) have emerged as key regulators of oligodendrocyte development, exerting effects on cell specification, proliferation, differentiation, and myelination. This article will review the role of miRNAs on oligodendrocyte biology and discuss their potential as promising therapeutic tools for remyelination.
Topics: Cell Differentiation; Humans; MicroRNAs; Multiple Sclerosis; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Remyelination
PubMed: 35536759
DOI: 10.1111/jnc.15618 -
Neuron Aug 2017Activity of the nervous system has long been recognized as a critical modulator of brain structure and function. Influences of experience on the cytoarchitecture and... (Review)
Review
Activity of the nervous system has long been recognized as a critical modulator of brain structure and function. Influences of experience on the cytoarchitecture and functional connectivity of neurons have been appreciated since the classic work of Hubel and Wiesel (1963; Wiesel and Hubel, 1963a, 1963b). In recent years, a similar structural plasticity has come to light for the myelinated infrastructure of the nervous system. While an innate program of myelin development proceeds independently of nervous system activity, increasing evidence supports a role for activity-dependent, plastic changes in myelin-forming cells that influence myelin structure and neurological function. Accumulating evidence of complementary and likely temporally overlapping activity-independent and activity-dependent modes of myelination are beginning to crystallize in a model of myelin plasticity, with broad implications for neurological function in health and disease.
Topics: Adaptation, Physiological; Brain; Cues; Myelin Sheath; Neuroglia; Neurons; Neurotransmitter Agents
PubMed: 28817797
DOI: 10.1016/j.neuron.2017.07.009 -
Nature Communications Sep 2022Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental...
Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.
Topics: Axons; Myelin Proteins; Myelin Sheath; Oligodendroglia; Vesicle-Associated Membrane Protein 2
PubMed: 36151203
DOI: 10.1038/s41467-022-33200-4 -
Nature Communications Oct 2023Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia...
Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8 T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
Topics: Animals; Mice; Axons; CD8-Positive T-Lymphocytes; Demyelinating Diseases; Microglia; Myelin Sheath; Neuroinflammatory Diseases
PubMed: 37903797
DOI: 10.1038/s41467-023-42570-2 -
Current Opinion in Neurobiology Dec 2017Myelin increases the speed and efficiency of action potential propagation. Yet, not all axons are myelinated and some axons are discontinuously myelinated, prompting the... (Review)
Review
Myelin increases the speed and efficiency of action potential propagation. Yet, not all axons are myelinated and some axons are discontinuously myelinated, prompting the question of how myelinating glia select axons for myelination. Whereas myelination by Schwann cells depends on axonal induction, oligodendrocytes can form myelin membrane in the absence of axons. However, oligodendrocytes alone cannot architect the complex myelination patterns of the central nervous system and recent advances have implicated axonal signaling in this process. This review considers how oligodendrocytes and their precursors could be influenced by inductive, attractive, permissive, repulsive, and preventative cues, and discusses recent evidence identifying synaptic activity and membrane-bound adhesion molecules as such cues directing axon selection.
Topics: Animals; Axons; Central Nervous System; Humans; Myelin Sheath; Neural Stem Cells; Oligodendroglia
PubMed: 28709021
DOI: 10.1016/j.conb.2017.06.005