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      Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner

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          Abstract

          Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the individual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of individual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS.

          Abstract

          Neuronal activity is known to increase myelination by oligodendrocytes in the mouse brain. Here, Mitew et al. demonstrate that chemogenetic manipulations of somatosensory axon activity both increase the generation of new oligodendrocytes and preferentially enhance myelination of the activated axons.

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            Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion

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              Neuronal activity biases axon selection for myelination in vivo

              An essential feature of vertebrate neural development is ensheathment of axons with myelin, an insulating membrane formed by oligodendrocytes. Not all axons are myelinated, but mechanisms directing myelination of specific axons are unknown. Using zebrafish we show that activity-dependent secretion stabilizes myelin sheath formation on select axons. When VAMP2-dependent exocytosis is silenced in single axons, oligodendrocytes preferentially ensheath neighboring axons. Nascent sheaths formed on silenced axons are shorter in length, but when activity of neighboring axons is also suppressed, inhibition of sheath growth is relieved. Using in vivo time-lapse microscopy, we show that only 25% of oligodendrocyte processes that initiate axon wrapping are stabilized during normal development, and that initiation does not require activity. Instead, oligodendrocyte processes wrapping silenced axons are retracted more frequently. We propose that axon selection for myelination results from excessive and indiscriminate initiation of wrapping followed by refinement that is biased by activity-dependent secretion from axons.
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                Author and article information

                Contributors
                tobias.merson@monash.edu
                emeryb@ohsu.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                22 January 2018
                22 January 2018
                2018
                : 9
                : 306
                Affiliations
                [1 ]ISNI 0000 0004 0606 5526, GRID grid.418025.a, The Florey Institute of Neuroscience and Mental Health, ; Parkville, VIC 3052 Australia
                [2 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Department of Anatomy & Neuroscience, , The University of Melbourne, ; Parkville, VIC 3010 Australia
                [3 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Australian Regenerative Medicine Institute, , Monash University, ; Clayton, VIC 3800 Australia
                [4 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Queensland Brain Institute, , The University of Queensland, ; St Lucia, QLD 4072 Australia
                [5 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Department of Pharmacology and Therapeutics, , The University of Melbourne, ; Parkville, VIC 3010 Australia
                [6 ]ISNI 0000 0000 9758 5690, GRID grid.5288.7, Jungers Center for Neurosciences Research, Department of Neurology, , Oregon Health and Science University, ; Portland, OR 97239 USA
                [7 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Florey Department of Neuroscience and Mental Health, , The University of Melbourne, ; Parkville, VIC 3010 Australia
                [8 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Schools of Biomedical Sciences, , The University of Queensland, ; St Lucia, QLD 4072 Australia
                [9 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Melbourne Neuroscience Institute, , The University of Melbourne, ; Parkville, VIC 3010 Australia
                Author information
                http://orcid.org/0000-0002-7397-8750
                http://orcid.org/0000-0002-7590-7390
                http://orcid.org/0000-0002-7246-3608
                http://orcid.org/0000-0002-9132-3045
                Article
                2719
                10.1038/s41467-017-02719-2
                5778130
                29358753
                d1aeb727-641f-4061-9d99-fea24e1acd2d
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 March 2017
                : 19 December 2017
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