Motor learning drives dynamic patterns of intermittent myelination on learning-activated axons

Bacmeister, Clara M.; Huang, Rongchen; Osso, Lindsay A.; Thornton, Michael A.; Conant, Lauren; Chavez, Anthony R; Poleg-Polsky, Alon; Hughes, Ethan G.

doi:10.1038/s41593-022-01169-4

Cited by 56 publications

(42 citation statements)

References 75 publications

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“…To study this, we used chemogenetics as this method allowed us to repeatedly stimulate specific neurons regulating anxiety-like behavior, while visualizing the manipulated axons for morphological analysis of nodes. Notably, paranodes were specifically modified on activated axons, but not on nonactivated axons within the same brain region, suggesting that neuronal activity directly elicits paranodal plasticity along the stimulated axons, as described previously for the formation of myelin sheaths [37,38], and recently in the motor cortex following learning [43]. Altogether, these findings suggest that node remodeling may play an important role in modulating neuronal communication in anxiety circuits.…”

Section: Discussionsupporting

confidence: 76%

Node of Ranvier remodeling in chronic psychosocial stress and anxiety

Koskinen

Laine

Abdollahzadeh

et al. 2023

Neuropsychopharmacol.

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Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for anxiety disorders. To determine whether and how stress affects structural remodeling of nodes of Ranvier, another form of myelin plasticity, we developed a 3D reconstruction analysis of node morphology in C57BL/6NCrl and DBA/2NCrl mice. We identified strain-dependent effects of chronic social defeat stress on node morphology in the medial prefrontal cortex (mPFC) gray matter, including shortening of paranodes in C57BL/6NCrl stress-resilient and shortening of node gaps in DBA/2NCrl stress-susceptible mice compared to controls. Neuronal activity has been associated with changes in myelin thickness. To investigate whether neuronal activation is a mechanism influencing also node of Ranvier morphology, we used DREADDs to repeatedly activate the ventral hippocampus-to-mPFC pathway. We found reduced anxiety-like behavior and shortened paranodes specifically in stimulated, but not in the nearby non-stimulated axons. Altogether, our data demonstrate (1) nodal remodeling of the mPFC gray matter axons after chronic stress and (2) axon-specific regulation of paranodes in response to repeated neuronal activity in an anxiety-associated pathway. Nodal remodeling may thus contribute to aberrant circuit function associated with anxiety disorders.

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Section: Discussionsupporting

confidence: 76%

Node of Ranvier remodeling in chronic psychosocial stress and anxiety

Koskinen

Laine

Abdollahzadeh

et al. 2023

Neuropsychopharmacol.

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“…Does oligodendrocyte calcium signaling also drive myelin remodeling to support learning? Experience and neuronal activity cause dramatic changes to the pattern of myelin in the adult brain, including addition of new myelin sheaths and morphological changes to existing sheaths [3][4][5][6][7][8][9] . Although such changes are predicted to affect the function of neuronal circuits, the overarching role of myelin dynamics in learning is still mostly hypothetical.…”

Section: Discussionmentioning

confidence: 99%

“…Myelin loss in diseases like multiple sclerosis or after injury causes severe disability 2 . In addition to its traditional role in increasing conduction velocity, the generation of new myelin and the remodeling of existing myelin sheaths has been increasingly implicated in supporting memory acquisition and learning [3][4][5][6][7][8][9] . Normal developmental myelin formation and its remodeling in the context of plasticity are thus essential for a properly functioning nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…During development, sheath length and thickness are dictated, at least in part, by properties of the underlying neurons including axon diameter, neuron type, and neuronal activity (reviewed in 10 ). In adults, length and thickness of existing myelin sheaths can be dynamically adjusted by experience or experimentally-induced neuronal activity 3,4,9,11,12 , and these changes are predicted to be sufficient to significantly alter axonal conduction velocity 3,13 . Together, myelin is likely to play a profoundly important role in regulating neural circuit activity-and the morphology of myelin sheaths is central to this function.…”

Section: Introductionmentioning

confidence: 99%

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Oligodendrocyte calcium signaling sculpts myelin sheath morphology

Iyer

Kantarci

Ambiel

et al. 2023

Preprint

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Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length and thickness are regulated by neuronal activity and can precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation and remodeling is unknown. Here, we used genetic tools to attenuate oligodendrocyte calcium signaling during active myelination in the developing mouse CNS. Surprisingly, we found that genetic calcium attenuation did not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation caused striking myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduced actin filaments in oligodendrocytes, and an intact actin cytoskeleton was necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a novel cellular mechanism required for accurate CNS myelin formation and provides mechanistic insight into how oligodendrocytes may respond to neuronal activity to sculpt myelin sheaths throughout the nervous system.

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“…For instance, Hasan et al are the first to reveal that schema-like learning can foster the growth and regeneration of brain myelin, thereby enhancing the learning and memory capacity [ 158 ]. Very recently, Bacmeister et al have shown that motor learning induces phase-specific changes in myelination on behaviorally activated axons that correlate with motor performance, suggesting myelin remodeling is involved in learning [ 159 ]. The increased pre-existing myelin sheaths plasticity would influence neuronal activity and learning, and new oligodendrogenesis is also required for several types of learning and memory [ 160 , 161 ].…”

Section: The Physiological Functions Of Chromatin Remodeling In the N...mentioning

confidence: 99%

Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration

Jiang

Guo

et al. 2023

Cell Biosci

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The dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stages of postnatal and adult neurogenesis. Chromatin deregulation, which leads to defects in epigenetic gene regulation and further pathological gene expression programs, often causes a wide range of pathologies. This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.

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Motor learning drives dynamic patterns of intermittent myelination on learning-activated axons

Cited by 56 publications

References 75 publications

Node of Ranvier remodeling in chronic psychosocial stress and anxiety

Node of Ranvier remodeling in chronic psychosocial stress and anxiety

Oligodendrocyte calcium signaling sculpts myelin sheath morphology

Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration

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