Motor skill learning requires active central myelination

McKenzie, Ian A.; Ohayon, David; Li, Hui‐Liang; Faria, Joana Paes de; Emery, Ben; Tohyama, Koujiro; Richardson, William D.

doi:10.1126/science.1254960

Cited by 942 publications

(1,017 citation statements)

References 36 publications

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“…In the context of learning, generation of new oligodendrocytes has been shown to be essential for mice to acquire motor skills, such as running on the complex wheel (McKenzie et al, 2014). Consistent with the concept that learning triggers neuronal activity changes, increased excitatory neuronal activity triggered by optogenetic stimulation in premotor cortex induced oligodendrocyte progenitor cell (OPC) proliferation and differentiation, and increased myelin thickness in mice, which led to improved motor function.…”

Section: Introductionmentioning

confidence: 87%

“…Myelination and oligodendrocytes, the myelin-forming cells of the CNS, respond to experience and neuronal activity, thereby contributing to physiological brain function and behavior (Sánchez et al, 1998;Makinodan et al, 2012;Gibson et al, 2014;McKenzie et al, 2014). Children suffering severe childhood neglect displayed reduced corpus callosum area (Teicher et al, 2004;Mehta et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

et al. 2016

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Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

et al. 2016

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“…This recently described process has been named adaptive myelination or myelin plasticity, in analogy to synaptic plasticity (Forbes & Gallo, 2017; Mount & Monje, 2017). For example, learning of a complex motor task entails proliferation and differentiation of adult oligodendrocyte progenitor cells (OPCs), and presumably generation of some new myelin segments (McKenzie et al, 2014). However, also apposition of new myelin lamella to already existing internodes might be involved in this process.…”

Section: Myelination and Metabolismmentioning

confidence: 99%

“…Based on (a) the metabolic challenge endured by myelinating cells during development (Forbes & Gallo, 2017; McKenzie et al, 2014); (b) the requirement of a regular supply of myelin components in adult life (in homeostasis and during adaptive myelination) (Bechler & Ffrench‐Constant, 2014; Gibson et al, 2014); and (c) the central role of remyelination after injury and in disease (Cole, Early, & Lyons, 2017), signaling pathways central to cell metabolism are likely to occupy strategically relevant positions in the regulation of myelination in health and disease. Among such pathways, we will focus in this review mainly on the role of mTOR and closely associated signaling components.…”

Section: Myelination and Metabolismmentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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“…Therefore, maintaining the integrity of white matter in health and disease, especially of OLs and the myelin sheath, is critical to the performance of a variety of brain functions. Furthermore, recent studies have shown that myelination and OL generation in adulthood are actively regulated in response to neural activities (3,4), highlighting the potential contribution of white matter plasticity to learning and higher cognitive functions.…”

mentioning

confidence: 99%

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Choi

Cui

Chowdhury

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/ TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions. white matter stroke | oligodendrocyte | toll-like receptor 2 | HMGB1 | myelination W hite matter in the vertebrate brain is characterized by the presence of myelinated axonal fibers and glial cells, predominantly myelin-producing oligodendrocytes (OLs) (1). The myelin sheath enables rapid communication of neural signals at a millisecond timescale between different parts of the cerebral cortex or different regions of the CNS (2). Therefore, maintaining the integrity of white matter in health and disease, especially of OLs and the myelin sheath, is critical to the performance of a variety of brain functions. Furthermore, recent studies have shown that myelination and OL generation in adulthood are actively regulated in response to neural activities (3, 4), highlighting the potential contribution of white matter plasticity to learning and higher cognitive functions.Ischemic stroke that occurs in the white matter often results in degeneration of OLs and demyelination (5, 6). Consequently, patients with white matter stroke suffer from a wide range of neurological dysfunctions. For example, focal ischemic stroke in the internal capsule may result in severe hemiparesis (7). Furthermore, both cognitive deficits and gait disturbance are hallmarks of Binswanger's subcortical vascular dementia that is the most severe form of white matter stroke (8). How ischemia leads to OL degeneration and demyelination is poorly understood. We previously reported that toll-like receptor 2 (TLR2) expressed in OLs plays a protect...

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Motor skill learning requires active central myelination

Cited by 942 publications

References 36 publications

Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

Myelination and mTOR

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

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