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  • Review article
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Adaptive and maladaptive myelination in health and disease

Nature Reviews Neurology volume 18, pages 735–746 (2022)Cite this article

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Abstract

Within the past decade, multiple lines of evidence have converged to identify a critical role for activity-regulated myelination in tuning the function of neural networks. In this Review, we provide an overview of accumulating evidence that activity-regulated myelination is required for brain adaptation and learning across multiple domains. We then discuss dysregulation of activity-dependent myelination in the context of neurological disease, a novel frontier with the potential to uncover new mechanisms of disease pathogenesis and to develop new therapeutic strategies. Alterations in myelination and neural network function can result from deficient myelin plasticity that impairs neurological function or from maladaptive myelination, in which intact activity-dependent myelination contributes to the disease process by promoting pathological patterns of neuronal activity. These emerging mechanisms suggest new avenues for therapeutic intervention that could more fully address the complex interactions between neurons and oligodendroglia.

Key points

  • Activity-regulated myelin plasticity is a process in which myelin structure can change in response to neuronal activity, and can involve de novo myelination, remodelling of existing myelin, and both increases and decreases in myelination.

  • In the healthy brain, myelin plasticity is adaptive and supports brain function and cognition across multiple domains; adaptive changes in myelin are thought to tune neural circuit dynamics to promote coordinated circuit function.

  • Mechanisms of neuron-to-oligodendrocyte progenitor cell communication include bona fide synapses, non-synaptic vesicle exocytosis, and paracrine signalling involving factors secreted by neurons; the key mechanisms underlying myelin plasticity are a topic of intense research.

  • In some diseases, neurological function is impaired by loss of activity-dependent myelination; a prominent example is cancer therapy-related cognitive impairment.

  • Maladaptive myelination is a distinct mechanism in which activity-dependent myelination is driven by, and subsequently promotes, pathological patterns of neuronal activity, such as seizures in generalized epilepsy.

  • Novel therapeutic strategies could address dysregulated neuron–oligodendroglial interactions in disease states by restoring deficient activity-dependent myelination or by modulating maladaptive myelination.

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Fig. 1: Activity-regulated myelination.
Fig. 2: Activity-regulated myelination in health and disease.

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Authors and Affiliations

  1. Department of Neurology, Stanford University, Stanford, CA, USA

    Juliet K. Knowles, Ankita Batra, Haojun Xu & Michelle Monje

  2. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Michelle Monje

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Contributions

J.K.K. and M.M. researched the literature for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. All authors wrote the article.

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Correspondence to Juliet K. Knowles or Michelle Monje.

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M.M. holds equity in MapLight Therapeutics and Syncopation Life Sciences. The other authors declare no competing interests.

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Nature Reviews Neurology thanks B. Emery and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Fractional anisotropy

A measure that reflects the relative constraint (anisotropy) of water diffusion in specific directions or eigenvectors; in brain tissue, it is thought to correlate with myelin integrity as well as myelin-independent axonal factors, such as axon size, number and orientation.

g-ratio

The ratio of the axon diameter to the total diameter of the axon and its myelin sheath; a lower g-ratio indicates a thicker myelin sheath relative to the axon diameter. The g-ratio is a major determinant of conduction velocity, in addition to axon diameter.

Mean diffusivity

A measure that indicates the overall degree of water diffusion, independent of the direction of diffusion; it is thought to be inversely proportional to myelin integrity.

Ocular dominance column

A stripe-like group of neurons across multiple cortical layers in the primary visual cortex that responds preferentially to thalamic input originating from one eye or the other.

Optomotor responses

A reflexive motor response in zebrafish that stabilizes body position after perceived motion and that can be induced by videos of moving gratings.

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Knowles, J.K., Batra, A., Xu, H. et al. Adaptive and maladaptive myelination in health and disease. Nat Rev Neurol 18, 735–746 (2022). https://doi.org/10.1038/s41582-022-00737-3

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