On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function

Abstract

Studies of activity-driven nervous system plasticity have primarily focused on the gray matter. However, MRI-based imaging studies have shown that white matter, primarily composed of myelinated axons, can also be dynamically regulated by activity of the healthy brain. Myelination in the CNS is an ongoing process that starts around birth and continues throughout life. Myelin in the CNS is generated by oligodendrocytes and recent evidence has shown that many aspects of oligodendrocyte development and myelination can be modulated by extrinsic signals including neuronal activity. Because modulation of myelin can, in turn, affect several aspects of conduction, the concept has emerged that activity-regulated myelination represents an important form of nervous system plasticity. Here we review our increasing understanding of how neuronal activity regulates oligodendrocytes and myelinated axonsin vivo, with a focus on the timing of relevant processes. We highlight the observations that neuronal activity can rapidly tune axonal diameter, promote re-entry of oligodendrocyte progenitor cells into the cell cycle, or drive their direct differentiation into oligodendrocytes. We suggest that activity-regulated myelin formation and remodeling that significantly change axonal conduction properties are most likely to occur over timescales of days to weeks. Finally, we propose that precise fine-tuning of conduction along already-myelinated axons may also be mediated by alterations to the axon itself. We conclude that future studies need to analyze activity-driven adaptations to both axons and their myelin sheaths to fully understand how myelinated axon plasticity contributes to neuronal circuit formation and function.

Glutamatergic signaling between neurons and oligodendrocyte lineage cells: Is it synaptic or non‐synaptic?

“…Changes in oligodendrogenesis and/or myelination have also been observed in many other paradigms where the alterations of neuronal activity may be more complex than simple reduction or increase (reviewed by Almeida & Lyons, 2017;Forbes & Gallo, 2017;Gibson, Geraghty, & Monje, 2018). Therefore, a simple concept stating that increased neuronal activity enhances myelination, while decreased neuronal activity reduces myelination most likely does not apply, and modulation of myelination by neuronal activity may be neuronal circuit specific and may involve multiple mechanisms.…”

Axoglial interactions in myelin plasticity: Evaluating the relationship between neuronal activity and oligodendrocyte dynamics

“…Why should myelination be responsive to levels of neuronal activity? A possibility receiving substantial interest is that activity‐driven changes to myelination might represent a form of neuroplasticity, fine tuning the functioning of neuronal circuits (for detailed review of these concepts see Almeida & Lyons, ; Fields, ; Fields, ; Pajevic, Basser, & Fields, ; Purger, Gibson, & Monje, ). Certainly, even within the mature CNS considerable scope exists for the modulation of axonal conduction rates through changes to myelin.…”

“…A possibility receiving substantial interest is that activity-driven changes to myelination might represent a form of neuroplasticity, fine tuning the functioning of neuronal circuits (for detailed review of these concepts see Almeida & Lyons, 2017;Fields, 2005;Fields, 2015;Pajevic, Basser, & Fields, 2014;Purger, Gibson, & Monje, 2016).…”

Uncovering the biology of myelin with optical imaging of the live brain

“…These cells are tiled and maintain a tightly regulated resident population by balancing self-renewal, apoptosis, and oligodendrocyte differentiation (Barres et al, 1992;Hill, Patel, Goncalves, Grutzendler, & Nishiyama, 2014;Hughes, Kang, Fukaya, & Bergles, 2013;Trapp, Nishiyama, Cheng, & Macklin, 1997). Much is known about the molecular cues that induce oligodendrocyte differentiation from NG2 glia (reviewed in Nishiyama, 2007;Emery, 2010;Liu & Casaccia, 2010;Zuchero & Barres, 2013); however, less is known about the mechanisms inducing myelination of some axons and not others and some axonal segments and not others, in specific patterns at discrete time points (Almeida & Lyons, 2017;Osso & Chan, 2017).…”