Introduction to the special issue on myelin plasticity in the central nervous system

Myelin, as defined in textbooks, is the “fatty” insulation surrounding axons necessary for saltatory nerve conduction. Myelin is formed by the membrane extension of specialized cells called oligodendrocytes in the central nervous system, and Schwann cells in peripheral nerves. Since not all axons are myelinated, nerve fibers have been classified either as myelinated fast-conducting or as unmyelinated and slowconducting. In the central nervous system, areas with abundance of myelinated axons are called white matter, while the rest is referred to as gray matter. Myelin formation has been traditionally viewed as a preestablished developmental program, and myelin itself as an unchanging structural component of the nervous system. However, a number of recent seminal discoveries have substantially challenged this static model and revealed a dynamic interplay between experiences and the generation of new myelin, the generation of new myelinating oligodendrocytes from progenitor cells, and the remodeling of existing myelin sheaths. This paradigm shift provides new ways to understand how the nervous system responds to and is changed by experience. Two critical discoveries that challenged the notion of myelination as a fixed process were reports showing that social isolation of adolescent mice impairs myelin formation (Makinodan et al., 2012), and that depriving mice of social contact during adulthood prevents formation of new myelin in the prefrontal cortex (Liu et al., 2012). These studies also showed that the isolation-driven myelin alterations lead to cognitive and behavioral impairments, highlighting the importance of myelin plasticity for brain function. Subsequent studies underscored the importance of myelin formation for motor learning, e.g. adult mice taught to use a complex running wheel were unable to properly learn if new myelin generation was prevented by genetic manipulations (McKenzie et al., 2014). Furthermore, studies using optogenetic stimulation showed that electrical activity modulated myelin thickness (Gibson et al., 2014). Collectively, these studies reinforced the concept that new generation of oligodendrocytes underlies new myelin formation in the adult brain. However, they also raised the question of whether this process is necessary to replace myelin that has been either damaged or simply replenished over time, or whether there maybe axons or axonal segments within the CNS that become myelinated at late stages. A study based on the serial sectioned-based ultrastructural analysis of single myelinated axons revealed the myelination of central axons can be indeed discontinuous, in the sense that some axons can have some myelinated segments interspersed with unmyelinated ones (Tomassy et al., 2014). Because myelin provides insulation, and therefore modulates axonal conductance, this report suggested that myelin serves as an important mechanism to modulate the flow of neural activity by regulating the speed of axonal conductance and therefore suggested a purpose for the formation of new myelin during learning paradigms. 2018 Wiley Periodicals, Inc. Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/dneu.22575