Wrapped to Adapt: Experience-Dependent Myelination

Abstract

Activity of the nervous system has long been recognized as a critical modulator of brain structure and function. Influences of experience on the cytoarchitecture and functional connectivity of neurons have been appreciated since the classic work of Hubel and Wiesel (1963; Wiesel and Hubel, 1963a, 1963b). In recent years, a similar structural plasticity has come to light for the myelinated infrastructure of the nervous system. While an innate program of myelin development proceeds independently of nervous system activity, increasing evidence supports a role for activity-dependent, plastic changes in myelin-forming cells that influence myelin structure and neurological function. Accumulating evidence of complementary and likely temporally overlapping activity-independent and activity-dependent modes of myelination are beginning to crystallize in a model of myelin plasticity, with broad implications for neurological function in health and disease.

Keywords: adaptive myleination; myelin; neurodevelopment; neuroplasticity; oligodendrocyte; oligodendrocyte precursor cells.

Figure 1. Innate and adaptive myelination

Traditional models of developmental myelination programs (top) emphasize an innate program of robust expansion of oligodendrocyte precursors (OPCs) during postnatal neurodevelopment, followed by widespread differentiation into oligodendrocytes (OLs) that myelinate target axons in a largely uniform pattern. Within the central nervous system (CNS), converging lines of evidence support an additional model of adaptive myelination (bottom). Defined as modulation of myelin in response to neuronal activity, adaptive myelination represents a program of continued myelination and myelin remodeling into adult life that is responsive to an animal’s experience. Modulation of neuronal activity in optogenetic, motor learning, and social interaction paradigms, among others, variably stimulate alterations in OL lineage dynamics and myelin sheath microstructure. Ultrastructural analysis and lineage tracing experiments also indicate that patterns of myelination in the adult brain may deviate significantly from the intrinsic model of continuous internode patterning, and that ongoing sheath remodeling or insertion of new sheaths may contribute to this discontinuity. A model recently proposed by ffrench-Constant and colleagues (Bechler et al., 2015) posits that adaptive myelination throughout life continues to shape an innate myelin infrastructure patterned during development.

Figure 2. Adaptive myelination effectors: from molecules to systems

Decoupling adaptive myelination cues from intrinsic oligodendroglial programs represents a significant challenge for uncovering the mechanisms of this process. Several lines of inquiry are under active investigation. Neuronal activity-regulated molecular cues, including neurotrophins and neurotransmitters, have long been known to modulate oligodendrocyte lineage dynamics and are therefore leading candidates for mediating neuronal activity-dependent myelination. Neuron-OPC synapses offer a particularly compelling route by which effector recruitment might occur with high spatiotemporal specificity, although the functional relevance of these synapses remains unclear. Beyond oligodendrogenesis, there is significant potential for activity-dependent signaling to influence myelin sheath dynamics. Investigation in developing zebrafish support a role for neuronal activity in myelin sheath recruitment and stabilization, and evidence of ongoing myelin turnover in rodents and humans suggest this may represent an additional axis along which adaptive myelination occurs. Critically, the systems-level mechanisms linking molecular and cellular processes of adaptive myelination to observed behavioral changes are unknown. Several existing hypotheses include conduction velocity tuning, synchronization of parallel impulses, and metabolic support of underlying neuronal activity. Exploring these and other means by which adaptive myelination can effect behavioral change represents an exciting ongoing challenge for the field.