Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes

Abstract

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activitydependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here, we report that while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases OPC differentiation, oligodendrocyte generation, and retraction of pre-existing myelin sheaths in the forelimb region of motor cortex. Immediately following demyelination, motor cortex neurons exhibit hyperexcitability, motor learning is impaired, and behavioral intervention provides no long-term benefit to remyelination. However, partial remyelination restores neuronal and behavioral function. Motor learning following partial remyelination increases oligodendrogenesis and enhances the ability of mature oligodendrocytes to generate new myelin sheaths, resulting in almost double the remyelination of denuded axons relative to untrained controls. Together, our findings demonstrate that the correct timing of behaviorally-induced neuronal circuit activation improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.

Age and axon-specific forms of cortical remyelination by divergent populations of NG2-glia

“…In the cuprizone model, for example, it is well established that demyelination occurs steadily over weeks, with peak myelin loss being achieved by around 6 weeks 42 . However, little is known about how demyelination proceeds on the single cell level, with recent intravital imaging experiments providing critical insight into the remyelination process after cuprizone cessation 27,28 . Our observations suggest that demyelination, in response to single cell oxidative DNA damage, occurs via the gradual loss of myelin sheaths from oligodendrocytes, rather than through single catastrophic death events.…”

“…Recent studies have provided evidence for remyelination by mature oligodendrocytes, raising the question of whether or not oligodendrogenesis is required for remyelination to occur. This data comes from postmortem analysis of shadow plaques in MS tissue 46,47 and from intravital imaging studies in mice exposed to cuprizone while undergoing a motor learning task 27 . Using our dual-reporter system, we found no evidence of pre-established myelinating oligodendrocytes participating in remyelination.…”

“…It remains to be determined, however, whether the same axons would also have an increased tendency to be remyelinated following degenerative events. Recent intravital imaging experiments do suggest that both sensory experience 27 and developmental myelin patterning 28,29 are important for remyelination success, lending credence to the idea that remyelination proceeds through similar checkpoints used during development.…”

Synaptic vesicle fusion along axons is driven by myelination and subsequently accelerates sheath growth in an activity-regulated manner

“…In vivo, myelin can be specifically targeted to individual axons in a complex milieu (5), and can be highly regulated throughout life (6). Indeed, dynamic changes to myelin sheaths have been proposed to adapt circuit function to novel experiences, including learning (7,8), social interactions (9)(10)(11), as well as memory formation and recall (12)(13)(14). Neuronal activity is now known to regulate oligodendrocyte lineage progression (15).…”

THAP1 Modulates Oligodendrocyte Maturation by Regulating ECM Degradation in Lysosomes

“…Developmental myelination during a critical period of post-natal development plays an important role in the establishment of neural circuits (Fields, 2008;Rice and Barone, 2000;Wang et al, 2018). Regulated myelination in the adult CNS is also increasingly recognized to play an essential role in circuit plasticity, including motor learning (Bacmeister et al, 2020;Bergles and Richardson, 2015;McKenzie et al, 2014;Pepper et al, 2018;Xiao et al, 2016). Mechanisms regulating OL maturation are therefore central to the development of neuronal circuits as well as their plasticity and maintenance.…”