The Role of Neuronal Activity in Adult Myelin Plasticity

Abstract

In the central nervous system, oligodendrocytes wrap membranes around axons to produce myelin. Their functional roles include rapid neurotransmission, synchronization, and functional maintenance. In the adult brain, 5% or more of the total cellular population consists of oligodendrocyte precursor cells, stem cells that proliferate and differentiate to produce new oligodendrocytes. While myelination is largely a postnatal process that occurs rapidly during development, it has been recently shown that new oligodendrocytes form throughout adulthood in both the grey and white matter; this de novo adult oligodendrogenesis plays a role in memory and learning. Research has also demonstrated that neuronal activity plays a central role in early myelin development and promotes oligodendrogenesis and adaptive myelination. Thus, it becomes important to understand how neuronal activity affects myelin. In this thesis, the role of neuronal activity in myelin plasticity during adulthood was investigated. Designer receptors exclusively activated by designer drugs were used to alter the activity of neurons bidirectionally to observe the activity dependence of myelin. Long-term neuronal activity changes were applied to the optic nerve, a tract in the central nervous system that is fully myelinated during adulthood, to determine how new and existing oligodendrocyte lineage cells respond. With sustained, increased neuronal activity over an 8-week period, it was observed that both existing and newly formed oligodendrocytes recapitulated the morphology of development by forming longer and fewer sheaths. With persistent, decreased neuronal activity, newly formed oligodendrocytes were fewer in numbers and formed shorter and fewer sheaths when compared to control, with existing oligodendrocytes following the same morphological pattern. Data presented in this thesis demonstrated that bidirectional neuronal activity manipulation yielded retraction, lengthening, and shortening of myelin sheaths in existing cells in a fully myelinated tract, which has not been demonstrated in the myelin remodelling field. Furthermore, on the circuitry level, it was demonstrated that with 8 weeks of sustained, increased neuronal activity, the signal conduction velocity from the retina to the visual cortex was significantly higher. This increase in signal transmission could be attributed to the myelin remodelling occurring during the activity modulation, yielding a functional change to the circuit. The work in this thesis shed light on how myelin remains plastic during adulthood and contributes to a greater understanding of how myelin is remodelled after development. Elucidating the role of neuronal activity on the white matter may lead to the discovery and development of more effective therapeutics for myelin-related diseases.