Oligodendrogenesis Inhibition in the Juvenile and Adolescent Periods Differentially Alters Myelin in Mice

Abstract

Introduction: The timing of myelination during development varies spatially according to the evolving functional demands of the maturing brain and is likely a mechanism of plasticity that contributes to sensitive periods of brain development during which the brain has heightened susceptibility to environmental influences. Disruption to this myelination process is therefore likely to have spatially and temporally heterogeneous effects. Myelinating oligodendrocytes arise from the differentiation of oligodendrocyte precursor cells, a process that depends on the transcription factor Myrf. In this study, the inducible Myrf conditional knockout mouse model is leveraged to characterize the impact of inhibiting oligodendrogenesis during the juvenile or adolescent period on white matter tracts with different timing of maturation.

Methods: Electron microscopy (EM) was used to quantify the fraction of myelinated axons, axon diameter, and myelin thickness, or T2- and diffusion-weighted MRI (dMRI) were used to compute white matter volumes and measures sensitive to microstructure.

Results: Mice with inhibited oligodendrogenesis during the juvenile period had a lower fraction of myelinated axons in the corpus callosum, which was not the case when oligodendrogenesis was halted during adolescence. Halting oligodendrogenesis in either developmental period had no effect on myelinated fraction in the earlier-to-mature optic tracts. Halted oligodendrogenesis during the juvenile period was detected with MRI as decreased volume of late-myelinating structures (corpus callosum, anterior commissure, and fornix) relative to controls. No group differences were observed in dMRI measures. Additionally, thinner myelin on larger calibre axons in the optics tracts of adolescent mice with halted oligodendrogenesis was detected with EM, but no MRI measures were sensitive to this difference.

Conclusion: This study demonstrates that the impact of disrupting developmental oligodendrogenesis on white matter differs depending on the timing of disruption relative to the developmental stage of the structure. The results also highlight that morphological measures from structural MRI have high sensitivity to disrupted developmental myelination of white matter tracts.

Keywords: Developing brain; Diffusion tensor imaging; MRI; Myelin; White matter.