From observations in rodents, it has been suggested that the cellular basis of learning-dependent changes, detected using structural magnetic resonance imaging (MRI), may be increased dendritic spine density, alterations in astrocyte volume, and adaptations within intracortical myelin. Myelin plasticity is crucial for neurological function and active myelination is required for learning and memory. However, the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown. We used a motor skill learning paradigm in male mice to evaluate experience-dependent brain plasticity by voxel-based morphometry (VBM) in longitudinal MRI, combined with a cross-sectional immunohistochemical investigation. Whole brain VBM revealed non-linear decreases in grey matter volume (GMV) juxtaposed to non-linear increases in white matter volume (WMV) within GM that were best modelled by an asymptotic time course. Using an atlas-based cortical mask, we found non-linear changes with learning in primary and secondary motor areas and in somatosensory cortex. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed an increase in myelin immunoreactivity followed by a return towards baseline levels. Further investigations using quantitative confocal microscopy confirmed these changes specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that non-linear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity. Together, these observations indicate a non-linear increase of intracortical myelin during learning and support the hypothesis that myelin is a component of structural changes observed by VBM during learning.

T1-weighted images were acquired using a magnetization transfer (MT) pulse for increased contrast between tissue types with different transfer susceptibilities. We used a T1 3D FLASH sequence (TR/TE = 50/8 ms, flip angle = 20°, using 4 repetitions) with MT-weighting by Gaussian-shaped off-resonance irradiation (30 μT MT pulse, frequency offset 1.5 kHz, pulse duration 1.8 ms, flip angle 351.2°) performed at 9.4 T (Bruker BioSpec 94/20, running Paravision 6.0 software) with 100 μm isotropic spatial resolution using a 1H Quadrature transmit/receive MRI cryogenic mouse brain RF coil (MRI CryoProbe, Bruker, Germany) for signal reception. 

Some images were excluded from analysis (missing values) based on expert visual inspection.