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Traditionally, structural plasticity in the human brain has been considered to follow a linear or asymptotic increase over the course of training. However, recent studies using structural MRI revealed transient increases in grey matter volume (GMV) with learning. Furthermore, significant increases in white matter microstructure have been observed in white matter underlying motor cortex in animals at the last training day. Nevertheless, the involvement of activity-dependent myelination has received little attention and the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown.

In this thesis, to characterize the dynamics of learning-related structural changes in the mouse brain, we have combined a motor skilled learning paradigm with longitudinal in vivo magnetic resonance imaging and immunohistochemical investigation. Wholebrain voxel-based morphometry (VBM) analysis revealed non-linear decreases in GMV juxtaposed with non-linear increases in white matter volume (WMV) in both cortical and subcortical areas of the brain. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed a transient increase in myelin immunoreactivity. Further investigation using confocal microscopy confirmed these changes, specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that nonlinear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity.

Whole-brain VBM revealed non-linear decreases in GMV with learning in primary motor cortex (MOp), secondary motor cortex (MOs) and posterior parietal cortex (PTLp). These areas of the brain are known to be involved in sensory discrimination and motor selection. Using cross-sectional correlational tractography we found an increase in fractional anisotropy (FA) values with learning between MOs and MOp, PTLp and MOs and PTLp and MOp. Increases in FA values suggest an increase in connectivity, which can be attributed to an increase in axon density or myelination. Based on existent literature and our non-linear VBM changes with learning in the deep cerebellar nuclei we investigated synaptic plasticity using immunohistochemical examination of glutamate transporters. We found an increase of vesicular glutamate transporter 2 in pre-existing vesicular glutamate 1 synapses. Our data indicate that remodeling of synapses - in contrast to synaptogenesis – plays an important role in motor learning.

Altogether, these results highlight the importance of non-linear structural plasticity in the acquisition of dexterous motor skill and stress the relevance of adaptive myelination in learning.