Insights gained from Voxel Based morphometry (VBM) tremendously advance the understanding of neurologic and psychiatric diseases. However, the cellular basis of VBM changes remains largely unclear. We used longitudinal two-photon fluorescence and magnetic resonance imaging in mice to explore the cellular basis of VBM. Our data shows that MRI volume changes are only limited reflected by physical volume changes, yet dominated by cellular composition and cytoarchitectural characteristics. This has great implications for findings in neuroimaging in general, and the novel approach introduced by this study can be applied to various disease models to potentially unravel key mechanisms of brain pathophysiology.