White matter microstructural integrity continues to develop from adolescence to young adulthood in mice and humans: Same phenotype, different mechanism

Abstract

As direct evaluation of a mouse model of human neurodevelopment, adolescent and young adult mice and humans underwent MR diffusion tensor imaging to quantify age-related differences in microstructural integrity of brain white matter fibers. Fractional anisotropy (FA) was greater in older than younger mice and humans. Despite the cross-species commonality, the underlying developmental mechanism differed: whereas evidence for greater axonal extension contributed to higher FA in older mice, evidence for continuing myelination contributed to higher FA in human adolescent development. These differences occurred in the context of species distinctions in overall brain growth: whereas the continued growth of the brain and skull in the murine model can accommodate volume expansion into adulthood, human white matter volume and myelination continue growth into adulthood within a fixed intracranial volume. Appreciation of the similarities and differences in developmental mechanism can enhance the utility of animal models of brain white matter structure, function, and response to exogenous manipulation.

Keywords: Adolescence; Development; Diffusion tensor imaging; Human; Mouse; Translational.

Fig. 1

TBSS skeletons for both mice (top) and humans (bottom) are presented in green. In red, the results of permutation testing showing voxels in which young adult mice or humans have higher FA than their early-adolescent counterparts.

Fig. 2

Mouse (left column) and human (right column) showing overlapping distributions of water diffusion indices. In both mice and humans, adults showed significantly higher fractional anisotropy (FA) compared with adolescents (row 1). However, species differed in underlying mechanism, with greater age-related axial diffusivity driving this effect in mice (row 3) but lower radial diffusivity driving this affect in older humans (row 4). Ellipsoid models showing age related differences in axial diffusivity in mice and radial diffusivity in humans present a schematic representation for the observed differences in water diffusion. Fig. 3 top: Mouse: Upper left—Adult mice had significantly larger white matter volumes than adolescent mice. Upper middle—White matter volume as a function of total brain volume for adolescents (gray) and adults (black). The across-group regression across all mice is dashed gray. Upper right—white matter volumes after regression on total brain volume. Note that the adult-adolescence difference endured after adjustment for total brain volume.

Fig. 3

Top: Mouse: Upper left—Adult mice had significantly larger white matter volumes than adolescent mice. Upper middle—White matter volume as a function of total brain volume for adolescents (gray) and adults (red). The across-group regression across all mice is dashed gray. Upper right—white matter volumes after regression on total brain volume. Note that the adult-adolescence difference endured after adjustment for total brain volume. Bottom: Human: Lower left—Adolescents and adults did not differ in white matter volume. Lower middle—White matter volume as a function of total brain volume across all participants, with adolescents in gray and adults in red and across all participant regression in dashed gray. Lower right—white matter volumes after regression on total intracranial volume (ICV). Note that an adult-adolescence difference manifest after adjustment for ICV.