Spatiotemporal maturation patterns of murine brain quantified by diffusion tensor MRI and deformation-based morphometry

Abstract

Highly heterogeneous spatiotemporal patterns of maturation of the murine brain during the first 80 postnatal days were examined by high-dimensional deformation-based morphometry applied to high-resolution diffusion tensor MRIs. The maturation profile revealed a sharp contrast between tissue anisotropy changes in the cortex and in major white-matter fibers. Radially oriented tissue anisotropy was measured during the first postnatal week in cortical regions, reflecting the underlying columnar organization of the cortex. Subsequently, tissue anisotropy reduced rapidly, potentially reflecting the growth of randomly oriented dendritic trees that reduce tissue coorientation. Distinct anisotropy patterns were also observed along layer I of the cortex and were attributed to thin fibers oriented parallel to the outer surface. Last, spatially complex patterns of maturation were measured in all major axonal pathways and in the hippocampus, caudate putamen, and cerebellum. This analysis provides a framework for quantifying normative maturation patterns against which phenotypes of mice of different genetic and environmental backgrounds can be contrasted.

Fig. 1.

Visualization of spatial coregistration. The 3D volume-rendered FA maps of three representative murine brains of ages 2, 10, and 80 days (postnatally) are color-coded (red, high; blue, low) to show the internal anatomy. Red arrows show renditions of their deformed versions. After coregistration, all deformed images were averaged to form the image rendered in Inset, along with sections revealing internal structures displaying high average FA across different ages.

Fig. 2.

Color-coded maps of rate of change of FA per day, obtained by regression on spatially coregistered mouse brains from days 2–80. The regions of special interest that show a large change in FA are as follows: A, cortex; B, ec; C, fissures of the cerebellum; D, genu of cc; E, ic; F, hpc; G, vhc; H, cpu; J, dhc; K, ac; and L, splenium of cc. The color coding shows, in the 80 days, the FA of the cortex, cpu, and hpc is reduced, whereas the FA of the ic and ec, splenium, and genu of the cc and ac increases.

Fig. 3.

Average and difference maps of FA. (a–c) Various slices from the average maps of the young (before day 10), adolescent (days 10–45), and near-adult mice (beyond day 45). (d) The difference between the young and adolescent mice. (e) The difference between adolescent and near-adult mice. The slices shown are 58, 80, 95, and 102, in which the total brain is represented by a 280 × 280 × 140 image. The left color bar is for a–c, and the right bar is for d and e.

Fig. 4.

Regional changes in FA value in the three developmental stages of young, adolescent, and near-adult mice (see Fig. 3). The following marked regions (see Fig. 2) were used to sample several structures and graph their temporal change: ic, ac, vhc, cortex (2 regions), cpu, fissures of the cerebellum (cereb1 and cereb2), dhc, two regions in the hpc (hpc1 and hpc2), ec, and the genu and the splenium of the cc. The graphs show the nonlinear regression maps of each of the regions.

Fig. 5.

Average of coregistered DT images of young and near-adult mice (see Fig. 3) color-coded according to tissue directionality. White lines in Left are representative samples from this orientation map, many of which reflect the radial orientation of cortical tissue, and others the orientation of fiber bundles. The orientation does not change much in Right, albeit the FA, represented by the color intensity, decreases in the cortex and increases in WM fibers, which can be attributed to formation of randomly oriented cortical dendritic trees and fiber maturation processes, respectively. Note that cyan, having equal blends of blue and green, corresponds to diagonal orientations. Red reflects orientation perpendicular to the image plane.