In vivo magnetic resonance imaging and semiautomated image analysis extend the brain phenotype for cdf/cdf mice

Abstract

Magnetic resonance imaging and computer image analysis in human clinical studies effectively identify abnormal neuroanatomy in disease populations. As more mouse models of neurological disorders are discovered, such an approach may prove useful for translational studies. Here, we demonstrate the effectiveness of a similar strategy for mouse neuroscience studies by phenotyping mice with the cerebellar deficient folia (cdf) mutation. Using in vivo multiple-mouse magnetic resonance imaging for increased throughput, we imaged groups of cdf mutant, heterozygous, and wild-type mice and made an atlas-based segmentation of the structures in 15 individual brains. We then performed computer automated volume measurements on the structures. We found a reduced cerebellar volume in the cdf mutants, which was expected, but we also found a new phenotype in the inferior colliculus and the olfactory bulbs. Subsequent local histology revealed additional cytoarchitectural abnormalities in the olfactory bulbs. This demonstrates the utility of anatomical magnetic resonance imaging and semiautomated image analysis for detecting abnormal neuroarchitecture in mutant mice.

Figure 1.

Image registration and labeling. Top, Five wild-type brain images acquired from the MRI. Middle, The average wild-type atlas image superimposed with manual labeling. Bottom, The original acquired images superimposed with automatic labeling. Yellow, Olfactory bulbs; green, lateral ventricles; orange, hippocampus; red, inferior colliculus; blue, cerebellum.

Figure 2.

Three-dimensional brain structure comparison. Volume renderings of the wild-type average atlas (left) and the cdf/cdf mutant average atlas (right). Large shape and volume differences are seen in the cerebellum and ventricular system of the cdf mutant mouse, whereas there is a subtle visible reduction in the volume of the inferior colliculus and olfactory bulbs.

Figure 3.

Brain structure volume measurements (mean ± SEM; n = 5). Significant findings are reported at the *p ≤ 0.05 level and the **p ≤ 0.001 level.

Figure 4.

Comparative MRI and histology in the inferior colliculus and olfactory bulbs. a, Slices at the inferior colliculus from the wild-type and cdf/cdf average MRI atlases. b, Corresponding H&E-stained sections. c, Slices at the olfactory bulb from the from the wild-type and cdf/cdf average MRI atlases. d, Corresponding H&E sections. e, Enlarged view of the H&E sections. GCL, Granule cell layer; IPL, internal plexiform layer; MCL, mitral cell layer; EPL, external plexiform layer; GL, glomerular layer. Note that the IPL is absent in the cdf/cdf mutant. Scale bars, 1 mm.