Genetic dissection of the mouse CNS using magnetic resonance microscopy

Abstract

Purpose of review: Advances in magnetic resonance microscopy (MRM) make it practical to map gene variants responsible for structural variation in brains of many species, including mice and humans. We review results of a systematic genetic analysis of MRM data using as a case study a family of well characterized lines of mice.

Recent advances: MRM has matured to the point that we can generate high contrast, high-resolution images even for species as small as a mouse, with a brain merely 1/3000th the size of humans. We generated 21.5-micron data sets for a diverse panel of BXD mouse strains to gauge the extent of genetic variation, and as a prelude to comprehensive genetic and genomic analyses. Here we review MRM capabilities and image segmentation methods; heritability of brain variation; covariation of the sizes of brain regions; and correlations between MRM and classical histological data sets.

Summary: The combination of high throughput MRM and genomics will improve our understanding of the genetic basis of structure-function correlations. Sophisticated mouse models will be critical in converting correlations into mechanisms and in determining genetic and epigenetic causes of differences in disease susceptibility.

Figure 1

a) Horizontal image through a mouse brain acquired in 2005 (Cyr et al, 2005), out of the skull, at 43μm resolution, required a 109 minute acquisition. While excised mouse brain can use a smaller field of view, within skull images should be favored because they preserve the integrity of tissue, especially in areas like olfactory bulbs and cerebellum; b) Horizontal slice at a corresponding level, acquired in 2009, within the skull, with acquisition time of 10 min, i.e. better images in 1/10th the time.

Figure 2

The main elements of analysis, and bioinformatics tools for an MR based SOP for neuroanatomical phenotyping.

Figure 3

The use of active staining (Gd) and multiple imaging protocols allows high resolution MRI (T1 weighted at 21.5 (a), T2 weighted at 43 microns (b)) to emphasize a large number of structures in the mouse brain. Besides the volume and shape for the total brain (c), 33 structures have been segmented and quantified, including olfactory areas (Olf), striatum (CPu), septal nuclei, fimbria, hippocampus (Hc), Superior and inferior colliculi (SupCol, InfCol), and cerebellum (Cblm).

Figure 4

The extent of morphometric changes compared to controls range from subtle so as not be identifiable in the global volume (but localized to smaller regions) in the hippocampi of the Reeler mice, to a few percent (9%) in the striatum of the DAT-KO (Cyr, Caron et al. 2005) to 300% in the ventricles of the reeler mouse (Badea, Nicholls et al. 2007).

Figure 5

Covariance structure in CNS and identification of functional subgroups (previously published: NeuroImage Volume 45, Issue 4, 1 May 2009, Pages 1067-1079).