4D MEMRI atlas of neonatal FVB/N mouse brain development

Abstract

The widespread use of the mouse as a model system to study brain development has created the need for noninvasive neuroimaging methods that can be applied to early postnatal mice. The goal of this study was to optimize in vivo three-(3D) and four-dimensional (4D) manganese (Mn)-enhanced MRI (MEMRI) approaches for acquiring and analyzing data from the developing mouse brain. The combination of custom, stage-dependent holders and self-gated (motion-correcting) 3D MRI sequences enabled acquisition of high-resolution (100-µm isotropic), motion artifact-free brain images with a high level of contrast due to Mn-enhancement of numerous brain regions and nuclei. We acquired high-quality longitudinal brain images from two groups of FVB/N strain mice, six mice per group, each mouse imaged on alternate odd or even days (6 3D MEMRI images at each day) covering the developmental stages between postnatal days 1 to 11. The effects of Mn-exposure, anesthesia and MRI were assessed, showing small but significant transient effects on body weight and brain volume, which recovered with time and did not result in significant morphological differences when compared to controls. Metrics derived from deformation-based morphometry (DBM) were used for quantitative analysis of changes in volume, position and signal intensity of a number of brain regions. The cerebellum, a brain region undergoing significant changes in size and patterning at early postnatal stages, was analyzed in detail to demonstrate the spatiotemporal characterization made possible by this new atlas of mouse brain development. These results show that MEMRI is a powerful tool for quantitative analysis of mouse brain development, with great potential for in vivo phenotype analysis in mouse models of neurodevelopmental diseases.

4D atlas of the mouse embryo for precise morphological staging

“…This development of an embryonic 4D atlas shares several ideas with a study by Szulc et al, which used in vivo 3D magnetic resonance imaging and image registration to describe the anatomical development of postnatal mouse brain (Szulc et al, 2015).…”

A Mathematical Model of Granule Cell Generation During Mouse Cerebellum Development

“…2), when the majority of granule cells are generated (Sudarov & Joyner, 2007; Legué et al , 2015; Szulc et al , 2015). Histological analysis clearly revealed the increase in cerebellum size and complexity of foliation (Fig.…”

“…Conversion between cell numbers and tissue areas was made using the following simple formula: $${\mathrm{N}}_{\mathrm{normalo},\mathrm{normali}}=\frac{{\mathrm{A}}_{\mathrm{normalo},\mathrm{normali}}\times L}{v_c}$$ where v c is the volume of a granule cell, assumed to be 300-μm 3 (Mares et al, 1970; Seil & Herndon, 1970; Altman & Bayer, 1997), and L is the medial-lateral width (measured in μm) of the vermis (central cerebellum), containing lobule III from which we measured the data. Both histological and MRI studies have shown that L is relatively constant over the early postnatal developmental period, with most of the growth of the cerebellum occurring in the anterior-posterior direction, along the length of each of the lobules (Legué et al , 2015, Szulc et al , 2015). From MRI data (Szulc et al , 2015), we estimated L (measured along the medial-lateral outer contour of the vermis) to be 1775-μm (± 20%) between P2 and P14.…”

“…Both histological and MRI studies have shown that L is relatively constant over the early postnatal developmental period, with most of the growth of the cerebellum occurring in the anterior-posterior direction, along the length of each of the lobules (Legué et al , 2015, Szulc et al , 2015). From MRI data (Szulc et al , 2015), we estimated L (measured along the medial-lateral outer contour of the vermis) to be 1775-μm (± 20%) between P2 and P14.…”

“…The mammalian cerebellum provides a striking example of postnatal brain growth. In mouse, the cerebellum volume increases approximately 5-fold over the first 2 weeks after birth (Szulc et al , 2015), a period of marked molecular, cellular and large scale patterning changes (Sillitoe & Joyner, 2007; Sudarov & Joyner, 2007; Martinez et al , 2013). At the cellular level, the granule cell precursor (gcp) cells proliferate in the outer layer of the EGL in response to the mitogen Sonic Hedgehog (SHH), secreted by nearby Purkinje neurons (Wechsler-Reya & Scott, 1999; Dahmane & Ruiz I Altaba, 1999; Wallace, 1999).…”