With the wide access to studies of selected gene expressions in transgenic animals, mice have become the dominant species as cerebral disease models. Many of these studies are performed on animals of not more than eight weeks, declared as adult animals. Based on the earlier reports that full brain maturation requires at least three months in rats, there is a clear need to discern the corresponding minimal animal age to provide an "adult brain" in mice in order to avoid modulation of disease progression/therapy studies by ongoing developmental changes. For this purpose, we have studied anatomical brain alterations of mice during their first six months of age. Using T2-weighted and diffusion-weighted MRI, structural and volume changes of the brain were identified and compared with histological analysis of myelination. Mouse brain volume was found to be almost stable already at three weeks, but cortex thickness kept decreasing continuously with maximal changes during the first three months. Myelination is still increasing between three and six months, although most dramatic changes are over by three months. While our results emphasize that mice should be at least three months old when adult animals are needed for brain studies, preferred choice of one particular metric for future investigation goals will result in somewhat varying age windows of stabilization.
Longitudinal studies on brain pathology and assessment of therapeutic strategies rely on a fully mature adult brain to exclude confounds of cerebral developmental changes. Thus, knowledge about onset of adulthood is indispensable for discrimination of developmental phase and adulthood. We have performed a high-resolution longitudinal MRI study at 11.7T of male Wistar rats between 21days and six months of age, characterizing cerebral volume changes and tissue-specific myelination as a function of age. Cortical thickness reaches final value at 1month, while volume increases of cortex, striatum and whole brain end only after two months. Myelin accretion is pronounced until the end of the third postnatal month. After this time, continuing myelination increases in cortex are still seen on histological analysis but are no longer reliably detectable with diffusion-weighted MRI due to parallel tissue restructuring processes. In conclusion, cerebral development continues over the first three months of age. This is of relevance for future studies on brain disease models which should not start before the end of month 3 to exclude serious confounds of continuing tissue development.
Magnetic resonance imaging (MRI) has become increasingly important in ischemic stroke experiments in mice, especially because it enables longitudinal studies. Still, quantitative analysis of MRI data remains challenging mainly because segmentation of mouse brain lesions in MRI data heavily relies on time-consuming manual tracing and thresholding techniques. Therefore, in the present study, a fully automated approach was developed to analyze longitudinal MRI data for quantification of ischemic lesion volume progression in the mouse brain. We present a level-set-based lesion segmentation algorithm that is built using a minimal set of assumptions and requires only one MRI sequence (T2) as input. To validate our algorithm we used a heterogeneous data set consisting of 121 mouse brain scans of various age groups and time points after infarct induction and obtained using different MRI hardware and acquisition parameters. We evaluated the volumetric accuracy and regional overlap of ischemic lesions segmented by our automated method against the ground truth obtained in a semi-automated fashion that includes a highly time-consuming manual correction step. Our method shows good agreement with human observations and is accurate on heterogeneous data, whilst requiring much shorter average execution time. The algorithm developed here was compiled into a toolbox and made publically available, as well as all the data sets.
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