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Structural correlates of active-staining following magnetic resonance microscopy in the mouse brain
Jon O Cleary1, Frances K Wiseman, Francesca C Norris
1Centre for Advanced Biomedical Imaging, Department of Medicine and Institute of Child Health, University College London, London, UK.
Abstract:
Extensive worldwide efforts are underway to produce knockout mice for each of the ~25,000 mouse genes, which may give new insights into the underlying pathophysiology of neurological disease. Microscopic magnetic resonance imaging (microMRI) is a key method for non-invasive morphological phenotyping, capable of producing high-resolution 3D images of ex-vivo brains, after fixation with an MR contrast agent. These agents have been suggested to act as active-stains, enhancing structures not normally visible on MRI. In this study, we investigated the structural correlates of the MRI agent Gd-DTPA, together with the optimal preparation and scan parameters for contrast-enhanced gradient-echo imaging of the mouse brain. We observed that in-situ preparation was preferential to ex-situ due to the degree of extraction damage. In-situ brains scanned with optimised parameters, enabled images with a high signal-to-noise-ratio (SNR ~30) and comprehensive anatomical delineation. Direct correlation of the MR brain structures to histology, detailed fine histoarchitecture in the cortex, cerebellum, olfactory bulb and hippocampus. Neurofilament staining demonstrated that regions of negative MR contrast strongly correlated to myelinated white-matter structures, whilst structures of more positive MR contrast corresponded to areas with high grey matter content. We were able to identify many sub-regions, particularly within the hippocampus, such as the unmyelinated mossy fibres (stratum lucidum) and their region of synapse in the stratum pyramidale, together with the granular layer of the dentate gyrus, an area of densely packed cell bodies, which was clearly visible as a region of hyperintensity. This suggests that cellular structure influences the site-specific distribution of the MR contrast agent, resulting in local variations in T(2)*, which leads to enhanced tissue discrimination. Our findings provide insights not only into the cellular distribution and mechanism of MR active-staining, but also allow for three dimensional analysis, which enables interpretation of magnetic resonance microscopy brain data and highlights cellular structure for investigation of disease processes in development and disease.
Insights
This study optimized microscopic magnetic resonance imaging (microMRI) for mouse brains using Gd-DTPA contrast agents. Optimized methods revealed detailed brain structures, correlating MRI contrast to cellular composition for neurological disease research.
Area of Science:
- Neuroscience
- Biomedical Imaging
- Radiology
Background:
- Knockout mouse models are crucial for understanding neurological disease pathophysiology.
- Microscopic magnetic resonance imaging (microMRI) is vital for non-invasive morphological phenotyping of mouse brains.
- MR contrast agents enhance structural visibility in microMRI, acting as active stains.
Purpose of the Study:
- Investigate the structural correlates of the MR contrast agent Gd-DTPA in mouse brains.
- Determine optimal preparation and scan parameters for contrast-enhanced gradient-echo microMRI.
- Correlate microMRI findings with histology to understand contrast agent distribution and mechanism.
Main Methods:
- Compared in-situ versus ex-situ brain preparation for microMRI.
- Optimized gradient-echo imaging parameters for contrast-enhanced microMRI.
- Performed histological analysis, including neurofilament staining, for direct correlation with microMRI data.
Main Results:
- In-situ preparation yielded superior results, minimizing extraction damage.
- Optimized parameters achieved high signal-to-noise ratio (SNR ~30) and comprehensive anatomical delineation.
- MR contrast directly correlated with tissue type: negative contrast in white matter (myelin), positive contrast in grey matter (cell bodies).
- Detailed sub-regions, including hippocampal mossy fibers and dentate gyrus granular layer, were clearly visualized.
- Identified site-specific contrast agent distribution influenced by cellular structure, leading to enhanced tissue discrimination via T(2)* variations.
Conclusions:
- Optimized in-situ microMRI with Gd-DTPA provides high-resolution 3D imaging of mouse brains.
- MR contrast actively stains tissues based on cellular composition, enabling detailed histoarchitectural analysis.
- This technique enhances the interpretation of microMRI data and facilitates the investigation of cellular structures in neurological development and disease.
