Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) of mouse brain development

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
NMR in Biomedicine (Impact Factor: 3.04). 11/2004; 17(8):613-9. DOI: 10.1002/nbm.932
Source: PubMed


Given the importance of genetically modified mice in studies of mammalian brain development and human congenital brain diseases, MRI has the potential to provide an efficient in vivo approach for analyzing mutant phenotypes in the early postnatal mouse brain. The combination of reduced tissue contrast at the high magnetic fields required for mice, and the changing cellular composition of the developing mouse brain make it difficult to optimize MRI contrast in neonatal mouse imaging. We have explored an easily implemented approach for contrast-enhanced imaging, using systemically administered manganese (Mn) to reveal fine anatomical detail in T1-weighted MR images of neonatal mouse brains. In particular, we demonstrate the utility of this Mn-enhanced MRI (MEMRI) method for analyzing early postnatal patterning of the mouse cerebellum. Through comparisons with matched histological sections, we further show that MEMRI enhancement correlates qualitatively with granule cell density in the developing cerebellum, suggesting that the cerebellar enhancement is due to uptake of Mn in the granule neurons. Finally, variable cerebellar defects in mice with a conditional mutation in the Gbx2 gene were analyzed with MEMRI to demonstrate the utility of this method for mutant mouse phenotyping. Taken together, our results indicate that MEMRI provides an efficient and powerful in vivo method for analyzing neonatal brain development in normal and genetically engineered mice.

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Available from: Youssef Zaim Wadghiri, Oct 11, 2015
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    • "ms, matrix = 280 × 168 × 168, field-of-view = 21 × 21 × 35 mm, repeats = 2, total imaging time = 1.5 h). Twenty-four hours before each imaging session, mice received 0.4 mmol/kg MnCl 2 intraperitoneally for contrast enhancement (Wadghiri et al., 2004). The MnCl 2 -solution was distributed equally across two injections administered 1 h apart to minimize potential adverse effects from peak MnCl 2 -concentration (Sepúlveda et al., 2012). "
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    ABSTRACT: Environmental enrichment is a model of increased structural brain plasticity. Previous histological observations have shown molecular and cellular changes in a few pre-determined areas of the rodent brain. However, little is known about the time course of enrichment-induced brain changes and how they distribute across the whole brain. Here we expose adult mice to three weeks of environmental enrichment using a novel re-configurable maze design. In-vivo MRI shows volumetric brain changes in brain areas related to spatial memory, navigation, and sensorimotor experience, such as the hippocampal formation and the sensorimotor cortex. Evidence from a second cohort of mice indicates that these plastic changes might occur as early as 24h after exposure. This suggests that novel experiences are powerful modulators of plasticity even in the adult brain. Understanding and harnessing the underlying molecular mechanisms could advance future treatments of neurological disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    NeuroImage 01/2015; 109. DOI:10.1016/j.neuroimage.2015.01.027 · 6.36 Impact Factor
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    • "In vivo MEMRI Allowed Noninvasive Detection of MB Tumors in Ptch1-CKO Mice As demonstrated previously [49] [53], in vivo MEMRI images showed region-specific signal and contrast enhancement in the mouse brain and allowed more detailed visualization of normal Cb morphology when compared to a non-MEMRI image (Figure 1, A and B). Abnormal Cb lesions were detected and easily delineated as hypointense regions within the enhanced Cb (Figure 1, C–E) in 74 of 92 Ptch1-CKO mice imaged with MEMRI between 11 and 28 weeks of age (80%). "
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    ABSTRACT: Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15 minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm(3). Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual Ptch1-CKO mice. These results show that MEMRI provides a powerful method for early in vivo detection and longitudinal imaging of MB progression in the mouse brain.
    Neoplasia (New York, N.Y.) 12/2014; 16(12):993. DOI:10.1016/j.neo.2014.10.001 · 4.25 Impact Factor
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    • "Importantly, Mn2+ accumulates intracellularly due to a slow rate of efflux and acts as an MRI contrast agent by increasing the tissue longitudinal relaxation rate (R1 = 1/T1) in proportion to manganese concentration [16], [17]. Manganese-enhanced MRI (MEMRI) has been successfully used to functionally image brain [16], [18], [19], [20], [21] and retinal [22], [23], [24] activity, as well as the activity of other tissues [25]. These considerations suggest that MEMRI might be usefully applied to monitor tumor cell proliferation. "
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    ABSTRACT: Tumor cell proliferation can depend on calcium entry across the cell membrane. As a first step toward the development of a non-invasive test of the extent of tumor cell proliferation in vivo, we tested the hypothesis that tumor cell uptake of a calcium surrogate, Mn(2+) [measured with manganese-enhanced MRI (MEMRI)], is linked to proliferation rate in vitro. Proliferation rates were determined in vitro in three different human tumor cell lines: C918 and OCM-1 human uveal melanomas and PC-3 prostate carcinoma. Cells growing at different average proliferation rates were exposed to 1 mM MnCl(2) for one hour and then thoroughly washed. MEMRI R(1) values (longitudinal relaxation rates), which have a positive linear relationship with Mn(2+) concentration, were then determined from cell pellets. Cell cycle distributions were determined using propidium iodide staining and flow cytometry. All three lines showed Mn(2+)-induced increases in R(1) compared to cells not exposed to Mn(2+). C918 and PC-3 cells each showed a significant, positive correlation between MEMRI R(1) values and proliferation rate (p≤0.005), while OCM-1 cells showed no significant correlation. Preliminary, general modeling of these positive relationships suggested that pellet R(1) for the PC-3 cells, but not for the C918 cells, could be adequately described by simply accounting for changes in the distribution of the cell cycle-dependent subpopulations in the pellet. These data clearly demonstrate the tumor-cell dependent nature of the relationship between proliferation and calcium influx, and underscore the usefulness of MEMRI as a non-invasive method for investigating this link. MEMRI is applicable to study tumors in vivo, and the present results raise the possibility of evaluating proliferation parameters of some tumor types in vivo using MEMRI.
    PLoS ONE 02/2012; 7(2):e30572. DOI:10.1371/journal.pone.0030572 · 3.23 Impact Factor
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