Neuroanatomical phenotyping of the mouse brain with three-dimensional autofluorescence imaging.

The structural organization of the brain is important for normal brain function and is critical to understand in order to evaluate changes that occur during disease processes. Three-dimensional (3D) imaging of the mouse brain is necessary to appreciate the spatial context of structures within the brain. In addition, the small scale of many brain structures necessitates resolution at the ∼10 μm scale.

Performing label-fusion-based segmentation using multiple automatically generated templates.

Classically, model-based segmentation procedures match magnetic resonance imaging (MRI) volumes to an expertly labeled atlas using nonlinear registration. The accuracy of these techniques are limited due to atlas biases, misregistration, and resampling error. Multi-atlas-based approaches are used as a remedy and involve matching each subject to a number of manually labeled templates.

Neuroanatomical Assessment of the Integrin β3 Mouse Model Related to Autism and the Serotonin System Using High Resolution MRI.

The integrinβ3 (ITGβ3) gene has been associated with both autism and the serotonin system. The purpose of this study was to examine the volumetric differences in the brain of an ITGβ3 homozygous knockout mouse model compared with a corresponding wild-type mouse using high resolution magnetic resonance imaging and detailed statistical analyses. The most striking difference found was an 11% reduction in total brain volume.

Preparation of fixed mouse brains for MRI.

In fixed mouse brain magnetic resonance images, a high prevalence of fixation artifacts have been observed. Of more than 1700 images of fixed brains acquired at our laboratory, fixation artifacts were present in approximately 30%. In this study, two of these artifacts are described and their causes are identified.

Expansion of the fetoplacental vasculature in late gestation is strain dependent in mice.

How the fetoplacental arterial tree grows and expands during late gestational development is largely unknown. In this study, we quantified changes in arterial branching in the fetal exchange region of the mouse placenta during late gestation, when capillarization increases rapidly. We studied two commonly used mouse strains, CD1 and C57Bl/6 (B6), at embryonic days (E)13.

Robust method for 3D arterial spin labeling in mice.

Arterial spin labeling is a versatile perfusion quantification methodology, which has the potential to provide accurate characterization of cerebral blood flow (CBF) in mouse models. However, a paucity of physiological data needed for accurate modeling, more stringent requirements for gradient performance, and strong artifacts introduced by magnetization transfer present special challenges for accurate CBF mapping in the mouse. This article describes robust mapping of CBF over three-dimensional brain regions using amplitude-modulated continuous arterial spin labeling.

Genes into geometry: imaging for mouse development in 3D.

Mammalian development is a sophisticated program coordinated by a complex set of genetic and physiological factors. Alterations in anatomy or morphology provide intrinsic measures of progress in or deviations from this program. Emerging three-dimensional imaging methods now allow for more sophisticated morphological assessment than ever before, enabling comprehensive phenotyping, visualization of anatomical context and patterns, automated and quantitative morphological analysis, as well as improved understanding of the developmental time course.

Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism.

Magnetic resonance imaging (MRI) has been used quite extensively for examining morphological changes in human and animal brains. One of the many advantages to examining mouse models of human autism is that we are able to examine single gene targets, like that of Neuroligin3 R451C knockin (NL3 KI), which has been directly implicated in human autism. The NL3 KI mouse model has marked volume differences in many different structures in the brain: gray matter structures, such as the hippocampus, the striatum, and the thalamus, were all found to be smaller in the NL3 KI.

Mouse phenotyping with MRI.

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. Image results can provide important comparisons of human conditions with mouse disease models, evaluations of treatment, development or disease progression, as well as direction for histological or other investigations. Effective mouse MRI studies require attention to many aspects of experiment design.

Multiple-mouse neuroanatomical magnetic resonance imaging.

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. MRI is an excellent modality for investigating genetically altered animals. It is capable of whole brain coverage, can be used in vivo, and provides multiple contrast mechanisms for investigating different aspects of neuranatomy and physiology.

Semi-automatic segmentation of multiple mouse embryos in MR images.

Background: The motivation behind this paper is to aid the automatic phenotyping of mouse embryos, wherein multiple embryos embedded within a single tube were scanned using Magnetic Resonance Imaging (MRI).

Results: Our algorithm, a modified version of the simplex deformable model of Delingette, addresses various issues with deformable models including initialization and inability to adapt to boundary concavities. In addition, it proposes a novel technique for automatic collision detection of multiple objects which are being segmented simultaneously, hence avoiding major leaks into adjacent neighbouring structures.

MRI phenotyping of genetically altered mice.

The laboratory mouse, with its genetic similarity to humans and rich set of tools for manipulating its genome, has emerged as one of the key models for experimental investigation of the genotype/phenotype relationships in mammals. Recent innovations have made MRI an increasingly popular tool for examining the phenotype of genetically altered mice. Advances in field strengths, mouse handling, image analysis and statistics have contributed greatly in this regard.

Vessel tortuousity and reduced vascularization in the fetoplacental arterial tree after maternal exposure to polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and the main toxicants found in cigarettes. Women are often exposed to PAHs before pregnancy, typically via prepregnancy smoking. To determine how prepregnancy exposure affects the fetoplacental vasculature of the placenta, we exposed female mice to PAHs before conception, perfused the fetoplacental arterial trees with X-ray contrast agent, and imaged the vasculature ex vivo by microcomputed tomography (micro-CT) at embryonic day 15.

Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning.

Multiple recent human imaging studies have suggested that the structure of the brain can change with learning. To investigate the mechanism behind such structural plasticity, we sought to determine whether maze learning in mice induces brain shape changes that are detectable by MRI and whether such changes are specific to the type of learning. Here we trained inbred mice for 5 days on one of three different versions of the Morris water maze and, using high-resolution MRI, revealed specific growth in the hippocampus of mice trained on a spatial variant of the maze, whereas mice trained on the cued version were found to have growth in the striatum.

Ultrasound and magnetic resonance microimaging of mouse development.

Ultrasound biomicroscopy (UBM) and magnetic resonance microimaging (micro-MRI) provide noninvasive, high-resolution images in mouse embryos and neonates, enabling volumetric and functional analyses of phenotypes, including longitudinal imaging of individual mice over critical stages of in utero and early-postnatal development. In this chapter, we describe the underlying principles of UBM and micro-MRI, including the advantages and limitations of these approaches for studies of mouse development, and providing a number of examples to illustrate their use. To date, most imaging studies have focused on the developing nervous and cardiovascular systems, which are also reflected in the examples shown in this chapter, but we also discuss the future application of these methods to other organ systems.

Comparative SNR for high-throughput mouse embryo MR microscopy.

MR microscopy is being explored as a useful imaging tool to phenotype mouse embryos due to its volume coverage with three-dimensional isotropic resolution. However, the main limitation for mouse embryo MR microscopy is the signal-to-noise ratio. Large numbers of embryos are needed for phenotypic screening, making high throughput essential.

Systems biology through mouse imaging centers: experience and new directions.

The completed sequencing of genomes has forced upon us the challenge of understanding how the detailed information in the genome gives rise to the specific characteristics--phenotype--of the individual. This is crucial for understanding not only normal development but also, from a medical perspective, the genetic basis of disease. Much of the mammalian genome-to-phenotype relationship will be worked out in the mouse, for which powerful genetic-manipulation tools are available.

Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging.

Fragile X Syndrome (FXS) is the most common single gene cause of inherited mental impairment, and cognitive deficits can range from simple learning disabilities to mental retardation. Human FXS is caused by a loss of the Fragile X Mental Retardation Protein (FMRP). The fragile X knockout (FX KO) mouse also shows a loss of FMRP, as well as many of the physical and behavioural characteristics of human FXS.

Aortic regurgitation dramatically alters the distribution of atherosclerotic lesions and enhances atherogenesis in mice.

Objective: Hemodynamics plays a critical role in atherogenesis, but the association between flow pattern and preferential localization of lesion is not fully understood. We developed a mouse model of aortic valve regurgitation (AR) to change the aortic flow pattern and observed the effects on plaque formation.

Methods And Results: High-frequency Doppler ultrasound imaging of 10 untreated C57BL/6J mice and 6 sham-treated low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice revealed consistent antegrade blood flow throughout the aorta and oscillatory flow only along the lesser curvature of the aortic arch.

Comparative structural and hemodynamic analysis of vascular trees.

The availability of detailed three-dimensional images of vascular trees from mammalian organs provides a wealth of essential data for understanding the processes and mechanisms of vascular patterning. Using this detailed geometric data requires the ability to compare individual representations of vascular trees in statistically meaningful ways. This article provides some comparisons of geometry and also of simulated hemodynamics, enabling the identification of similarities and differences among 10 individual specimens (5 placenta specimens and 5 lung specimens).

The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1.

Nedd4 (Nedd4-1) is a Hect domain E3 ubiquitin ligase that also contains a C2 domain and three WW domains. Despite numerous in vitro studies, its biological function in vivo is not well understood. Here we show that disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities.

Cerebral asymmetries in 12-week-old C57Bl/6J mice measured by magnetic resonance imaging.

Asymmetries of multiple components of the rodent cerebrum have been described at various levels of organization. Yet, despite its ubiquitous nature, many confusing and sometimes contradictory reports regarding structural asymmetries in the rodent brain have been published. There is a need, therefore, for a whole-brain imaging analysis technique for asymmetry studies that is both accurate, reproducible and robust.

Information content of SNR/resolution trade-offs in three-dimensional magnetic resonance imaging.

In MRI, a trade-off exists between resolution and signal-to-noise ratio, since different fractions of the available scan time can be used to acquire data at higher spatial frequencies and to perform signal averaging. By comparing a wide variety of 3D isotropic MR scans with different combinations of SNR, resolution, and scan duration, the impact of this trade-off on the image information content was assessed. The information content of mouse brain, mouse whole-body, and human brain images was evaluated using a simple numerical approach, which sums the information contribution of each individual k-space data point.

Measurement of cerebral blood volume in mouse brain regions using micro-computed tomography.

Micro-computed tomography (micro-CT) is an X-ray imaging technique that can produce detailed 3D images of cerebral vasculature. This paper describes the development of a novel method for using micro-CT to measure cerebral blood volume (CBV) in the mouse brain. As an application of the methodology, we test the hypotheses that differences in CBV exist over anatomical brain regions and that high energy demanding primary sensory regions of the cortex have locally elevated CBV, which may reflect a vascular specialization.

Trading off SNR and resolution in MR images.

With a fixed time to acquire a magnetic resonance (MR) image, time can be spent to acquire better spatial resolution with decrease in signal-to-noise ratio (SNR) or decreased resolution with increase in SNR. This resolution/SNR tradeoff at fixed time has been investigated by a visual rater study using images of ex vivo mouse brains. Simulated images with a tradeoff between SNR and resolution were produced from high-quality, 3D isotropic mouse brain images to emulate shorter constant acquisition times.