Automated pipeline for anatomical phenotyping of mouse embryos using micro-CT.

The International Mouse Phenotyping Consortium (IMPC) plans to phenotype 20,000 single-gene knockout mice to gain an insight into gene function. Approximately 30% of these knockout mouse lines will be embryonic or perinatal lethal. The IMPC has selected three-dimensional (3D) imaging to phenotype these mouse lines at relevant stages of embryonic development in an attempt to discover the cause of lethality using detailed anatomical information.

Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome.

A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3.

Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia.

Tissue hypoxia likely contributes to anemia-induced organ injury and mortality. Severe anemia activates hypoxia-inducible factor (HIF) signaling by hypoxic- and neuronal nitric oxide (NO) synthase- (nNOS) dependent mechanisms. However, organ-specific hemoglobin (Hb) thresholds for increased HIF expression have not been defined.

Whole-brain mapping of behaviourally induced neural activation in mice.

The ability to visualize behaviourally evoked neural activity patterns across the rodent brain is essential for understanding the distributed brain networks mediating particular behaviours. However, current imaging methods are limited in their spatial resolution and/or ability to obtain brain-wide coverage of functional activity. Here, we describe a new automated method for obtaining cellular-level, whole-brain maps of behaviourally induced neural activity in the mouse.

Brain sparing in fetal mice: BOLD MRI and Doppler ultrasound show blood redistribution during hypoxia.

Mice reproduce many features of human pregnancy and have been widely used to model disorders of pregnancy. However, it has not been known whether fetal mice reproduce the physiologic response to hypoxia known as brain sparing, where blood flow is redistributed to preserve oxygenation of the brain at the expense of other fetal organs. In the present study, blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) and Doppler ultrasound were used to determine the effect of acute hypoxia on the fetal blood flow in healthy, pregnant mice.

Automatic anatomical labeling of the complete cerebral vasculature in mouse models.

Study of cerebral vascular structure broadens our understanding of underlying variations, such as pathologies that can lead to cerebrovascular disorders. The development of high resolution 3D imaging modalities has provided us with the raw material to study the blood vessels in small animals such as mice. However, the high complexity and 3D nature of the cerebral vasculature make comparison and analysis of the vessels difficult, time-consuming and laborious.

Gray matter volume is associated with rate of subsequent skill learning after a long term training intervention.

The ability to predict learning performance from brain imaging data has implications for selecting individuals for training or rehabilitation interventions. Here, we used structural MRI to test whether baseline variations in gray matter (GM) volume correlated with subsequent performance after a long-term training of a complex whole-body task. 44 naïve participants were scanned before undertaking daily juggling practice for 6weeks, following either a high intensity or a low intensity training regime.

PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria.

Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models.

Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression.

In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype × developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HTT gene (HET) vs.

Structural stabilization of tissue for embryo phenotyping using micro-CT with iodine staining.

The International Mouse Phenotyping Consortium has been established to conduct large-scale phenotyping of the approximately 23,000 single-gene knockout mice generated by the International Knockout Mouse Consortium to investigate the role of each gene in the mouse genome. Of the generated mouse lines, 30% are predicted to be embryonic lethal, requiring the implementation of imaging techniques and analysis tools specific to late gestation mouse embryo phenotyping. A well-adopted technique combines the use of iodinated contrast solutions and micro-computed tomography imaging.

Motor skill learning induces changes in white matter microstructure and myelination.

Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry.

Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas.

Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals' genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout.

Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs-linking magnetic resonance imaging findings to cellular pathology.

Background: Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear.

Methods: With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex.

A perfusion procedure for imaging of the mouse cerebral vasculature by X-ray micro-CT.

Background: Micro-CT is a novel X-ray imaging modality which can provide 3D high resolution images of the vascular network filled with contrast agent. The cerebrovascular system is a complex anatomical structure that can be imaged with contrast enhanced micro-CT. However, the morphology of the cerebrovasculature and many circulatory anastomosis in the brain result in high variations in the extent of contrast agent filling in the blood vessels and as a result, the vasculature of different subjects appear differently in the acquired images.

Design and implementation of a custom built optical projection tomography system.

Optical projection tomography (OPT) is an imaging modality that has, in the last decade, answered numerous biological questions owing to its ability to view gene expression in 3 dimensions (3D) at high resolution for samples up to several cm(3). This has increased demand for a cabinet OPT system, especially for mouse embryo phenotyping, for which OPT was primarily designed for. The Medical Research Council (MRC) Technology group (UK) released a commercial OPT system, constructed by Skyscan, called the Bioptonics OPT 3001 scanner that was installed in a limited number of locations.

Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion.

Recurrent deletions at the 22q11.2 locus have been established as a strong genetic risk factor for the development of schizophrenia and cognitive dysfunction. Individuals with 22q11.

A method for 3D immunostaining and optical imaging of the mouse brain demonstrated in neural progenitor cells.

It is important to understand changes in cell distribution that occur as a part of disease progression. This is typically achieved using standard sectioning and immunostaining, however, many structures and cell distribution patterns are not readily appreciated in two-dimensions, including the distribution of neural stem and progenitor cells in the mouse forebrain. Three-dimensional immunostaining in the mouse brain has been hampered by poor penetration.

Evaluation of bi-ventricular coronary flow patterns using high-frequency ultrasound in mice with transverse aortic constriction.

Using high-frequency color and pulsed Doppler ultrasound, we evaluated the flow patterns of the left (LCA), septal (SCA) and right (RCA) coronary arteries in mice with and without transverse aortic constriction (TAC). Fifty-two male C57BL/6J mice were subjected to TAC or a corresponding sham operation. At 2 and 8 wk post-surgery, Doppler flow spectra from the three coronary arteries, together with morphologic and functional parameters of the left and right ventricles, were measured.

Hippocampal volumes differ across the mouse estrous cycle, can change within 24 hours, and associate with cognitive strategies.

Recent human and rodent brain imaging studies have shown that the shape of the brain can be changed by experience. These mesoscopic alterations in neuroanatomy are hypothesized to be driven by changes at the level of neuronal processes. To examine whether the shape of the brain changes rapidly, we used MRI to examine changes in the volume of the hippocampus across the 4-6 day estrous cycle in the female mouse.

Mapping registration sensitivity in MR mouse brain images.

Nonlinear registration algorithms provide a way to estimate structural (brain) differences based on magnetic resonance images. Their ability to align images of different individuals and across modalities has been well-researched, but the bounds of their sensitivity with respect to the recovery of salient morphological differences between groups are unclear. Here we develop a novel approach to simulate deformations on MR brain images to evaluate the ability of two registration algorithms to extract structural differences corresponding to biologically plausible atrophy and expansion.

Cellular imaging and texture analysis distinguish differences in cellular dynamics in mouse brain tumors.

Purpose: The heterogeneous tumor cell population and dynamic microenvironment within a tumor lead to regional variations in cell proliferation, migration, and differentiation. In this work, MRI and optical projection tomography were used to examine and compare the redistribution of a cellular label in two mouse glioma models.

Methods: GL261 and 4C8 glioma cells labeled with iron oxide particles or with a fluorescent probe were injected into the brains of syngeneic mice and allowed to develop into ∼10-mm(3) tumors.

Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging.

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Autism-relevant phenotypes in the inbred mouse strain BTBR T+tf/J (BTBR) offer translational tools to discover biological mechanisms underlying unusual mouse behaviors analogous to symptoms of autism. Two of the most consistent findings with BTBR are lack of sociability as measured by the three-chamber social approach task and increased amount of time engaged in self-grooming in an empty cage.

Radiation-induced alterations in mouse brain development characterized by magnetic resonance imaging.

Purpose: The purpose of this study was to identify regions of altered development in the mouse brain after cranial irradiation using longitudinal magnetic resonance imaging (MRI).

Methods And Materials: Female C57Bl/6 mice received a whole-brain radiation dose of 7 Gy at an infant-equivalent age of 2.5 weeks.

If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse.

The mammalian brain and skull develop concurrently in a coordinated manner, consistently producing a brain and skull that fit tightly together. It is common that abnormalities in one are associated with related abnormalities in the other. However, this is not always the case.