Rong Xue

In vivo three-dimensional reconstruction of rat brain axonal projections by diffusion tensor imaging.

The in situ assessment of axonal projections of the brain has been severely limited by the lack of noninvasive techniques to study this type of anatomy. We show here that in vivo three‐dimensional (3D) reconstruction of axonal projections can be achieved using a rapid 3D high‐resolution diffusion‐weighted imaging technique combined with a recently designed fiber reconstruction algorithm. As a first example, neuronal pathways in the rat brain were probed. Eight well‐known fiber projections; genu and splenium of corpus callosum, internal and external capsule, fimbria, anterior commissure, optic tract, and stria terminalis were tracked and shown to be in agreement with the location of these known axonal projections. The experiment took 2 hr and shorter times should be possible in the clinical situation. By combining anisotropy information with fiber tracking, the anisotropy of individual projections was also documented. Magn Reson Med 42:1123–1127, 1999.

Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans

Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the αCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.

Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood–brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia

The formation of brain edema, commonly occurring as a potentially lethal complication of acute hyponatremia, is delayed following knockout of the water channel aquaporin‐4 (AQP4). Here we show by high‐resolution immunogold analysis of the blood–brain‐barrier that AQP4 is expressed in brain endothelial cells as well as in the perivascular membranes of astrocyte endfeet. A selective removal of perivascular AQP4 by α‐syntrophin deletion delays the buildup of brain edema (assessed by Diffusion‐weighted MRI) following water intoxication, despite the presence of a normal complement of endothelial AQP4. This indicates that the perivascular membrane domain, which is peripheral to the endothelial blood–brain barrier, may control the rate of osmotically driven water entry. This study is also the first to demonstrate that the time course of edema development differs among brain regions, probably reflecting differences in aquaporin‐4 distribution. The resolution of the molecular basis and subcellular site of osmotically driven brain water uptake should help design new therapies for acute brain edema.

Poly(ADP-Ribose) Polymerase Impairs Early and Long-Term Experimental Stroke Recovery

Background and Purpose— Poly(ADP-ribose) polymerase (PARP-1; Enzyme Commission 2.4.30) is a nuclear DNA repair enzyme that mediates early neuronal ischemic injury. Using novel 3-dimensional, fast spin-echo-based diffusion-weighted imaging, we compared acute (21 hours) and long-term (3 days) ischemic volume after middle cerebral artery (MCA) occlusion in PARP-1-null mutants (PARP−/−) versus genetically matched wild-type mice (WT mice). PARP−/− mice were also treated with viral transfection of wild-type PARP-1 to determine whether protection from MCA occlusion is lost with restoration of the gene product. Methods— Halothane-anesthetized mice were treated with reversible MCA occlusion via intraluminal suture technique. Ischemic volumes were delineated by diffusion-weighted imaging with high spatial and temporal resolution during MCA occlusion and reperfusion. Recombinant Sindbis virus carrying &bgr;-galactosidase (lacZ) or PARP-1 was injected into ipsilateral striatum, then animals underwent MCA occlusion 3 days later. Infarction volume was measured at 22 hours of reperfusion (2,3,5-triphenyltetrazolium chloride histology). Results— Reduction in regional water apparent diffusion coefficient (ADC) during occlusion or secondary ADC decline during reperfusion was not different between groups. Ischemic volume was smaller early in occlusion in PARP−/− versus WT mice and remained less at 21 hours of reperfusion. Ischemic volume then increased from 1 to 2 days in all mice, then stabilized without further change. Ischemic damage was smaller in PARP−/− than in WT mice at 3 days. Transfection of PARP-1 into PARP−/− mice increased stroke damage relative to lacZ-injected PARP−/− and increased damage to that of the WT mice. Intraischemic laser-Doppler flowmetry and physiological variables were not different among groups. Conclusions— PARP-1 deficiency provides both early and prolonged protection from experimental focal stroke. The mechanism is not linked to preservation of ADC and mitigation of secondary energy depletion during early reperfusion.

Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice

Neural stem cell (NSC) transplantation has been shown to attenuate the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Central to the future success of NSC transplantation in MS is the ability of transplanted cells to migrate from the site of transplantation to relevant foci of disease. Using magnetically labeled mouse neurospheres and human embryonic stem cell (hESC)‐derived neurospheres, we applied serial magnetic resonance imaging (MRI) to assess the biodynamics of transplanted cell migration in a chronic mouse EAE model. Magnetic labeling did not affect the in vitro and in vivo characteristics of cells as multipotential precursors. Cell migration occurred along white matter (WM) tracts (especially the corpus callosum (CC), fimbria, and internal capsule), predominantly early in the acute phase of disease, and in an asymmetric manner. The distance of cell migration correlated well with clinical severity of disease and the number of microglia in the WM tracts, supporting the notion that inflammatory signals promote transplanted cell migration. This study shows for the first time that hESC‐derived neural precursors also respond to tissue signals in an MS model, similarly to rodent cells. The results are directly relevant for designing and optimizing cell therapies for MS, and achieving a better understanding of in vivo cell dynamics and cell–tissue interactions. Magn Reson Med 57:164–171, 2007.

Rapid three-dimensional diffusion MRI facilitates the study of acute stroke in mice

MRI studies using mouse brain models of ischemia are becoming a valuable tool for understanding the mechanism of stroke, since transgenic models are now available. However, the small size of the mouse brain and the surgical complexity of creating ischemia in mice make it technically challenging to obtain high‐quality MRI data. Therefore, there are few reports of MRI studies in murine cerebral ischemia. In this project a newly developed rapid 3D diffusion‐weighted imaging (DWI) technique was applied to study experimental stroke in a mouse model of reversible middle cerebral artery occlusion (MCAO). Ischemic volumes were successfully delineated using this 3D whole‐brain imaging technique with high spatial (0.34 × 0.5 × 1.0 mm3 before zero‐filling) and temporal (7 min) resolution. The 3D observation revealed the characteristic evolution of stroke after transient MCAO. There was a temporarily high diffusion constant in the cortex during early reperfusion, followed by a secondary energy failure in the cortex and caudate‐putamen at 6 and 21 h of reperfusion. Magn Reson Med 46:183–188, 2001.

Delayed reduction of tissue water diffusion after myocardial ischemia

The apparent diffusion coefficient (ADC) of water after regional myocardial ischemia was measured in isolated, perfused rabbit hearts by using magnetic resonance imaging (MRI) techniques. After ligation of the left anterior descending coronary artery, the ADC of the nonperfused region showed a gradual but significant decreasing trend over time, whereas that of the normally perfused myocardium remained constant. Morphological analysis revealed that the ADC decrease reflected the expansion of a subregion of reduced ADC within the nonperfused myocardium. The dynamics of the diffusion change and the morphological progression of the affected tissue suggest that the ADC decrease may be linked to the onset of myocardial infarction, which is known to involve myocyte swelling. The ADC reduction provides a potentially valuable MRI tissue-contrast mechanism for noninvasively determining the viability of the ischemic myocardium and assessing the dynamics of acute myocardial infarction.The apparent diffusion coefficient (ADC) of water after regional myocardial ischemia was measured in isolated, perfused rabbit hearts by using magnetic resonance imaging (MRI) techniques. After ligation of the left anterior descending coronary artery, the ADC of the nonperfused region showed a gradual but significant decreasing trend over time, whereas that of the normally perfused myocardium remained constant. Morphological analysis revealed that the ADC decrease reflected the expansion of a subregion of reduced ADC within the nonperfused myocardium. The dynamics of the diffusion change and the morphological progression of the affected tissue suggest that the ADC decrease may be linked to the onset of myocardial infarction, which is known to involve myocyte swelling. The ADC reduction provides a potentially valuable MRI tissue-contrast mechanism for noninvasively determining the viability of the ischemic myocardium and assessing the dynamics of acute myocardial infarction.

Suivi IRM de cellules souches mesenchymateuses (CSM) marquees par un agent superparamagnetique et injectees par voie intra-veineuse dans un modele de nephropathie renale chez le rat

Objectifs Evaluation de l’IRM dans la detection in et ex-vivo de CSM marquees par Feridex ® , injectees IV dans un modele experimental de mesangiolyse. Materiels et methodes Quatorze rats sont repartis en deux groupes. Groupe pathologique (n = 10) avec atteinte mesangiale irreversible induite par injection de PAN et d’anticorps OX7 puis injection intra-veineuse del0 7 cellules souches co-marquees par Feridex ® et Dil (marqueur fulorescent de membrane), et groupe temoin (n = 4). Etude in-vivo a 4,7T avant et 6 jours apres injection des CSM. Etude ex-vivo a 9,4T sur rein isole. Realisation de cryocoupes du rein image pour analyse histologique (HES, Perls, alpha-actine, fluorescence). Resultats En SpT2* in-vivo : chute de signal absente dans les reins (p = 0,7) mais importante dans le foie (p Conclusion Les CSM marquees injectees par voie intra-veineuse ciblent specifiquement les territoires leses des reins pathologiques mais ne peuvent etre detectees qu’en IRM ex-vivo.