Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity.

Chronic low-grade inflammation is known to be linked to obesity, and to occur in the early stages of the disease. This mechanism is complex and involves numerous organs, cells, and cytokines. In this context, inflammation of white adipose tissue seems to play a key role in the development of obesity. Because of its properties, prostaglandin E2 (PGE2), an emblematic inflammatory mediator, has been proposed as an actor linking inflammation and obesity. Indeed, PGE2 is involved in mechanisms that are dysregulated in obesity such as lipolysis and adipogenesis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which specifically catalyzes the final step of PGE2 biosynthesis. Interestingly, mPGES-1 invalidation dramatically alters the production of PGE2 during inflammation. In the present work, we sought to determine whether mPGES-1 could contribute to inflammation associated with obesity. To this end, we analyzed the energy metabolism of mPGES-1 deficient mice (mPGES-1-/-) and littermate controls, fed with a high-fat diet. Our data showed that mPGES-1-/- mice exhibited resistance to diet-induced obesity when compared to wild-type littermates. mPGES-1-/- mice fed with a high-fat diet, showed a lower body weight gain and a reduced adiposity, which were accompanied by a decrease in adipose tissues inflammation. We also observed an increase in energy expenditures in mPGES-1-/- mice fed with a high-fat diet without any changes in activity and browning process. Altogether, these data suggest that mPGES-1 inhibition may prevent diet-induced obesity.

Using MRI to predict the fate of excitotoxic lesions in rats.

Excitotoxic lesions are frequently used to assess the role of cerebral structures in cognitive processes in rodents. However, the precise site and extent of these lesions remain unknown without histological verifications. Using a 7-Teslas MRI system and a T2-weighted turbo-RARE sequence, MR images were acquired at several time points following NMDA lesions (1h, 6h, 24h, 48h, 1 week and 2 weeks). NMDA infusions into the parenchyma induced a clear and delineable hyperintense signal from 1h up to 1-week post-surgery. Hyperintensity volumes were compared with NeuN and Cresyl violet histological quantifications of the lesion magnitude. NMDA-induced hypersignal is observed as soon as 1h post-injection and is a reliable estimate of the presence (or absence) of a lesion. Compared to NeuN, Cresyl violet staining underestimates the extent of the lesion in significant proportions. The MRI hyperintensity generated by NMDA instillation into the parenchyma can be used as a powerful tool to confirm the diffusion of the drug into the cerebral tissue, to ascertain the locus of injection and predict with a high success rate the fate of NMDA lesions as soon as 1h post-surgery. This approach could be very useful in a large variety of lesion studies in rodents.

Global cerebral ischemia in rats leads to amnesia due to selective neuronal death followed by astroglial scar formation in the CA1 layer.

Global Cerebral Ischemia (GCI) occurs following cardiac arrest or neonatal asphyxia and leads to harmful neurological consequences. In most cases, patients who survive cardiac arrest develop severe cognitive and motor impairments. This study focused on learning and memory deficits associated with brain neuroanatomical reorganization that appears after GCI. The four-vessel occlusion (4VO) model was performed to produce a transient GCI. Hippocampal lesions in ischemic rats were visualized using anatomical Magnetic Resonance Imaging (aMRI). Then, the learning and memory abilities of control and ischemic (bilaterally or unilaterally) rats were assessed through the olfactory associated learning task. Finally, a "longitudinal" histological study was carried out to highlight the cellular reorganizations occurring after GCI. We demonstrated that the imaging, behavioral and histological results are closely related. In fact, aMRI revealed the appearance of hyper-intense signals in the dorsal hippocampus at day 3 post-GCI. Consequently, we showed a rise in cell proliferation (Ki 67+ cells) and endogenous neurogenesis especially in the dentate gyrus (DG) at day 3 post-GCI. Then, hyper-intense signals in the dorsal hippocampus were confirmed by strong neuronal losses in the CA1 layer at day 7 post-GCI. These results were linked with severe learning and memory impairments only in bilaterally ischemic rats at day 14 post-GCI. This amnesia was accompanied by huge astroglial and microglial hyperactivity at day 30 post-GCI. Finally, Nestin+ cells and astrocytes gave rise to astroglial scars, which persisted 60days post-GCI. In the light of these results, the 4VO model appears a reliable method to produce amnesia in order to study and develop new therapeutic strategies.

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice.

We hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures.

Investigation on NMR relaxivity of nano-sized cyano-bridged coordination polymers.

We present the first comparative investigation of the Nuclear Magnetic Resonance (NMR) relaxivity of a series of nanosized cyano-bridged coordination networks stabilized in aqueous solution. These Ln(3+)/[Fe(CN)6](3-) (Ln = Gd, Tb, Y) and M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) nanoparticles with sizes ranging from 1.4 to 5.5 nm are stabilized by polyethylene glycols (MW = 400 or 1000), polyethylene glycol functionalized with amine groups (MW = 1500), or by N-acetyl-D-glucosamine. The evaluation of NMR relaxivity allowed estimation of the Magnetic Resonance Imaging (MRI) contrast efficiency of our systems. The results demonstrate that Gd(3+)/[Fe(CN)6](3-) nanoparticles have r1p and r2p relaxivities about four times higher than the values observed in the same conditions for the commercial Contrast Agents (CAs) ProHance or Omniscan, regardless of the stabilizing agent used, while nanoparticles of Prussian blue and its analogues M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) present relatively modest values. The influence of the chemical composition of the nanoparticles, their crystal structure, spin values of lanthanide and transition metal ions, and stabilizing agent on the relaxivity values are investigated and discussed.

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions.

Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.

Developmental vitamin D deficiency alters learning in C57Bl/6J mice.

Epidemiological studies have highlighted a season of birth effect in multiple sclerosis and schizophrenia. As a result, low prenatal vitamin D has been proposed as a candidate risk factor for these brain diseases, with cognitive impairments. In order to further investigate the long-term consequences of a transient gestational hypovitaminosis D, we used a mouse developmental vitamin D (DVD) deficiency model. Female C57Bl/6J mice were fed a vitamin D-free diet for 6 weeks prior to conception and during gestation. At birth, dams and their offspring were fed a normal vitamin D-containing diet. The adult offspring underwent a learning test based on olfactory cues, at 30 weeks and 60 weeks of age. In addition, using magnetic resonance imaging (MRI), volumes of cerebrum, hippocampus and lateral ventricles were measured at 30 weeks and 70 weeks of age. We found that DVD-deficient mice, when compared to control animals at Week 30, displayed impaired learning and smaller lateral ventricles. At Weeks 60-70, both groups deteriorated when compared to young mice and no significant difference was observed between groups. This study confirms that transient prenatal vitamin D deficiency alters brain development and functioning and induces cognitive impairments in the young adult offspring.

Perseveration related to frontal lesion in mice using the olfactory H-maze.

The delayed reaction paradigm, consisting to discover two different rules consecutively (delayed alternation and non-alternation task) followed by a delayed reversal task, is a specific marker for the functioning of primate prefrontal cortex. Although several works in rodents report the use of operant delayed alternation tasks, in none of the studies mice with lesion of the prefrontal cortex were used in this paradigm. In the current study, mouse experiments were conducted using a new, totally automated device, the olfactory H-maze. Here, we show that unilateral lesion of the dorsomedial prefrontal cortex in mice induced similar deficits to those observed after frontal lesions in monkeys and humans. These pronounced learning deficits seem to come from difficulty elaborating a new rule and the inability to inhibit the previous rule, characterized by perseveration after prefrontal cortex lesion. The present results demonstrate that this very simple experimental paradigm using the olfactory H-maze presents the advantage to be fast (one training session) and well suited to assess the frontal functions in mice. It should be useful for testing pharmacological or stem cell approaches in order to reduce organic damages or gain insight into the cognitive functions of the frontal cortex using transgenic or gene-targeting mice.

Sensorimotor training promotes functional recovery and somatosensory cortical map reactivation following cervical spinal cord injury.

Sensorimotor activity has been shown to play a key role in functional recovery after partial spinal cord injury (SCI). Most studies in rodents have focused on the rehabilitation of hindlimb locomotor functions after thoracic or lumbar SCI, whereas forelimb motor and somatosensory abilities after cervical SCI remain largely uninvestigated, despite the high incidence of such injuries in humans. Moreover, little is known about the neurophysiological substrates of training-induced recovery in supraspinal structures. This study was aimed at evaluating the effects of a training procedure combining both motor and sensory stimulation on behavioral performance and somatosensory cortical map remodeling after cervical (C4-C5) spinal hemisection in rats. This SCI severely impaired both sensory and motor capacities in the ipsilateral limbs. Without training, post-lesion motor capacities gradually improved, whereas forepaw tactile abilities remained impaired. Consistently, no stimulus-evoked responses were recorded within the forepaw representational zone in the primary somatosensory (S1) cortex at 2 months after the SCI. However, our data reveal that with training started from the 7th day post-lesion, a nearly complete recovery (characterized by an early and rapid improvement of motor functions) was associated with a gradual compensation of tactile deficits. Furthermore, the recovery of tactile abilities was correlated with the areal extent of reactivation of S1 cortex forepaw representations. Rehabilitative training promoted post-lesion adaptive plasticity, probably by enhancing endogenous activity within spared spinal and supraspinal circuits and pathways sustaining sensory and motor functions. This study highlights the beneficial effect of sensorimotor training in motor improvement and its critical influence on tactile recovery after SCI.

Detection of acoustic waves by NMR using a radiofrequency field gradient.

A B(1) field gradient-based method previously described for the detection of mechanical vibrations has been applied to detect oscillatory motions in condensed matter originated from acoustic waves. A ladder-shaped coil generating a quasi-constant RF-field gradient was associated with a motion-encoding NMR sequence consisting in a repetitive binomial 13;31; RF pulse train (stroboscopic acquisition). The NMR response of a gel phantom subject to acoustic wave excitation in the 20-200 Hz range was investigated. Results showed a linear relationship between the NMR signal and the wave amplitude and a spectroscopic selectivity of the NMR sequence with respect to the input acoustic frequency. Spin displacements as short as a few tens of nanometers were able to be detected with this method.

MR detection of mechanical vibrations using a radiofrequency field gradient.

A new method for NMR characterization of mechanical waves, based upon radiofrequency field gradient for motion encoding, is proposed. A binomial B1 gradient excitation scheme was used to visualize the mobile spins undergoing a periodic transverse mechanical excitation. A simple model was designed to simulate the NMR signal as a function of the wave frequency excitation and the periodicity of the NMR pulse sequence. The preliminary results were obtained on a gel phantom at low vibration frequencies (0-200 Hz) by using a ladder-shaped coil generating a nearly constant RF field gradient along a specific known direction. For very small displacements and/or B1 gradients, the NMR signal measured on a gel phantom was proportional to the vibration amplitude and the pulse sequence was shown to be selective with respect to the vibration frequency. A good estimation of the direction of vibrations was obtained by varying the angle between the motion direction and the B1 gradient. The method and its use in parallel to more conventional MR elastography techniques are discussed. The presented approach might be of interest for noninvasive investigation of elastic properties of soft tissues and other materials.