Micrornas involvement in cortical plasticity in adult mouse barrel cortex

In rodents, sensory experience alters the whisker representation in layer IV of the barrel cortex (Woolsey and Van der Loos, 1970). Excitatory and inhibitory interneurons, together with the astrocytic network, modify the functional representation in an integrated manner. Our group showed that continuous whisker stimulation induces structural and functional changes in the corresponding barrel. These modifications include the depression of neuronal responses and an insertion of new inhibitory synapses on dendritic spines (Knott et al., 2002; Genoud et al., 2006; Quairiaux et al., 2007). This form of cortical plasticity is controlled by several gene regulatory mechanisms including the activation of genetic programs controlling the expression of microRNAs (miRNAs). The transitory and localized expression of miRNAs in dendrites and their capacity to respond in an activity-dependent manner make them ideal candidates for the fine tuning of gene expression associated with neural plasticity. In a previous study of our group (Johnston- Wenger, 2010) using microarray analysis on laser-dissected barrels in order to compare the gene expression levels in stimulated and non-stimulated barrels after whisker stimulation, 261 genes were found significantly regulated, among these genes there were two miRNAs (miR- 132 and miR-137). In this study I tested the initial observation on the up-regulation of miR-132 and miR-137 after whisker stimulation and the possible involvement of two other miRNAs (miR-138 and miR-125b) that are known play a role in other form of synaptic plasticity. I used in situ hybridization (ISH) after unilateral stimulation of three whiskers (Cl-3) in the adult mouse. We found that sensory stimulation increases the expression, of miR-132 after 3hours of stimulation (p<0.01) and miR-137 (pO.Ol; 24 hrs of stim.), whereas it reduces the level of miR-125b (pO.Ol; 9 hrs of stim.). No significant difference was detected for miR-138. We further determined a correlation between the level of expression of the four selected miRNAs in the cortical barrels (measured by ISH) and in blood plasma (measured by qPCR). In addition to this quantitative comparison, we combined miRNAs ISH and immunolabeling for various neuronal markers that were chosen for the localization in both excitatory and inhibitory circuits as well as in astrocytes. Analysis of three-dimensional confocal acquisitions showed that stimulation alters significantly the degree of co-localization in the stimulated barrel of miR-132 with GAD65/67 and VGLUT2; miR-125b with GAD65/67 and parvalbumin; miR-138 with parvalbumin, VGLUT1 and PSD95; and miR-137 with VGLUT1 and astrocytic markers (GS; GFAP and SlOOß). To conclude, using increased neuronal activity in the whisker-to-barrel pathway; our results suggest that miRNAs can be regulated in an activity-dependent manner and they may regulate local mRNA translation to shape neuronal responses. These findings motivate further investigation of the different modes in which miRNAs may regulate cortical plasticity. -- Chez les rongeurs, l'expérience sensorielle modifie la représentation des vibrisses au niveau du cortex somatosensoriel primaire (Woolsey and Van der Loos, 1970). Les interneurones excitateurs et inhibiteurs, en collaboration avec le réseau astrocytaire, modifient la représentation fonctionnelle d'une manière intégrée. Notre groupe a montré que la stimulation continue des vibrisses induit des changements structuraux et fonctionnels dans le tonneau correspondant. Ces modifications incluent la dépression des réponses neuronales et une insertion de nouvelles synapses inhibitrices sur les épines dendritiques (Knott et al., 2002 ; Genoud et al., 2006 ; Quairiaux et al., 2007). Cette forme de plasticité corticale est contrôlée par plusieurs mécanismes de régulation génique dont l'activation des programmes géniques contrôlant l'expression des microARNs (miARNs). Par leur expression transitoire et localisée dans les dendrites et leur capacité à réagir d'une manière dépendante de l'activité, les miARNs sont des candidats idéaux pour le réglage fin de l'expression des gènes associée à la plasticité neuronale. Afin de comparer le niveau d'expression des gènes dans les tonneaux stimulés et non-stimulés après stimulation des vibrisses, une étude antérieure dans notre groupe (Johnston-Wenger, 2010), utilisant l'analyse par microarray sur des tonneaux disséqués par laser, a montré l'altération significative de 261 gènes. Parmi ces gènes, il y avait deux miARNs (miR-132 et miR-137). Dans la présente étude, j'ai testé l'observation initiale sur la régulation de miR-132 et miR-137 après stimulation des vibrisses et la possible implication de deux autres miARNs (miR-138 et miR-125b) connus avoir jouer un rôle important dans d'autres formes de plasticité synaptique. J'ai utilisé l'hybridation in situ (ISH) après stimulation unilatérale de trois vibrisses (Cl-3) chez la souris adulte. J'ai trouvé que la stimulation sensorielle augmente l'expression, de miR-132 après 3 heures de stimulation (p < 0.01) et miR-137 (p < 0.01 ; 24 hrs de stim.), alors qu'elle réduit le niveau de miR-125b (p < 0.01; 9 hrs de stim.). Aucune différence significative n'a été détectée pour miR-138. J'ai aussi déterminé une corrélation entre le niveau d'expression des quatre miARNs sélectionnés dans les tonneaux (mesurés par ISH) et dans le plasma sanguin (mesuré par qPCR). En plus de cette comparaison quantitative, j'ai combiné le miR-ISH et l'immunomarquage pour divers marqueurs neuronaux qui ont été choisis pour étudier la localisation dans les circuits excitateurs et inhibiteurs, ainsi que dans les astrocytes. Les acquisitions tridimensionnelles montrent que la stimulation modifie considérablement le degré de co-localisation dans le tonneau stimulé de miR-132 avec GAD65/67 et VGLUT2; miR-125b avec GAD65/67 et parvalbumine; miR-138 avec parvalbumine, VGLUT1 et PSD95; et miR-137 avec VGLUT1 et les marqueurs astrocytaires (GS ; GFAP et SlOOß). En conclusion, à l'aide de l'activité neuronale accrue dans la voie de vibrisses-au-baril; les résultats suggèrent que les miARNs peuvent être régulé d'une manière dépendante de l'activité et peuvent résulter la stabilité des ARNm et la traduction pour façonner les réponses neuronales ultérieures. Ces résultats incitent d'investiguer davantage les voies importantes par lesquels les miARNs peuvent réguler la plasticité corticale.

Differential patterns of functional and structural plasticity within and between inferior frontal gyri support training-induced improvements in inhibitory control proficiency.

Ample evidence indicates that inhibitory control (IC), a key executive component referring to the ability to suppress cognitive or motor processes, relies on a right-lateralized fronto-basal brain network. However, whether and how IC can be improved with training and the underlying neuroplastic mechanisms remains largely unresolved. We used functional and structural magnetic resonance imaging to measure the effects of 2 weeks of training with a Go/NoGo task specifically designed to improve frontal top-down IC mechanisms. The training-induced behavioral improvements were accompanied by a decrease in neural activity to inhibition trials within the right pars opercularis and triangularis, and in the left pars orbitalis of the inferior frontal gyri. Analyses of changes in brain anatomy induced by the IC training revealed increases in grey matter volume in the right pars orbitalis and modulations of white matter microstructure in the right pars triangularis. The task-specificity of the effects of training was confirmed by an absence of change in neural activity to a control working memory task. Our combined anatomical and functional findings indicate that differential patterns of functional and structural plasticity between and within inferior frontal gyri enhanced the speed of top-down inhibition processes and in turn IC proficiency. The results suggest that training-based interventions might help overcoming the anatomic and functional deficits of inferior frontal gyri manifesting in inhibition-related clinical conditions. More generally, we demonstrate how multimodal neuroimaging investigations of training-induced neuroplasticity enable revealing novel anatomo-functional dissociations within frontal executive brain networks. Hum Brain Mapp 36:2527-2543, 2015. © 2015 Wiley Periodicals, Inc.

Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.

Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (<45y). Interestingly, this association was totally driven by patients meeting lifetime criteria for atypical depression, i.e. major depressive episodes characterized by symptoms such as an increased appetite. Indeed, patients with atypical depression carrying rs7754794-TT had 1.17 kg/m2 (p = 0.04) lower BMI values as compared to C-allele carriers, the effect being stronger in younger individuals (-2.50 kg/m2; p = 0.03; interaction between rs7754794 and age: p-value = 0.08). This study provides new insights on the possible influence of MCHR2 and/or MCHR2-AS1 on obesity in psychiatric patients and on the pathophysiology of atypical depression.

Characterization and genetic mapping of eceriferum-ym (cer-ym), a cutin deficient barley mutant with impaired leaf water retention capacity.

The cuticle covers the aerial parts of land plants, where it serves many important functions, including water retention. Here, a recessive cuticle mutant, eceriferum-ym (cer-ym), of Hordeum vulgare L. (barley) showed abnormally glossy spikes, sheaths, and leaves. The cer-ym mutant plant detached from its root system was hypersensitive to desiccation treatment compared with wild type plants, and detached leaves of mutant lost 41.8% of their initial weight after 1 h of dehydration under laboratory conditions, while that of the wild type plants lost only 7.1%. Stomata function was not affected by the mutation, but the mutant leaves showed increased cuticular permeability to water, suggesting a defective leaf cuticle, which was confirmed by toluidine blue staining. The mutant leaves showed a substantial reduction in the amounts of the major cutin monomers and a slight increase in the main wax component, suggesting that the enhanced cuticle permeability was a consequence of cutin deficiency. cer-ym was mapped within a 0.8 cM interval between EST marker AK370363 and AK251484, a pericentromeric region on chromosome 4H. The results indicate that the desiccation sensitivity of cer-ym is caused by a defect in leaf cutin, and that cer-ym is located in a chromosome 4H pericentromeric region.

Meta-analysis of the influence of bonding parameters on the clinical outcome of tooth-colored cervical restorations

PURPOSE: To meta-analyze the literature on the clinical performance of Class V restorations to assess the factors that influence retention, marginal integrity, and marginal discoloration of cervical lesions restored with composite resins, glass-ionomer-cement-based materials [glass-ionomer cement (GIC) and resin-modified glass ionomers (RMGICs)], and polyacid-modified resin composites (PMRC). MATERIALS AND METHODS: The English literature was searched (MEDLINE and SCOPUS) for prospective clinical trials on cervical restorations with an observation period of at least 18 months. The studies had to report about retention, marginal discoloration, marginal integrity, and marginal caries and include a description of the operative technique (beveling of enamel, roughening of dentin, type of isolation). Eighty-one studies involving 185 experiments for 47 adhesives matched the inclusion criteria. The statistical analysis was carried out by using the following linear mixed model: log (-log (Y /100)) = β + α log(T ) + error with β = log(λ), where β is a summary measure of the non-linear deterioration occurring in each experiment, including a random study effect. RESULTS: On average, 12.3% of the cervical restorations were lost, 27.9% exhibited marginal discoloration, and 34.6% exhibited deterioration of marginal integrity after 5 years. The calculation of the clinical index was 17.4% of failures after 5 years and 32.3% after 8 years. A higher variability was found for retention loss and marginal discoloration. Hardly any secondary caries lesions were detected, even in the experiments with a follow-up time longer than 8 years. Restorations placed using rubber-dam in teeth whose dentin was roughened showed a statistically significantly higher retention rate than those placed in teeth with unprepared dentin or without rubber-dam (p < 0.05). However, enamel beveling had no influence on any of the examined variables. Significant differences were found between pairs of adhesive systems and also between pairs of classes of adhesive systems. One-step self-etching had a significantly worse clinically index than two-step self-etching and three-step etch-and-rinse (p = 0.026 and p = 0.002, respectively). CONCLUSION: The clinical performance is significantly influenced by the type of adhesive system and/or the adhesive class to which the system belongs. Whether the dentin/enamel is roughened or not and whether rubberdam isolation is used or not also significantly influenced the clinical performance. Composite resin restorations placed with two-step self-etching and three-step etch-and-rinse adhesive systems should be preferred over onestep self-etching adhesive systems, GIC-based materials, and PMRCs.

The ADO Index as a Predictor of Two-Year Mortality in General Practice-Based Chronic Obstructive Pulmonary Disease Cohorts.

BACKGROUND: Existing prediction models for mortality in chronic obstructive pulmonary disease (COPD) patients have not yet been validated in primary care, which is where the majority of patients receive care. OBJECTIVES: Our aim was to validate the ADO (age, dyspnoea, airflow obstruction) index as a predictor of 2-year mortality in 2 general practice-based COPD cohorts. METHODS: Six hundred and forty-six patients with COPD with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV were enrolled by their general practitioners and followed for 2 years. The ADO regression equation was used to predict a 2-year risk of all-cause mortality in each patient and this risk was compared with the observed 2-year mortality. Discrimination and calibration were assessed as well as the strength of association between the 15-point ADO score and the observed 2-year all-cause mortality. RESULTS: Fifty-two (8.1%) patients died during the 2-year follow-up period. Discrimination with the ADO index was excellent with an area under the curve of 0.78 [95% confidence interval (CI) 0.71-0.84]. Overall, the predicted and observed risks matched well and visual inspection revealed no important differences between them across 10 risk classes (p = 0.68). The odds ratio for death per point increase according to the ADO index was 1.50 (95% CI 1.31-1.71). CONCLUSIONS: The ADO index showed excellent prediction properties in an out-of-population validation carried out in COPD patients from primary care settings. © 2014 S. Karger AG, Basel.

Persistent spatial clusters of high body mass index in a Swiss urban population as revealed by the 5-year GeoCoLaus longitudinal study.

OBJECTIVE: Body mass index (BMI) may cluster in space among adults and be spatially dependent. Whether and how BMI clusters evolve over time in a population is currently unknown. We aimed to determine the spatial dependence of BMI and its 5-year evolution in a Swiss general adult urban population, taking into account the neighbourhood-level and individual-level characteristics. DESIGN: Cohort study. SETTING: Swiss general urban population. PARTICIPANTS: 6481 georeferenced individuals from the CoLaus cohort at baseline (age range 35-74 years, period=2003-2006) and 4460 at follow-up (period=2009-2012). OUTCOME MEASURES: Body weight and height were measured by trained healthcare professionals with participants standing without shoes in light indoor clothing. BMI was calculated as weight (kg) divided by height squared (m(2)). Participants were geocoded using their postal address (geographic coordinates of the place of residence). Getis-Ord Gi statistic was used to measure the spatial dependence of BMI values at baseline and its evolution at follow-up. RESULTS: BMI was not randomly distributed across the city. At baseline and at follow-up, significant clusters of high versus low BMIs were identified and remained stable during the two periods. These clusters were meaningfully attenuated after adjustment for neighbourhood-level income but not individual-level characteristics. Similar results were observed among participants who showed a significant weight gain. CONCLUSIONS: To the best of our knowledge, this is the first study to report longitudinal changes in BMI clusters in adults from a general population. Spatial clusters of high BMI persisted over a 5-year period and were mainly influenced by neighbourhood-level income.

Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischemia and acidosis in hippocampal CA1 neurons

The CA1 region of the hippocampus is particularly vulnerable to ischemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca2+ -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a) which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischemic neuronal death and to physiologically induced LTP. This raises the question - does ASIC1a activation drive the post-ischemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPN) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.

Adaptation of Root Function by Nutrient-Induced Plasticity of Endodermal Differentiation.

Plant roots forage the soil for minerals whose concentrations can be orders of magnitude away from those required for plant cell function. Selective uptake in multicellular organisms critically requires epithelia with extracellular diffusion barriers. In plants, such a barrier is provided by the endodermis and its Casparian strips-cell wall impregnations analogous to animal tight and adherens junctions. Interestingly, the endodermis undergoes secondary differentiation, becoming coated with hydrophobic suberin, presumably switching from an actively absorbing to a protective epithelium. Here, we show that suberization responds to a wide range of nutrient stresses, mediated by the stress hormones abscisic acid and ethylene. We reveal a striking ability of the root to not only regulate synthesis of suberin, but also selectively degrade it in response to ethylene. Finally, we demonstrate that changes in suberization constitute physiologically relevant, adaptive responses, pointing to a pivotal role of the endodermal membrane in nutrient homeostasis.