Impact neurobiologique de la séparation mère/nouveau-né chez le rongeur

Chez les mammifères, les liens entre la mère et le nouveau-né sont d’une importance fondamentale dans le développement harmonieux de la progéniture. Cela rend les modèles murins de séparation mère/nouveau-né d’un grand intérêt dans le cadre des hypothèses neuro-développementales des affections psychiatriques. Des séparations longues tendent à installer, chez le raton devenu adulte, des troubles anxieux, « dépressifs », et une conduite de dépendance aux drogues. Les analyses neurobiologiques montrent une perturbation de nombreux systèmes neuronaux limbiques, en particulier neuropeptidergiques, dont l’explication pourrait se trouver dans l’impact du stress précoce sur le développement cérébral. La mise en place de modèles prenant en compte les facteurs environnementaux précoces pourrait contribuer à une meilleure prévention/prédiction des troubles mentaux et améliorer nos stratégies thérapeutiques

CCKA, but not CCKB, agonists suppress the hyperlocomotion induced by endogenous enkephalins, protected from enzymatic degradation by systemic RB 101

International audienceInteractions between CCKergic and enkephalinergic systems were studied in mice using behavioral responses measured in Animex. The hyperlocomotion induced by 5 mg/kg of RB 101, a mixed inhibitor of enkephalin-degrading enzymes able to cross the blood-brain barrier, was previously shown to be mediated by delta-opioid receptor stimulation. The IP administration of a CCKA agonist, Boc-Tyr-Lys-(CONH-o-tolyl)-Asp-Phe-NH2 (0.1, 1, 10 micrograms/kg), suppressed the hyperlocomotion produced by IV injection of 5 mg/kg of RB 101. The effect of the CCKA agonist was suppressed by a selective CCKA antagonist, devazepide, injected IP at doses of 20 and 200 micrograms/kg and was potentiated by the selective delta-opioid antagonist naltrindole at the doses of 0.03 mg/kg. IP injection of the selective CCKB agonist BC 264 (0.1-1 mg/kg) did not modify the RB 101-induced hyperlocomotor effect. These results reinforce the observed physiological antagonism between the endogenous CCK and opioid systems but are at variance with the responses measured in stressful conditions. It is concluded that CCKA, but not CCKB, receptor activation counteracts the opioid-related hyperlocomotion

Impact of the gut microbiota on the neuroendocrine and behavioural responses to stress in rodents

The gastro-intestinal tract hosts a complex microbial ecosystem, the gut microbiota, whose collective genome coding capacity exceeds that of the host genome. The gut microbiota is nowadays regarded as a full organ, likely to contribute to the development of pathologies when its dynamic balance is disrupted (dysbiosis). In the last decade, evidence emerged that the gut microbiota influences brain development and function. In particular, comparisons between germ-free and conventional laboratory rodents showed that the absence of the gut microbiota exacerbates the hypothalamic pituitary adrenal (HPA) system reactivity to stress and alters the anxiety-like behaviour. Furthermore, the dysfunctions observed in germ-free animals can be corrected if the gut microbiota is restored in early life but not in adulthood, suggesting a critical period for microbiota imprinting on the responsiveness to stress. The modes of action are still to be deciphered. They may involve transport of neuroactive bacterial metabolites to the brain through the bloodstream, stimulation of the vagus nerve or of entero-endocrine cells, or modulation of the immune system and, consequently, of the inflammatory status. The discovery that the gut microbiota regulates the neuroendocrine and behavioural responses to stress paves the way for the hypothesis that gut microbiota dysbioses could contribute to the pathophysiology of anxiety-related disorders. In this regard, treatments of anxiety-prone rodent strains with probiotics or antibiotics aimed at modifying their gut microbiota have shown an anxiolytic-like activity. Clinical trials are now needed to know if results obtained in preclinical studies can translate to humans

Impact of the gut microbiota on the neuroendocrine and behavioural responses to stress in rodents

The gastro-intestinal tract hosts a complex microbial ecosystem, the gut microbiota, whose collective genome coding capacity exceeds that of the host genome. The gut microbiota is nowadays regarded as a full organ, likely to contribute to the development of pathologies when its dynamic balance is disrupted (dysbiosis). In the last decade, evidence emerged that the gut microbiota influences brain development and function. In particular, comparisons between germ-free and conventional laboratory rodents showed that the absence of the gut microbiota exacerbates the hypothalamic pituitary adrenal (HPA) system reactivity to stress and alters the anxiety-like behaviour. Furthermore, the dysfunctions observed in germ-free animals can be corrected if the gut microbiota is restored in early life but not in adulthood, suggesting a critical period for microbiota imprinting on the responsiveness to stress. The modes of action are still to be deciphered. They may involve transport of neuroactive bacterial metabolites to the brain through the bloodstream, stimulation of the vagus nerve or of entero-endocrine cells, or modulation of the immune system and, consequently, of the inflammatory status. The discovery that the gut microbiota regulates the neuroendocrine and behavioural responses to stress paves the way for the hypothesis that gut microbiota dysbioses could contribute to the pathophysiology of anxiety-related disorders. In this regard, treatments of anxiety-prone rodent strains with probiotics or antibiotics aimed at modifying their gut microbiota have shown an anxiolytic-like activity. Clinical trials are now needed to know if results obtained in preclinical studies can translate to humans

Developmental and environmental causes for potential changes in odour perception in germ free rodents

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Tenasübü'l-Kur'an İlmi Açısından Kıyamet Suresi'nin incelenmesi

Kur'an'ın rehberliğinden en üst düzeyde istifade edilebilmesi, onun daha iyi anlaşılabilmesiyle doğru orantılıdır. Kur'an bu anlamda birçok yönden araştırma ve inceleme konusu olmuştur. Bunlardan birisi de "Ayetler ve Sureler Arasındaki Münasebet" konusudur. Bu husus zamanla tefsirlerde ve Kur'an ilimlerinde yer almaya başlamış, müstakil eseriere konu olmuştur. Kıyamet Suresi, sure içi ve sure dışı bütünlü- ğü ve anlam örgüsüyle bu konunun Kur'an'daki olağanüstü boyutlarını çok net bir şekilde ortaya koyan tipik bir örnek niteliğindedir

Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats

Background and aims: Establishment of the gut microbiota is one of the most important events in early life and emerging evidence indicates that the gut microbiota influences several aspects of brain functioning, including reactivity to stress. To better understand how the gut microbiota contributes to a vulnerability to the stress-related psychiatric disorders, we investigated the relationship between the gut microbiota, anxiety-like behavior and HPA axis activity in stress-sensitive rodents. We also analyzed the monoamine neurotransmitters in the brain upper structures involved in the regulation of stress and anxiety. Methods: Germfree (GF) and specific pathogen free (SPF) F344 male rats were first subjected to neurological tests to rule out sensorimotor impairments as confounding factors. Then, we examined the behavior responses of rats to social interaction and open-field tests. Serum corticosterone concentrations, CRF mRNA expression levels in the hypothalamus, glucocorticoid receptor (GR) mRNA expression levels in the hippocampus, and monoamine concentrations in the frontal cortex, hippocampus and striatum were compared in rats that were either exposed to the open-field stress or not. Results: GF rats spent less time sniffing an unknown partner than SPF rats in the social interaction test, and displayed a lower number of visits to the aversive central area, and an increase in latency time, time spent in the corners and number of defecations in the open-field test. In response to the open-field stress, serum corticosterone concentrations were 2.8-fold higher in GF than in SPF rats. Compared to that of SPF rats, GF rats showed elevated CRF mRNA expression in the hypothalamus and reduced GR mRNA expression in the hippocampus. GF rats also had a lower dopaminergic turnover rate in the frontal cortex, hippocampus and striatum than SPF rats. Conclusions: In stress-sensitive F344 rats, absence of the gut microbiota exacerbates the neuroendocrine and behavioral responses to acute stress and the results coexist with alterations of the dopaminergic turnover rate in brain upper structures that are known to regulate reactivity to stress and anxiety-like behavior. (C) 2014 Elsevier Ltd. All rights reserved

Vulnerability to opiate intake in maternally deprived rats: implication of MeCP2 and of histone acetylation

We previously showed that maternal deprivation predisposes male rats to anxiety, accompanied with an increase in their opiate consumption. In the present report, we searched for brain epigenetic mechanisms that possibly underlie this increase. For that, we examined the expression of the methyl-CpG-binding protein MeCP2 and of the histone deacetylases HDAC2 and HDAC3, as well as the acetylation status of histone H3 and H4 in mesolimbic structures of adult maternally deprived rats, using immunohistochemistry and Western blot analysis. A long-lasting increase in MeCP2 expression was found throughout the striatum of deprived rats. Enhanced HDAC2 expression and increased nuclear HDAC activity in the nucleus accumbens of deprived rats were associated with lower acetylation levels of histone H3 and H4. Treatment for 3 weeks with the HDAC inhibitor sodium valproate abolished HDAC activation together with the decrease in the acetylation levels of histone H4, and was accompanied with normalized oral morphine consumption. The data indicate that epigenetic mechanisms induced by early adverse environment memorize life experience to trigger greater opiate vulnerability during adult life. They suggest that sodium valproate may lessen vulnerability to opiate intake, particularly in subgroups of individuals subjected to adverse postnatal environments

Indole, a signaling molecule produced by the gut microbiota, negatively impacts emotional behaviors in rats

Gut microbiota produces a wide and diverse array of metabolites that are an integral part of the host metabolome. The emergence of the gut microbiome-brain axis concept has prompted investigations on the role of gut microbiota dysbioses in the pathophysiology of brain diseases. Specifically, the search for microbe-related metabolomic signatures in human patients and animal models of psychiatric disorders has pointed out the importance of the microbial metabolism of aromatic amino acids. Here, we investigated the effect of indole on brain and behavior in rats. Indole is produced by gut microbiota fromtryptophan, through the tryptophanase enzyme encoded by the tnaA gene. First, we mimicked an acute and high overproduction of indole by injecting this compound in the cecum of conventional rats. This treatment led to a dramatic decrease of motor activity. The neurodepressant oxidized derivatives of indole, oxindole and isatin, accumulated in the brain. In addition, increase in eye blinking frequency and in c-Fos protein expression in the dorsal vagal complex denoted a vagus nerve activation. Second, we mimicked a chronic and moderate overproduction of indole by colonizing germ-free rats with the indole-producing bacterial species Escherichia coli. We compared emotional behaviors of these rats with those of germ-free rats colonized with a genetically-engineered counterpart strain unable to produce indole. Rats overproducing indole displayed higher helplessness in the tail suspension test, and enhanced anxiety-like behavior in the novelty, elevated plus maze and open-field tests. Vagus nerve activation was suggested by an increase in eye blinking frequency. However, unlike the conventional rats dosed with a high amount of indole, the motor activity was not altered and neither oxindole nor isatin could be detected in the brain. Further studies are required for a comprehensive understanding of the mechanisms supporting indole effects on emotional behaviors. As our findings suggest that people whose gut microbiota is highly prone to produce indole could be more likely to develop anxiety and mood disorders, we addressed the issue of the inter-individual variability of indole producing potential in humans. An in silico investigation of metagenomic data focused on the tnaA gene products definitively proved this inter-individual variability

A Probiotic Mixture Induces Anxiolytic- and Antidepressive-Like Effects in Fischer and Maternally Deprived Long Evans Rats

International audienceA role of the gut microbiota in psychiatric disorders is supported by a growing body of literature. The effects of a probiotic mixture of four bacterial strains were studied in two models of anxiety and depression, naturally stress-sensitive Fischer rats and Long Evans rats subjected to maternal deprivation. Rats chronically received either the probiotic mixture (1.10(9) CFU/day) or the vehicle. Anxiety- and depressive-like behaviors were evaluated in several tests. Brain monoamine levels and gut RNA expression of tight junction proteins (Tjp) and inflammatory markers were quantified. The gut microbiota was analyzed in feces by 16S rRNA gene sequencing. Untargeted metabolite analysis reflecting primary metabolism was performed in the cecal content and in serum. Fischer rats treated with the probiotic mixture manifested a decrease in anxiety-like behaviors, in the immobility time in the forced swimming test, as well as in levels of dopamine and its major metabolites, and those of serotonin metabolites in the hippocampus and striatum. In maternally deprived Long Evans rats treated with the probiotic mixture, the number of entries into the central area in the open-field test was increased, reflecting an anxiolytic effect. The probiotic mixture increased Tjp1 and decreased Ifn gamma mRNA levels in the ileum of maternally deprived rats. In both models, probiotic supplementation changed the proportions of several Operational Taxonomic Units (OTU) in the gut microbiota, and the levels of certain cecal and serum metabolites were correlated with behavioral changes. Chronic administration of the tested probiotic mixture can therefore beneficially affect anxiety- and depressive-like behaviors in rats, possibly owing to changes in the levels of certain metabolites, such as 21-deoxycortisol, and changes in brain monoamines