BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities.

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses

Impact of type 2 diabetes on depressive-like phenotype and antidepressant response in mice

Evidence indicates that the prevalence of depression in diabetic subjects is higher than that in the general population. Despite these observations, the mechanisms underpinning the link between metabolic and psychiatric disorders are poorly understood. Moreover, it has been proposed that an impairment of glucose homeostasis may result in blunted antidepressant response to selective serotonin reuptake inhibitors (SSRI). To confirm and better understand the impact of type 2 diabetes (T2D) on the physiopathology and treatment of depression, this study evaluated the effects of a long-term (8 weeks) high fat diet (HFD) on depressive-like phenotype and SSRI response in mice. The results indicated that mice fed a HFD (protein 21% - fat 5%) exhibited a higher body weight (34,5±0.9 vs 28±0.6 g; p<0.001) and basal blood glucose level (180±4 vs 139±5 mg/dL; p<0.001) associated with a moderate insulin resistance compared to control mice fed a standard diet (STD: protein 20% - fat 45%). The alteration of these metabolic parameters, were accompanied by a high level of anxiety in HFD mice as shown by a decrease in the time spent in the anxiogenic areas (402±41 vs 701±50 sec. in the center of the arena; p<0.001 and 29±3 vs 42±6 sec. in the open arms; p<0.05) in the open-field and the elevated plus maze tests; respectively. Another symptom of depression such as helplessness reflected by a decreased immobility time in the tail suspension test was also unveiled in HFD compared to STD mice (120±12 vs 72±10 sec.; p<0.05). Finally, in the splash test measuring the time of grooming after the application of sweetened solution on the coat, this parameter was decreased in HFD compared to STD mice (95±7 vs 180±10 sec.; p<0.001). This result indicated a carelessness frequently observed in depressed patients. These data support the idea that T2D may precipitate depression. Experiments are in progress to test the antidepressant-like response of chronic administration of SSRIs in HFD and STD mice. This aspect is important for the “well-being” of diabetic-depressed patients. Indeed, an early and adapted psychiatric care may improve the efficacy of their anti-diabetic treatment by a better style of life and compliance

Antinociceptive activity of the new triple reuptake inhibitor NS18283 in a mouse model of chemotherapy-induced neuropathic pain

Abstract Background: Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain. Method: Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively. Results: In vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXAinduced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXAinduced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/ kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechanohypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice. Conclusions: Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation

Perception du risque et évaluation économique de l'exposition aux inondations. Étude de deux territoires aux contextes hydrologiques différents

[Departement_IRSTEA]Eaux [TR1_IRSTEA]GEUSI [TR2_IRSTEA]SYNERGIEObjectives of this project are at different levels. First, it aims at strengthen and links two research actions conducted in parallel so far. The first action is an interdisciplinary study of risk perception, conducted on Vilaine catchment, second one is an economic valuation of territory exposure to flood, conducted in Orb catchment. The link expected between the two research actions consists in applying each action (perception and valuation) in both catchment. We expect that contrasted hydrological contexts and spatial approach underlying each action is an opportunity to study relations between a territory exposure and the perception inhabitants or actors have of flood risk. The choice of two catchments with contrasted characteristics is perceived as a necessary condition for generalization of results. Second, we expect results for each research actions. For the perception study, we aim at testing and strengthening survey techniques for collecting opinions from different group of social actors. Methodology used will used both opened and closed surveys, with an effort of interdisciplinary (economic, geomatics, sociology and economics). Aims of the surveys are to identify main parameters that contribute to the construction of flood perception. For the economic valuation of territory exposure study, we aim at propose a modelling of territory vulnerability (relation between of submersion hazard and induced consequences). The question of the scale of study will be investigated, depending on stakes studied. A consequent part of the study will concern the study of uncertainty of the modelling proposed, which will be allowed by an interdisciplinary approach (economics, geography, geomatics, hydrology and hydraulics). We expect to find an articulation between both approaches: perception and economic valuation. Consolidation of knowledge on both study areas is also en expected outcome.Les objectifs de cette proposition sont à différents niveaux. Au premier niveau, cette proposition vise à consolider deux actions de recherche menées de façon parallèle et à les mettre en réseau. La première action de recherche consiste en une étude interdisciplinaire sur la perception du risque d'inondation sur le bassin versant de la Vilaine, la seconde en une évaluation économique de l'exposition d'un territoire aux inondations, avec pour cas d'étude le bassin versant de l'Orb. Cette mise en réseau consistera en l'application de chacune des actions (perception ou évaluation) sur chacun des bassins. Elle est justifiée par les faits que (1) les contextes (au moins hydrologiques) des deux bassins versants sont contrastés et (2) l'approche spatialisée favorisée pour les deux actions est un atout pour étudier les relations pressenties entre exposition d'un territoire aux inondations et perception du risque par les habitants ou acteurs de ce territoire. Le choix de deux bassins versants aux caractéristiques contrastées est d'ailleurs une condition nécessaire à une montée en généralité des résultats de la présente proposition. Au second niveau, les objectifs de recherche sont propres à chacune des approches. Concernant la perception, la proposition visera à tester et consolider les techniques de recueil de la perception du risque d'inondation pour différents groupes d'acteurs sociaux (acteurs de la prévention; individus directement soumis au risque; individus non directement soumis au risque). Les méthodes s'appuieront sur des enquêtes ouvertes et fermées, avec un effort particulier d'interdisciplinarité (géographie, géomatique, sociologie et économie). L'objectif de ces enquêtes sera d'identifier les principaux paramètres qui participent à la construction des perceptions des inondations par les acteurs sociaux. Concernant l'évaluation de l'exposition d'un territoire aux inondations, la proposition visera à proposer une modélisation de la vulnérabilité du territoire (relation entre événement de submersion et conséquences induites). En s'appuyant sur les approches existantes, cette modélisation aura une entrée spatiale forte (les enjeux seront localisés, les conséquences subies dépendront de la submersion qu'ils subissent). La proposition visera à discuter le grain de résolution adéquat en fonction du type d'enjeux (ponctuel, surfacique, non territorialisé pour les effets indirects par exemple); l'adéquation entre la modélisation proposée et la disponibilité des données. Un accent particulier sera mis sur l'analyse des incertitudes. Les différents points de cette discussion seront favorisés par une approche interdisciplinaire (économie, géographie, géomatique, hydrologie-hydraulique). Outre les avancées sur chacune des approches, l'un des enjeux de recherche central à notre proposition repose sur l'articulation possible entre les approches elles-mêmes (approche plutôt «objective» de l'évaluation et approche plutôt «subjective» de la perception). Cette articulation est l'un des enjeux de cette proposition, qui vise à dépasser une simple juxtaposition d'approches supposées complémentaires. La consolidation des connaissances sur chacun des terrains d'études est aussi un des résultats attendus

A New Tool for In Vivo Study of Astrocyte Connexin 43 in Brain

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