Stress, depression and the hippocampus: modulatory effects of continuous LPA treatment

The LPA1, one of the six characterized G protein-coupled receptors (LPA1–6) through which lysophosphatidic acid acts may be involved in promoting normal emotional behaviors. Evidence also imply a role for the LPA1 receptor in mediating the consequences of stress on the hippocampus. However, to date, there is not available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. Changes in glutamate/GABA cycling could be one possible mechanism. To gain further insight into how LPA-LPA1 may prevent the negative consequences of chronic stress, we assessed the effects of chronic ICV administration of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Then, gene expression for molecular markers for excitatory and inhibitory neurotransmission was determined. In addition, the hippocampal expression of mineralocorticoid receptor and glucocorticoid receptor genes and proteins were determined, as well as plasma corticosterone levels. Contrary to expectations, the continuous delivery of LPA in chronically stressed animals instead of inhibiting, potentiated some, though not all, negative effects of stress. Furthermore, this treatment induced as well altered the excitatory/inhibitory balance in the ventral hippocampus. In conclusion, the results of this study reinforce the assumption that LPA, mainly through the LPA1 receptor, regulates hippocampal-dependent behaviour and functions.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Funding: This study was supported by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (SEJ1863 to C.P.; CTS-643 to G.E.-T), Ministerio de Economía y Competitividad and the European Regional Development Fund (PSI2017-83408-P to C.P.), Consejería de Salud de la Junta de Andalucía (NICOLÁS MONARDE Program to G.E:T) Ministerio de Educación, Cultura y Deporte (FPU14/01610 to R.D.M.-F.; FPDI2010 to C.R-V. (Junta de Andalucía) and intramural funding from the EPFL to C.S. I Plan propio de investigación y transferencia de la Universidad de Málaga (Congress attendance of C.P)

LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance.

The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1-receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour.This study was supported by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación/__(PSI2017-83408-P) to C.P., Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (SEJ1863 to C.P. and CTS-643 to G.E.-T), Consejería de Salud, Junta de Andalucía, (NICOLÁS MONARDE to G.E-T). Ministerio de Educación, Cultura y Deporte (FPU14/01610 to R.D.M.-F. and intramural funding from the EPFL to C.S

Rôle du transporteur de cations organiques 2 dans la clairance des monoamines dans le cerveau et les comportements liés à l'humeur

La neurotransmission monoaminergique est principalement contrôlée par la recapture à l aide de transporteurs à haute affinité, qui sont les cibles de nombreux antidépresseurs. Au cours de ma thèse, je me suis intéressé au rôle d un transporteur à faible affinité des monoamines, le transporteur de cations organiques 2 (OCT2).OCT2 est fortement exprimé dans les régions limbiques, et est retrouvé dans de nombreuses régions régulant la réponse au stress et l axe hypothalamo-hypophyso-surrénalien dans le cerveau ainsi que dans les glandes surrénales. Dans ces régions, OCT2 participe à la clairance de la sérotonine (5-HT) et de la noradrénaline (NE), en complément des transporteurs à haute affinité. Nous avons montré qu OCT2 joue un rôle significatif dans les comportements liés à l humeur, comme l anxiété et le désespoir comportemental. De plus, dans un modèle de dépression chronique, nous avons montré qu OCT2 est requis pour l action à long terme des antidépresseurs. OCT2 joue également un rôle important dans la réponse au stress. J ai montré en effet que les souris OCT2-/- présentent une augmentation considérable (150%) de la sécrétion de corticostérone plasmatique en réponse à un stress aigu, sans suractivité des glandes surrénales. Réciproquement, le transport de 5-HT et de NE ex vivo médié par les OCTs n est pas altéré par la corticostérone. Ces expériences indiquent que l activité d OCT2 dans le cerveau contrôle la réponse hormonale au stress, sans pour autant interagir directement avec la corticostérone. Ce travail a permis de démontrer pour la première fois un rôle d OCT2 dans la clairance des monoamines dans le cerveau et les fonctions centrales régulant l humeurMonoaminergic neurotransmission is primarily controlled by high-affinity reuptake transporters, which are targets of several antidepressants. During my PhD thesis, I studied the role of a low-affinity reuptake transporter, the organic cation transporter 2 (OCT2). I showed that OCT2 is highly enriched in limbic regions, and is also found in several regions regulating the response to stress and the hypothalamo-pituitary-adrenal axis in the brain and in adrenal glands. In these regions, OCT2 is involved in serotonin (5-HT) and norepinephrine (NE) clearance, in complement with high-affinity transporters. We showed that OCT2 plays a significant role in mood-related behaviors, such as anxiety and behavioral despair. Moreover, in a chronic depression-like model, we showed that OCT2 is required for the correct long-term effect of antidepressants. OCT2 also plays an important role in response to stress. Indeed, I showed that OCT2-/- mice present a significant corticosterone secretion increase (150%) in response to an acute stress, without overactivity of adrenal glands. Reciprocally, 5-HT and NE ex vivo OCT2-mediated uptake is not altered by corticosterone. These experiments show that brain OCT2 activity controls the hormonal response to stress, without interacting directly with corticosterone. This work demonstrates for the first time a role of OCT2 in brain monoamines clearance and central functions regulating moodPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

EXPERIMENTAL AND NUMERICAL INVESTIGATION OF THE AIR RATIO ON THE TAR CONTENT IN THE SYNGAS OF A TWO-STAGE GASIFIER

This paper reports the experimental results obtained on a two-sage gasification pilot plant base on the NOTAR® concept. The facility is described together with the main adjustable parameters. Among them, the air ratio determining the amount of air introduced in the pyrolyzer is further studied. Two experimental campaigns show that the air ratio has an influence on the gas quality. First, the upper and lower limits for the ratio are examined based on the gas quality and operating conditions. Then, in the defined interval, the ratio of 0.28 is shown to be close the optimum value. However, as long as the pyrolyzer operated at sufficiently high temperature, no significant influence of the air ratio on the tar content of the syngas has been observed. This is confirmed by numerical simulations where the impact of the air ratio on the tar decrease in the combustion zone is studied

Experimental Investigation on the Gasification of Creosoted Wood Using a Two-Stage Gasifier

The wooden railroad ties have a lifespan of approximately 50 years. When replaced, they need to be stored and destroyed very carefully because they are impregnated by creosote and polluted by the rail use. In combustion applications of this biomass, the pollutants, mainly polycyclic aromatic hydrocarbons and heavy metals are freed restricting the energetic valorization of crossties to incinerators equipped with suitable flue gas treatment. As an alternative, this paper presents the results of an experimental study on the gasification of creosoted wooden crossties and the subsequent combustion of the gas in a cogeneration engine. The experiments are focused on the similarities with natural wood gasification in a fixed bed downdraft gasifier to validate this conversion route and on the emissions of pollutants at the exhaust of the engine. It is shown that, without specific exhaust gas treatment, the emission regulations are respected

Experimental investigation of sewage sludge gasification using a two-stage fixed bed downdraft gasifier

Biomass wastes show a great potential as an energy source. The problems usually reside in the conversion of these unclean biomasses into a convenient fuel to produce heat and/or power. Sewage sludge from water waste treatment plant could be converted into a syngas in order to be used in cogeneration plants based on internal combustion engines, thus reducing their treatment and destruction costs by the production of electricity and heat used on site. The main challenge of the use of sludge for gasification resides in the high ashes content (>30%) in comparison with wood (<1%). To investigate the potential of the gasification for this type of high mineral matter content biomass, gasification of sludge was successfully tested in an industrial gasification pilot plant. This paper presents the results of two gasification campaigns using sludge from different processes mixed with wood in concentrations from 25 to 100%

Experimental investigation of sewage sludge gasification using a two-stage fixed bed downdraft gasifier

Biomass wastes show a great potential as an energy source. The problems usually reside in the conversion of these unclean biomasses into a convenient fuel to produce heat and/or power. Sewage sludge from water waste treatment plant could be converted into a syngas in order to be used in cogeneration plants based on internal combustion engines, thus reducing their treatment and destruction costs by the production of electricity and heat used on site. The main challenge of the use of sludge for gasification resides in the high ashes content (>30%) in comparison with wood (<1%). To investigate the potential of the gasification for this type of high mineral matter content biomass, gasification of sludge was successfully tested in an industrial gasification pilot plant. This paper presents the results of two gasification campaigns using sludge from different processes mixed with wood in concentrations from 25 to 100%

Environmental benefits with used railway sleepers fueling Xylowatt's NOTAR Gasification technology

With a share of about 40 to 50%, wooden sleepers are widely used across Europe on railways. Beside wood benefits on this application (CO2 storage, technical advantages, etc..), wooden sleepers also have a negative impact on the environment because of the preservative treatment that contains carcinogenic compounds. Classified as hazardous waste when removed, the valorization of the 0.5 to 1 million tons per year is under incineration directive. The lack of environmental effective solution and the geographical dispersion of the stocks opened the way for gasification process. XYLOWATT's NOTAR® gasification technology showed its ability to handle this type of contaminated material. This paper details the experiments based on measurements of exhaust gas emissions on a pilot unit of 100kW LHV 100% fueled with used railway sleepers. Specific design of the reactor leads to high temperatures and allows destruction of the major part of organic compounds. High metallic compounds levels are managed through the temperature drop in the reduction zone as well as passing through the gas conditioning unit, preventing the release to the environment. Comparison of air emissions with incineration emission value limits demonstrated the effectiveness and environmental benefits when used railway sleepers are valorized with XYLOWATT's NOTAR® gasification process

Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

International audienceBACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT-/-) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT-/- mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET)