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2. The epigenetic hallmark of early-life α-hexabromocyclododecane exposure: From cerebellar 6-mA levels to locomotor performance in adulthood

Author

Cyrielle Holuka, Chloé Morel, Sarah Roth, Yordenca Lamartinière, Sophie B. Mériaux, Justine Paoli, Pauline Guébels, Radu C. Duca, Lode Godderis, An van Nieuwenhuyse, Pascaline Kremarik-Bouillaud, Ronan Cariou, Claude Emond, Henri Schroeder, Jonathan D. Turner, and Nathalie Grova

Subjects
α-hexabromocyclododecane, Early-life exposure, 6 methyl-adenine, Cerebellum, Developmental neurotoxicity, Rat, Environmental sciences, GE1-350
Abstract

There is a growing evidence that methylation at the N6 position of adenine (6-mA), whose modulation occurs primarily during development, would be a reliable epigenetic marker in eukaryotic organisms. The present study raises the question as to whether early-life exposure to α-hexabromocyclododecane (α-HBCDD), a brominated flame retardant, may trigger modifications in 6-mA epigenetic hallmarks in the brain during the development which, in turn could affect the offspring behaviour in adulthood. Pregnant Wistar rats were split into two groups: control and α-HBCDD (66 ng/kg/per os, G0-PND14). At PND1, α-HBCDD levels were assessed in brain and liver by LC-MS/MS. At PND14, DNA was isolated from the offspring’s cerebellum. DNA methylation was measured by 6-mA-specific immunoprecipitation and Illumina® sequencing (MEDIP-Seq). Locomotor activity was finally evaluated at PND120. In our early-life exposure model, we confirmed that α-HBCDD can cross the placental barrier and be detected in pups at birth. An obvious post-exposure phenotype with locomotor deficits was observed when the rats reached adulthood. This was accompanied by sex-specific over-methylation of genes involved in the insulin signaling pathway, MAPK signaling pathway as well as serotonergic and GABAergic synapses, potentially altering the normal process of neurodevelopment with consequent motor impairments crystalized at adulthood.

Published
2023
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4. Head-to-Head Study of Developmental Neurotoxicity and Resultant Phenotype in Rats: α-Hexabromocyclododecane versus Valproic Acid, a Recognized Model of Reference for Autism Spectrum Disorders

Author

Chloé Morel, Armelle Christophe, Katy Maguin-Gaté, Justine Paoli, Jonathan David Turner, Henri Schroeder, and Nathalie Grova

Subjects
α-HBCDD, Autism Spectrum Disorders, early life exposure, brain functionality, neuroglia, synaptic plasticity, Chemical technology, TP1-1185
Abstract

Evidence is now growing that exposure to environmental pollutants during the critical early-life period of brain development may contribute to the emergence of Autism Spectrum Disorders (ASD). This study seeks to compare the developmental neurotoxicity of the α-isomer of hexabromocyclododecane (α-HBCDD), a persistent brominated flame retardant, to the valproic acid (VPA) model of ASD in rodents. Pregnant Wistar rats were divided into three groups: control, α-HBCDD (100 ng/kg/day p.o., GD0-PND21) and VPA (600 mg/kg i.p., GD12). Male offspring were tested for their neuromotor development from PND2-21. At PND21, brain functionality was assessed by measuring cytochrome oxidase activity (CO). Modifications in neuroglia and synaptic plasticity were evaluated in the cortex. Similar subtle behavioural changes related to neuromotor maturation and noise reaction were observed in both treated groups. At PND21, a reduction in CO activity was measured in the VPA group only, in specific areas including auditory nuclei, visual cortex, cingulate and frontal cortices. At the same age, α-HBCDD pointed out significant overexpression of cortical markers of synaptic plasticity while both treated groups showed a significant under expression of astrocyte proteins (S100-β and GFAP). Early-life exposure to a low dose of α-HBCDD may trigger neurobehavioural alterations in line with ASD.

Published
2022
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5. The machine as a partner: Human-machine teaming design using the PRODEC method

Author

Guy André, Boy and Chloé, Morel

Subjects
Engineering, Aircraft, Artificial Intelligence, Rehabilitation, Public Health, Environmental and Occupational Health, Humans, Computer Simulation, Trust
Abstract

BACKGROUND: Human-machine teaming (HMT) typically combines perspectives from systems engineering, artificial intelligence (AI) and human-centered design (HCD), to achieve human systems integration (HSI) through the development of an integrative systems representation that encapsulates human and machine attributes and properties. OBJECTIVE: The study explores the main factors contributing to performance, trust and collaboration between expert human operators and increasingly autonomous machines, by developing and using the PRODEC method. PRODEC supports HSI by improving the agile HCD of advanced sociotechnical systems at work, which qualify as human-machine teamwork. METHODS: PRODEC incorporates scenario-based design and human-in-the-loop simulation at design and development time of a sociotechnical system. It is associated with the concept of digital twin. A systemic representation was developed and used, associated with metrics for the evaluation of human-machine teams. RESULTS: The study is essentially methodological. In practice, PRODEC has been used and validated in the MOHICAN project that dealt with the integration of pilots and virtual assistants onboard advanced fighter aircraft. It enabled the development of appropriate metrics and criteria of performance, trust, collaboration, and tangibility (i.e., issues of complexity, maturity, flexibility, stability, and sustainability), which were associated with the identification of emergent functions that help redesign and recalibrate the air combat virtual assistant as well as fighter pilot training. CONCLUSION: PRODEC addresses the crucial issue of how AI systems could and should influence requirements and design of sociotechnical systems that support human work, particularly in contexts of high uncertainty. However, PRODEC is still work in progress and advanced visualization techniques and tools are needed to increase physical and figurative tangibility.

Published
2022

6. Brominated flame retardants, a cornelian dilemma

Author

Chloé Morel, Henri Schroeder, Claude Emond, Jonathan D. Turner, Eric Lichtfouse, Nathalie Grova, Composés Alimentaires : Biofonctionnalités et risques Neurotoxiques (CALBINOTOX), Université de Lorraine (UL), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université du Québec à Montréal = University of Québec in Montréal (UQAM), PKSH Inc., Luxembourg Institute of Health (LIH), Xi'an Jiaotong University (Xjtu), Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and ANR-17-CE37-0020,MADAM,Diabète maternel et vulnérabilité neuropsychiatrique chez la descendance : rôle de la méthylation de l'ADN(2017)

Subjects
MESH: hexabromocyclododecane, MESH: e-waste, MESH: flammable materials, MESH: brain disease, MESH: intelligent quotient points, MESH: Organophosphate flame retardants, MESH: tetrabromobisphenol A, MESH: Indoor air quality, humanities, MESH: Brominated flame retardants, MESH: autism spectrum disorder, MESH: polybrominated diphenyl ether, Editorial, fluids and secretions, MESH: organochlorine flame retardants, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDE]Environmental Sciences, Environmental Chemistry, MESH: COVID-19, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: foetal germ cells, MESH: tumorigenesis, reproductive and urinary physiology
Abstract

International audience; Dying immediately in flames or from poisoning in the long run is the cornelian dilemma induced by the use of brominatedflame-retardants. Indeed, these compounds have been intensively used to slow down fires in houses and buildings, thus increasing escape time from about 2 min to 20 min. They were initially thought to be safe, notably because their adhesive properties make them unlikely to reach human tissues. However, recent research has disclosed that brominated flame-retardants are developmental neurotoxicants that trigger neurodevelopmental deficits in young children. Since infants and young children have been exposed to brominated flame-retardants since the early 1970s, we are now observing the long-term developmental impact of this 50-year-old ticking time bomb. Here we discuss the occurrence of brominated flame-retardants, exposure at home, neurodevelopmental diseases and alternative flame retardants.

Published
2023

7. Prebiotics Supplementation Impact on the Reinforcing and Motivational Aspect of Feeding

Author

Anne-Sophie Delbès, Julien Castel, Raphaël G. P. Denis, Chloé Morel, Mar Quiñones, Amandine Everard, Patrice D. Cani, Florence Massiera, and Serge H. Luquet

Subjects
food intake, hedonic and motivational component, dopaminergic system, prebiotic, reward, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiota–gut–brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight. However, the consequences of manipulating the implication of the microbiota–gut–brain axis in the control motivational and hedonic/reinforcing aspects of food are still underexplored. In this study, we investigate whether and how dietary prebiotic fructo-oligosaccharides (FOS) could oppose, or revert, the change in hedonic and homeostatic control of feeding occurring after a 2-months exposure to high-fat high-sugar (HFHS) diet. The reinforcing and motivational components of food reward were assessed using a two-food choice paradigm and a food operant behavioral test in mice exposed to FOS either during or after HFHS exposure. We also performed mRNA expression analysis for key genes involved in limbic and hypothalamic control of feeding. We show in a preventive-like approach, FOS addition of HFHS diet had beneficial impact of hypothalamic neuropeptides, and decreased the operant performance for food but only after an overnight fast while it did not prevent the imbalance in mesolimbic markers for DA signaling induced by palatable diet exposure nor the spontaneous tropism for palatable food when given the choice. However, when FOS was added to control diet after chronic HFHS exposure, although it did not significantly alter body weight loss, it greatly decreased palatable food tropism and consumption and was associated with normalization of MCL markers for DA signaling. We conclude that the nature of the diet (regular chow or HFHS) as well as the timing at which prebiotic supplementation is introduced (preventive or curative) greatly influence the efficacy of the gut–microbiota–brain axis. This crosstalk selectively alters the hedonic or motivational drive to eat and triggers molecular changes in neural substrates involved in the homeostatic and non-homeostatic control of body weight.

Published
2018
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8. Low-Dose Alkylphenol Exposure Promotes Mammary Epithelium Alterations and Transgenerational Developmental Defects, But Does Not Enhance Tumorigenic Behavior of Breast Cancer Cells

Author

Clémence Chamard-Jovenin, Charlène Thiebaut, Amand Chesnel, Emmanuel Bresso, Chloé Morel, Malika Smail-Tabbone, Marie-Dominique Devignes, Taha Boukhobza, and Hélène Dumond

Subjects
mammary gland, alkylphenol mix, cancer, development, estrogen receptor alpha 36, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Fetal and neonatal exposure to long-chain alkylphenols has been suspected to promote breast developmental disorders and consequently to increase breast cancer risk. However, disease predisposition from developmental exposures remains unclear. In this work, human MCF-10A mammary epithelial cells were exposed in vitro to a low dose of a realistic (4-nonylphenol + 4-tert-octylphenol) mixture. Transcriptome and cell-phenotype analyses combined to functional and signaling network modeling indicated that long-chain alkylphenols triggered enhanced proliferation, migration ability, and apoptosis resistance and shed light on the underlying molecular mechanisms which involved the human estrogen receptor alpha 36 (ERα36) variant. A male mouse-inherited transgenerational model of exposure to three environmentally relevant doses of the alkylphenol mix was set up in order to determine whether and how it would impact on mammary gland architecture. Mammary glands from F3 progeny obtained after intrabuccal chronic exposure of C57BL/6J P0 pregnant mice followed by F1–F3 male inheritance displayed an altered histology which correlated with the phenotypes observed in vitro in human mammary epithelial cells. Since cellular phenotypes are similar in vivo and in vitro and involve the unique ERα36 human variant, such consequences of alkylphenol exposure could be extrapolated from mouse model to human. However, transient alkylphenol treatments combined to ERα36 overexpression in mammary epithelial cells were not sufficient to trigger tumorigenesis in xenografted Nude mice. Therefore, it remains to be determined if low-dose alkylphenol transgenerational exposure and subsequent abnormal mammary gland development could account for an increased breast cancer susceptibility.

Published
2017
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9. Mammary epithelial cell phenotype disruption in vitro and in vivo through ERalpha36 overexpression.

Author

Charlène Thiebaut, Clémence Chamard-Jovenin, Amand Chesnel, Chloé Morel, El-Hadi Djermoune, Taha Boukhobza, and Hélène Dumond

Subjects
Medicine, Science
Abstract

Estrogen receptor alpha 36 (ERα36) is a variant of the canonical estrogen receptor alpha (ERα66), widely expressed in hormone sensitive cancer cells and whose high expression level correlates with a poor survival prognosis for breast cancer patients. While ERα36 activity have been related to breast cancer progression or acquired resistance to treatment, expression level and location of ERα36 are poorly documented in the normal mammary gland. Therefore, we explored the consequences of a ERα36 overexpression in vitro in MCF-10A normal mammary epithelial cells and in vivo in a unique model of MMTV-ERα36 transgenic mouse strain wherein ERα36 mRNA was specifically expressed in the mammary gland. By a combination of bioinformatics and computational analyses of microarray data, we identified hierarchical gene networks, downstream of ERα36 and modulated by the JAK2/STAT3 signaling pathway. Concomitantly, ERα36 overexpression lowered proliferation rate but enhanced migration potential and resistance to staurosporin-induced apoptosis of the MCF-10A cell line. In vivo, ERα36 expression led to duct epithelium thinning and disruption in adult but not in prepubescent mouse mammary gland. These phenotypes correlated with a loss of E-cadherin expression. Here, we show that an enhanced expression of ERα36 is sufficient, by itself, to disrupt normal breast epithelial phenotype in vivo and in vitro through a dominant-positive effect on nongenomic estrogen signaling pathways. These results also suggest that, in the presence of adult endogenous steroid levels, ERα36 overexpression in vivo contributes to alter mammary gland architecture which may support pre-neoplastic lesion and augment breast cancer risk.

Published
2017
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10. Major role of MT2 receptors in the beneficial effect of melatonin on long-term recognition memory in C57BL/6J male mice

Author

Céline Héraud, Paul Pévet, Marie-Paule Felder-Schmittbuhl, Stéphanie Dumont-Kientzy, Amandine Zimmermann, Chantal Mathis, Karine Herbeaux, Chloé Morel, Cristiana Pistono, Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Institut des Neurosciences Cellulaires et Intégratives (INCI)

Subjects
Male mice, melatonin, C57bl 6j, object recognition, Melatonin, 03 medical and health sciences, Behavioral Neuroscience, MT1 deficiency, [SCCO]Cognitive science, 0302 clinical medicine, Endocrinology, medicine, Circadian rhythm, Receptor, 030304 developmental biology, Recognition memory, 0303 health sciences, Endocrine and Autonomic Systems, Mt1 receptor, business.industry, object location, Object (computer science), MT2 deficiency, long-term recognition memory, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Melatonin, a major signal of the circadian system, is also involved in brain functions such as learning and memory. Chronic melatonin treatment is known to improve memory performances, but the respective contribution of its central receptors, MT1 and MT2, is still unclear. Here, we used new single receptor deficient MT1-/and MT2-/mice to investigate the contribution of each receptor in the positive effect of chronic melatonin treatment on long-term recognition memory. The lack of MT2 receptor precluded memory-enhancing effect of melatonin in the object recognition task and to a lesser extent in the object location task, whereas the lack of MT1 receptor mitigated its effect in the object location task only. Our findings support a key role of MT2 in mediating melatonin's beneficial action on long-term object recognition memory, whereas MT1 may contribute to the effect on object location memory.

Published
2021

11. Major role of MT

Author

Cristiana, Pistono, Amandine, Zimmermann, Chloé, Morel, Karine, Herbeaux, Céline, Héraud, Stéphanie, Dumont-Kientzy, Paul, Pevet, Marie-Paule, Felder-Schmittbuhl, and Chantal, Mathis

Subjects
Male, Mice, Inbred C57BL, Mice, Cognition, Receptor, Melatonin, MT2, Receptor, Melatonin, MT1, Animals, Melatonin
Abstract

Melatonin, a major signal of the circadian system, is also involved in brain functions such as learning and memory. Chronic melatonin treatment is known to improve memory performances, but the respective contribution of its central receptors, MT

Published
2021

12. Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis

Author

Giuseppe Gangarossa, Casper Gravesen Salinas, Vincent Prevot, Heidi Solvang Nielsen, Wineke Bakker, Chloé Morel, Martin Heni, Serge Luquet, Jacob Hecksher-Sørensen, Thomas Åskov Pedersen, Raphaël G. P. Denis, Anna Secher, Julien Castel, Manon Duquenne, Daniela Herrera Moro Chao, Claire Martin, Walter Matzler, Monica Imbernon, Rim Hassouna, Andreas Peter, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Agonist, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Type 2 diabetes, Energy homeostasis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Glucose homeostasis, 030304 developmental biology, Circumventricular organs, 0303 health sciences, biology, business.industry, Insulin, Area postrema, medicine.disease, Insulin receptor, Endocrinology, medicine.anatomical_structure, biology.protein, business, 030217 neurology & neurosurgery
Abstract

The control of body weight and glucose homeostasis are the bedrock of type 2 diabetes medication. Therapies based on co-administration of glucagon-like peptide-1 (GLP-1) long-acting analogues and insulin are becoming popular in the treatment of T2D. Both insulin and GLP-1 receptors (InsR and GLP1-R, respectively) are expressed in brain regions critically involved in the regulation of energy homeostasis, suggesting a possible cooperative action. However, the mechanisms underlying the synergistic action of insulin and GLP-1R agonists on body weight loss and glucose homeostasis remain largely under-investigated. In this study, we provide evidence that peripheral insulin administration modulates the action of GLP-1R agonists onto fatty acids oxidation. Taking advantage of fluorescently labeled insulin and GLP-1R agonists, we found that glucoprivic condition, either achieved by insulin or by 2-deoxyglucose (2-DG), acts as a permissive signal on the blood-brain barrier (BBB) at circumventricular organs, including the median eminence (ME) and the area postrema (AP), enhancing the passage and action of GLP-1-R agonists. Mechanistically, this phenomenon relied on the release of tanycyctic vascular endothelial growth factor A (VEGF-A) and it was selectively impaired after calorie-rich diet exposure. Finally, we found that in human subjects, low blood glucose also correlates with enhanced blood-to-brain passage of insulin suggesting that changes in glycaemia also affect passage of peptide hormones into the brain in humans.In conclusion, we describe a yet unappreciated mechanism by which acute variations of glycaemia gate the entry and action of circulating energy-related signals in the brain. This phenomenon has physiological and clinical relevance implying that glycemic control is critical to harnessing the full benefit of GLP-1R agonist co-treatment in body weight loss therapy.

Published
2020

13. Circulating triglycerides gate dopamine-associated behaviors through DRD2-expressing neurons

Author

Giuseppe Gangarossa, Mary Sullivan, Xavier Fioramonti, Philippe Faure, Stefania Tolu, Maud Martinat, Xue S. Davis, Fabio Marti, Julien Castel, Serge Luquet, Chloé Morel, Dana M. Small, Chloé Berland, Thomas S. Hnasko, Enrica Montalban, Casper Gravesen Salinas, Matthias H. Tschöp, Stéphanie Caillé, Yuko Nakamura, Mathieu Di Miceli, Sylvie Perez, Claire Martin, Sophie Layé, Elodie Perrin, Martine Cador, Jacob Hecksher-Sørensen, Mohammad Ali Shenasa, Laurent Venance, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition et Neurobiologie intégrée (NutriNeur0), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The Modern Diet and Physiology Research Center, Yale University School of Medicine, University of California [San Diego] (UC San Diego), University of California, Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark [Lyngby] (DTU), Technical University of Munich (TUM), Research Service VA San Diego Healthcare System, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et Neurobiologie intégrée (NutriNeuro), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), DESAILLY, Marion, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL), Institut Polytechnique de Bordeaux (Bordeaux INP), Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Gubra [Hørsholm, Denmark] (GUt and BRAin), Novo Nordisk A/S [Maløv, Denmark], Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Physiology, nucleus accumbens, striatum, dopamine receptor D2, Striatum, Medical Biochemistry and Metabolomics, Inbred C57BL, Mice, Comportement alimentaire, 0302 clinical medicine, Receptors, triglycerides, Neurons, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dopaminergic, fMRI, Santé humaine, Ventral tegmental area, medicine.anatomical_structure, Dopamine receptor, Compulsive behavior, Female, medicine.symptom, dopamine, medicine.drug, Adult, Adolescent, food-reward, ventral tegmental area, Dopamine, Dopamine Receptor D2, Fmri, Food-reward, Lipoprotein Lipase, Nucleus Accumbens, Triglycerides, Ventral Tegmental Area, lipoprotein lipase, Nucleus accumbens, Biology, Basic Behavioral and Social Science, 03 medical and health sciences, Young Adult, Endocrinology & Metabolism, Dopamine receptor D2, Dopamine D2, Behavioral and Social Science, medicine, Animals, Humans, Obesity, Molecular Biology, Nutrition, Motivation, Prevention, Neurosciences, Cell Biology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, Biochemistry and Cell Biology, Neuroscience, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, postprandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior.

Published
2020

14. The Dopamine Receptor Subtype 2 (DRD2) Regulates the Central Reinforcing Actions of Dietary Lipids in Humans and Rodents

Author

Chloé Berland, Mohammad Ali Shenasa, Dana M. Small, Matthias H. Tschöp, Yuko Nakamura, Fabio Marti, Casper Bo Jensen, Giuseppe Gangarossa, Martine Cador, Jacob Hecksher-Sørensen, Philippe Faure, Serge Luquet, Stefania Tolu, Chloé Morel, Mary Sullivan, Julien Castel, Xue S. Davis, Claire Martin, Thomas Hnasko, Stéphanie Caillé, Team Dynamic and Pathophysiology of Neuronal Networks, Center for Interdisciplinary Research in Biology (CIRB), Department of biological information-Tokyo Institute of Technology (DBI), Tokyo Institute of Technology [Tokyo] (TITECH), Aquitaine Institute for Cognitive and Integrative Neuroscience, Université de Bordeaux (UB), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aquitaine Institute of Cognitive and Integrative Neurosciences, Neurobiologie des processus adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0303 health sciences, Lipoprotein lipase, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Dopaminergic, Striatum, Biology, Cell biology, Ventral tegmental area, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Dopamine, Dopamine receptor, Dopamine receptor D2, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract

Emerging evidence suggests that energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote the development of compulsive-like feeding, reward dysfunction, and ultimately weight gain. Yet the mechanisms by which metabolic signals influence MCL circuitry to control behavior remain poorly understood. Circulating triglycerides (TG) are a conserved post-prandial metabolic signature among mammals and high plasma TG are associated with reduced reward responsiveness in humans. Here, we show that the TG-processing enzyme lipoprotein lipase (LPL) is enriched throughout the MCL of both mouse and human, including DA-releasing neurons in the ventral tegmental area and DA-receptive neurons in the striatum. Using brain-specific TG delivery in mice, we show that nutritional TG are metabolized within the MCL system where they acutely control D2 DA receptor (DRD2) signaling. We also show that TG are directly reinforcing in mice, and that central TG sensing relies on LPL activity in the MCL. Likewise, in humans, post-prandial TG excursions modulate brain response to food cues in MCL with the direction of the association determined by a DRD2 dependent genotype. Collectively, these findings reveal a mechanism by which dietary TG directly alter MCL signaling to regulate behavior, providing a new mechanistic basis by which energy-rich diets can lead to adaptations in DA signaling that underlie compulsive behavior.

Published
2019

15. Prebiotics Supplementation Impact on the Reinforcing and Motivational Aspect of Feeding

Author

Chloé Morel, Florence Massiera, Raphael G. P. Denis, Anne-Sophie Delbes, Amandine Everard, Julien Castel, Mar Quiñones, Patrice D. Cani, Serge Luquet, UCL - SSS/LDRI - Louvain Drug Research Institute, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, DIET-INDUCED OBESITY, FOOD-INTAKE, medicine.medical_specialty, food intake, OLIGOFRUCTOSE PROMOTES SATIETY, HIGH-FAT DIET, DOPAMINE D2 RECEPTORS, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, medicine.medical_treatment, GUT-BRAIN AXIS, Central nervous system, HOST METABOLISM, Biology, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Energy homeostasis, 03 medical and health sciences, Endocrinology, 0302 clinical medicine, Dopamine, hedonic and motivational component, Internal medicine, medicine, Tropism, reward, GENE-EXPRESSION, Original Research, media_common, 2. Zero hunger, lcsh:RC648-665, Prebiotic, digestive, oral, and skin physiology, Appetite, AKKERMANSIA-MUCINIPHILA, medicine.disease, Obesity, 030104 developmental biology, medicine.anatomical_structure, dopaminergic system, prebiotic, NERVOUS-SYSTEM CONTROL, 030217 neurology & neurosurgery, Homeostasis, medicine.drug
Abstract

International audience; Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiotagut-brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight. However, the consequences of manipulating the implication of the microbiota-gut-brain axis in the control motivational and hedonic/reinforcing aspects of food are still underexplored. In this study, we investigate whether and how dietary prebiotic fructo-oligosaccharides (FOS) could oppose, or revert, the change in hedonic and homeostatic control of feeding occurring after a 2-months exposure to high-fat high-sugar (HFHS) diet. The reinforcing and motivational components of food reward were assessed using a two-food choice paradigm and a food operant behavioral test in mice exposed to FOS either during or after HFHS exposure. We also performed mRNA expression analysis for key genes involved in limbic and hypothalamic control of feeding. We show in a preventive-like approach, FOS addition of HFHS diet had beneficial impact of hypothalamic neuropeptides, and decreased the operant performance for food but only after an overnight fast while it did not prevent the imbalance in mesolimbic markers for DA signaling induced by palatable diet exposure nor the spontaneous tropism for palatable food when given the choice. However, when FOS was added to control diet after chronic HFHS exposure, although it did not significantly alter body weight loss, it greatly decreased palatable food tropism and consumption and was associated with normalization of MCL markers for DA signaling. We conclude that the nature of the diet (regular chow or HFHS) as well as the timing at which prebiotic supplementation is introduced (preventive or curative) greatly influence the efficacy of the gut-microbiota-brain axis. This crosstalk selectively alters the hedonic or motivational drive to eat and triggers molecular changes in neural substrates involved in the homeostatic and non-homeostatic control of body weight.

Published
2018

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