Emilien Stragier

Institut de Psychiatrie et Neurosciences de Paris

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Laurence Lanfumey

Université Paris Cité

Raymond Mongeau

Université Paris Cité

Renaud Massart

Inserm

Renato Corradetti

University of Florence

E. Davenas

Institut de Psychiatrie et Neurosciences de Paris

Corinne Poilbout

Institut de Psychiatrie et Neurosciences de Paris

Fabien Boulle

Visma (Norway)

V. V. MARTIN

Inserm

Louai Zaidan

Université Paris-Est Créteil

Marine Salery

Allen Institute for Brain Science

Cooperative Institutions

Inserm

Sorbonne Université

Centre National de la Recherche Scientifique

Institut de Psychiatrie et Neurosciences de Paris

Assistance Publique – Hôpitaux de Paris

Université Paris Cité

Universidade Federal de Santa Catarina

Pitié-Salpêtrière Hospital

Délégation Paris 5

Sorbonne Paris Cité

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Hippocampal and behavioral dysfunctions in a mouse model of environmental stress: normalization by agomelatine

Translational Psychiatry (2014)

Fabien Boulle Renaud Massart Emilien Stragier Eleni Païzanis Louai Zaidan

Stress-induced alterations in neuronal plasticity and in hippocampal functions have been suggested to be involved in the development of mood disorders. In this context, we investigated in the hippocampus the activation of intracellular signaling cascades, the expression of epigenetic markers and plasticity-related genes in a mouse model of stress-induced hyperactivity and of mixed affective disorders. We also determined whether the antidepressant drug agomelatine, a MT1/MT2 melatonergic receptor agonist/5-HT2C receptor antagonist, could prevent some neurobiological and behavioral alterations produced by stress. C57BL/6J mice, exposed for 3 weeks to daily unpredictable socio-environmental stressors of mild intensity, were treated during the whole procedure with agomelatine (50 mg kg−1 per day, intraperitoneal). Stressed mice displayed robust increases in emotional arousal, vigilance and motor activity, together with a reward deficit and a reduction in anxiety-like behavior. Neurobiological investigations showed an increased phosphorylation of intracellular signaling proteins, including Atf1, Creb and p38, in the hippocampus of stressed mice. Decreased hippocampal level of the repressive epigenetic marks HDAC2 and H3K9me2, as well as increased level of the permissive mark H3K9/14ac suggested that chronic mild stress was associated with increased gene transcription, and clear-cut evidence was further indicated by changes in neuroplasticity-related genes, including Arc, Bcl2, Bdnf, Gdnf, Igf1 and Neurod1. Together with other findings, the present data suggest that chronic ultra-mild stress can model the hyperactivity or psychomotor agitation, as well as the mixed affective behaviors often observed during the manic state of bipolar disorder patients. Interestingly, agomelatine could normalize both the behavioral and the molecular alterations induced by stress, providing further insights into the mechanism of action of this new generation antidepressant drug.

Agomelatine

10.1038/tp.2014.125

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Ethanol et épigénétique : conséquences neuroplastiques et fonctionnelles chez la souris

Emilien Stragier

La consommation chronique et excessive d’ethanol provoque des modifications neurobiologiques adaptatives. Les mecanismes qui les controlent sont multiples et certains ont ete relies a des regulations epigenetiques conduisant a des modifications structurelles et fonctionnelles. L’ethanol induit egalement une neurodegenerescence de l’hippocampe responsable de deficits cognitifs. Parmi l’ensemble des modeles animaux qui sont utilises pour etudier les effets d’une consommation chronique d’alcool, figurent les souris de la lignee C57BL/6J. Ces souris possedent une appetence naturelle pour l’ethanol faisant d’elles un modele de choix pour etudier les consequences de la consommation chronique d’ethanol. Le but de ce travail de these a ete d’etudier les relations entre les mecanismes epigenetiques et la modulation de la neuroplasticite de l’hippocampe a la suite d’une consommation chronique d’ethanol chez les souris C57BL/6J, et d’en evaluer les consequences comportementales. Nous avons montre que la consommation chronique d’ethanol induit, au niveau de l’hippocampe, des modulations epigenetiques globales correlees a un remodelage chromatinien au sein du gene du BDNF, impliquant a la fois les modifications post-traductionnelles des histones et la methylation de l’ADN. Ces modifications epigenetiques sont certainement responsables de l’augmentation d’expression proteique du BDNF observee dans l’hippocampe, et plus particulierement dans le gyrus dente, apres 3 semaines de consommation chronique d’ethanol en libre choix. L’accroissement de l’expression du BDNF induit une stimulation des voies de la signalisation intracellulaire dependantes de l’activation du recepteur TrkB du BDNF, et une augmentation de la neurogenese du gyrus dente. Les effets de l’antagoniste specifique du recepteur TrkB, ANA 12, demontrent que l’augmentation de la neurogenese observee chez les souris C57BL/6J apres la prise chronique d’ethanol, est sous le controle unique du complexe BDNF/TrkB. L’analyse comportementale des souris C57BL/6J ayant consomme de l’ethanol, montre une deterioration des capacites d’apprentissage et de memoire sans modification de la plasticite synaptique dans l’hippocampe, suggerant ainsi que d’autres mecanismes sont impliques dans ces deficits cognitifs. L’ensemble de ces donnees apporte de nouveaux elements de comprehension concernant la stimulation de la neurogenese hippocampique chez les souris C57BL/6J lors d’une consommation chronique en libre choix d’ethanol. Il est probable que cette apparente augmentation de plasticite soit un mecanisme adaptatif et compensatoire a la deterioration des fonctions cognitives induite par une consommation chronique d’alcool.

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Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behavior of mice

Neuroscience (2014)

Aderbal S. Aguiar Emilien Stragier Débora da Luz Scheffer Aline Pertile Remor Paulo Alexandre de Oliveira

TFAM

Neurochemical

Physical exercise

Aerobic Exercise

10.1016/j.neuroscience.2014.04.027

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Citations (78)

S.07.06 Epigenetic modifications of the BDNF gene at hippocampal level induced by chronic ethanol intake in C57BL/6J mice

European Neuropsychopharmacology (2013)

Emilien Stragier Renaud Massart M. Hamon Laurence Lanfumey

10.1016/s0924-977x(13)70150-0

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P.6.a.014 Chronic ethanol consumption in C57BL/6J mice induces BDNF epigenetic and signaling alterations, and cognitive deficits

European Neuropsychopharmacology (2014)

Emilien Stragier Victoria Martin E. Davenas Corinne Poilbout Raymond Mongeau

10.1016/s0924-977x(14)71063-6

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Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice

Molecular Psychiatry (2014)

Emilien Stragier Renaud Massart Marine Salery M. Hamon David Gény

10.1038/mp.2014.38

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Glucocorticoids induce CCN5/WISP-2 expression and attenuate invasion in oestrogen receptor-negative human breast cancer cells

Biochemical Journal (2012)

Nathalie Ferrand Emilien Stragier Gérard Redeuilh Michèle Sabbah

CCN5 (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed 5)/WISP-2 [WNT1 (wingless-type MMTV integration site family, member 1)-inducible signalling pathway protein 2] is an oestrogen-regulated member of the CCN family. CCN5 is a transcriptional repressor of genes associated with the EMT (epithelial–mesenchymal transition) and plays an important role in maintenance of the differentiated phenotype in ER (oestrogen receptor)-positive breast cancer cells. In contrast, CCN5 is undetectable in more aggressive ER-negative breast cancer cells. We now report that CCN5 is induced in ER-negative breast cancer cells such as MDA-MB-231 following glucocorticoid exposure, due to interaction of the endogenous glucocorticoid receptor with a functional glucocorticoid-response element in the CCN5 gene promoter. Glucocorticoid treatment of MDA-MB-231 cells is accompanied by morphological alterations, decreased invasiveness and attenuated expression of mesenchymal markers, including vimentin, cadherin 11 and ZEB1 (zinc finger E-box binding homeobox 1). Interestingly, glucocorticoid exposure did not increase CCN5 expression in ER-positive breast cancer cells, but rather down-regulated ER expression, thereby attenuating oestrogen pathway signalling. Taken together, our results indicate that glucocorticoid treatment of ER-negative breast cancer cells induces high levels of CCN5 expression and is accompanied by the appearance of a more differentiated and less invasive epithelial phenotype. These findings propose a novel therapeutic strategy for high-risk breast cancer patients.

10.1042/bj20120311

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A Model of Chronic Exposure to Unpredictable Mild Socio-Environmental Stressors Replicates Some Spaceflight-Induced Immunological Changes

Frontiers in Physiology (2018)

Fanny Gaignier Christine Legrand-Frossi Emilien Stragier Julianne Mathiot Jean‐Louis Merlin

During spaceflight, astronauts face radiations, mechanical, and socio-environmental stressors. To determine the impact of chronic socio-environmental stressors on immunity, we exposed adult male mice to chronic unpredictable mild psychosocial and environmental stressors (CUMS model) for three weeks. This duration was chosen to simulate a long flight at the human scale. Our data show that this combination of stressors induces an increase of serum IgA, a reduction of normalized splenic mass and tends to reduce the production of pro-inflammatory cytokines, as previously reported during or after space missions. However, CUMS did not modify major splenic lymphocyte sub-populations and the proliferative responses of splenocytes suggesting that these changes could be due to other factors such as gravity changes. Thus, CUMS, which is an easy to implement model, could contribute to deepen our understanding of some spaceflight-associated immune alterations and could be useful to test countermeasures.

Spaceflight

Stressor

Chronic Stress

10.3389/fphys.2018.00514

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Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice

Translational Psychiatry (2015)

Emilien Stragier V. V. MARTIN E. Davenas Corinne Poilbout Raymond Mongeau

Abstract Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications. We showed that a 3-week chronic free-choice ethanol consumption in C57BL/6J mice led to a decrease in DNA methylation of the Bdnf gene within the CA1 and CA3 subfields of the hippocampus, and upregulated hippocampal BDNF signaling pathways mediated by ERK, AKT and CREB. However, this activation did not affect long-term potentiation in the CA1. Conversely, ethanol intake impaired learning and memory capacities analyzed in the contextual fear conditioning test and the novel object recognition task. In addition, ethanol increased behavioral perseveration in the Barnes maze test but did not alter the mouse overall spatial capacities. These data suggested that in conditions of chronic and moderate ethanol intake, the chromatin remodeling leading to BDNF signaling upregulation is probably an adaptive process, engaged via epigenetic regulations, to counteract the cognitive deficits induced by ethanol.

Barnes maze

10.1038/tp.2015.183

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Citations (69)

Ethanol and epigenetic : neuroplastic and functional consequences in mice

HAL (Le Centre pour la Communication Scientifique Directe) (2014)

Emilien Stragier

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