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1. Organic cation transporter 2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain

Author

Alejandro Orrico-Sanchez, Bruno P. Guiard, Stella Manta, Jacques Callebert, Jean-Marie Launay, Franck Louis, Antoine Paccard, Carole Gruszczynski, Catalina Betancur, Vincent Vialou, and Sophie Gautron

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain. Contrarily to wild-type mice, OCT2-invalidated mice failed to respond to prolonged fluoxetine treatment in a chronic depression model induced by corticosterone exposure recapitulating core symptoms of depression, i.e., anhedonia, social withdrawal, anxiety, and memory impairment. After corticosterone and fluoxetine treatment, the levels of tryptophan and its metabolites serotonin and kynurenine were decreased in the brain of OCT2 mutant mice compared to wild-type mice and reciprocally tryptophan and kynurenine levels were increased in mutants’ plasma. OCT2 was detected by immunofluorescence in several structures at the blood-cerebrospinal fluid (CSF) or brain-CSF interface. Tryptophan supplementation during fluoxetine treatment increased brain concentrations of tryptophan and, more discreetly, of 5-HT in wild-type and OCT2 mutant mice. Importantly, tryptophan supplementation improved the sensitivity to fluoxetine treatment of OCT2 mutant mice, impacting chiefly anhedonia and short-term memory. Western blot analysis showed that glycogen synthase kinase-3β (GSK3β) and mammalian/mechanistic target of rapamycin (mTOR) intracellular signaling was impaired in OCT2 mutant mice brain after corticosterone and fluoxetine treatment and, conversely, tryptophan supplementation recruited selectively the mTOR protein complex 2. This study provides the first evidence of the physiological relevance of OCT2-mediated tryptophan transport, and its biological consequences on serotonin homeostasis in the brain and SSRI efficacy.

Published
2023
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2. Characterisation of radioactivity arising from the integrated steelworks in the UK and assessment of occupational exposure situations

Author

Dal Molin, Franck Louis Georges and Read, David

Subjects
540
Abstract

Most of the materials found on the Earth’s surface, such as iron ores and all other materials entering the integrated steel-making process, contain measurable amounts of natural radioactivity mainly due to the presence of uranium-238 (238U), thorium-232 (232Th) and their respective daughter decay products. Some materials after being processed can present a relatively high concentration of natural radionuclides. These materials are defined as Naturally Occurring Radioactive Materials (NORM). Since 2010, in the United Kingdom, industries producing NORM are subject to a new permitting regime. The current regime is named Environmental Permitting Regulations 2010 (EPR 2010), recently amended and replaced by EPR2016 and is directly derived from the European Directive EURATOM 1996, itself reviewed in 2013 and replaces the previous exemption limits defined in the previous regime Radioactive Substances Act 1993 (RSA93). As a result, the steel industry is now potentially producing materials above the new exemption levels to dispose of and therefore has a new environmental duty to accurately determine the radioactivity content of a wide range of iron- and steel-making materials used on site within the processes and/or sold off to third parties. In the steel industry, the main isotopes of concern are polonium-210 (210Po) and lead-210 (210Pb), which concentrate in the waste off-gas dusts from the iron ore sintering and blast furnaces processes, and radium-226 (226Ra) which can be found in slag materials from the blast furnace process. NORM can also result in potential exposure of the workforce to radioactive substances, mainly in workplaces where NORM are handled, stockpiled or processed. The UK steel industry has a duty of care to protect the workers and assess the potential occupational exposure to natural radioactivity in its workplaces in accordance with the Ionising Radiations Regulations 1999 (IRR99), recently replaced by IRR17 since 1st January 2018.

Published
2018

3. Spin-dependent Klein tunneling in polariton graphene with photonic spin-orbit interaction

Author

Solnyshkov, Dmitry, Nalitov, Anton, Teklu, Berihu, Franck, Louis, and Malpuech, Guillaume

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics, Condensed Matter - Other Condensed Matter
Abstract

We study Klein tunneling in polariton graphene. We show that the photonic spin-orbit coupling associated with the energy splitting between TE and TM photonic modes can be described as an emergent gauge field. It suppresses the Klein tunnelling in small energy range close to the Dirac points. Thanks to polariton spin-anisotropic interactions, polarized optical pumping allows to create potential barriers acting on a single polariton spin. We show that the resulting spin-dependent Klein tunneling can be used to create a perfectly transmitting polarization rotator operating at microscopic scale.

Published
2015
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4. Astrocytes control cocaine-induced synaptic plasticity and reward through the matricellular protein hevin

Author

Raphaële Mongrédien, Augusto Anesio, Gustavo J. D. Fernandes, Andrew L. Eagle, Steeve Maldera, Cuong Pham, Adèle Vilette, Paula Bianchi, Clara Franco, Franck Louis, Carole Gruszczynski, Catalina Betancur, Amaia M. Erdozain, Alfred J. Robison, Antony A. Boucard, Dongdong Li, Fabio C. Cruz, Sophie Gautron, Nicolas Heck, and Vincent Vialou

Abstract

Drug addiction involves profound modifications of neuronal plasticity in the nucleus accumbens, which may engage various cell types. Here, we report prominent effects of cocaine on calcium signals in astrocytes characterized byin vivofiber photometry. Astrocyte calcium signals in the nucleus accumbens are sufficient and necessary for the acquisition of cocaine seeking behavior. We identify the astrocyte-secreted matricellular protein hevin as an effector of the action of cocaine and calcium signals on reward and neuronal plasticity.

Published
2023
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6. Viral vector-mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine-related behaviors and hallmarks of programmed cell death

Author

Franck Louis, Jean-Marie Launay, Bruno P. Guiard, Vincent Vialou, Sophie Gautron, Jacques Callebert, Carole Gruszczynski, Sara Rezai Amin, Catalina Betancur, 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), Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-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), Service de Biochimie et de Biologie Moléculaire [AP-HP Hôpital Lariboisière] (Inserm U942), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by INSERM, CNRS, Sorbonne Université and the Agence Nationale de la Recherche (ANR-13-SAMENTA-0003-01). S.R. was a recipient of a fellowship from the French Ministry for Research., 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), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Gautron, Sophie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-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), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Dopamine, [SDV]Life Sciences [q-bio], Genetic Vectors, Nigrostriatal pathway, Cre recombinase, Apoptosis, Mice, Transgenic, Substantia nigra, Biology, Biochemistry, Viral vector, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], programmed cell death, Neurons, Integrases, Pars compacta, Dopaminergic, Neurodegeneration, dopaminergic neurotransmission, Dependovirus, medicine.disease, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, substantia nigra, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Pars reticulata, Locomotion, 030217 neurology & neurosurgery
Abstract

This work is dedicated to the memory of Dr. Marie-Pascale Martres.; International audience; Cre/loxP recombination is a widely used approach to study gene function in vivo, using mice models expressing the Cre recombinase under the control of specific promoters or through viral delivery of Cre-expressing constructs. A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP-like sites present in the genome. However, most studies reporting the consequences of Cre-lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data. In this study, we report the anatomical, neurochemical and behavioral consequences in mice of adeno-associated virus (AAV)-mediated Cre expression in the dopaminergic nuclei substantia nigra, at commonly used viral titers (3×109 genome copies/0.3 μL or 2×109 genome copies/0.6 μL). We found that injecting AAV-eGFP-Cre into the SN engendered drastic and reproducible modifications of behavior, with increased basal locomotor activity as well as impaired locomotor response to cocaine compared to AAV-eGFP-injected controls. Cre expression in the SN induced a massive decrease in neuronal populations of both pars compacta and pars reticulata, and dopamine depletion in the nigrostriatal pathway. This anatomical injury was associated with typical features of programmed cell death, including an increase in DNA break markers, evidence of apoptosis and disrupted macroautophagy. These observations underscore the need for careful control of Cre toxicity in the brain and the reassessment of previous studies. In addition, our findings suggest that Cre-mediated ablation may constitute an efficient tool to explore the function of specific cell populations and areas in the brain, and the impact of neurodegeneration in these populations. This article is protected by copyright. All rights reserved.

Published
2019
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7. Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Author

Teodoro Zornoza, Franck Louis, Sara Rezai Amin, Rodolphe Alves de Sousa, Patrick M. Dansette, Carole Gruszczynski, Sophie Gautron, Vincent Vialou, Alejandro Orrico-Sanchez, Basile Coutens, Nicolas Pietrancosta, Francine Acher, Bruno P. Guiard, Laetitia Chausset-Boissarie, Assia Hessani, Bruno Giros, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), 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), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), PMSNC, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), McGill University, Neuropharmacologie des troubles anxieux-dépressifs et neurogénèse, Université Paris-Sud - Paris 11 (UP11), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universitat de València (UV), McGill University = Université McGill [Montréal, Canada], Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS-05), 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 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), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS 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)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, Gautron, Sophie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI)

Subjects
Male, 0301 basic medicine, Anhedonia, Organic Cation Transport Proteins, medicine.drug_class, Anxiety, Pharmacology, Anxiolytic, Reuptake, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Memory, Fluoxetine, medicine, Animals, Humans, [CHIM]Chemical Sciences, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Organic cation transport proteins, biology, Depression, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Antidepressive Agents, 3. Good health, Ventral tegmental area, Disease Models, Animal, Psychiatry and Mental health, 030104 developmental biology, Monoamine neurotransmitter, medicine.anatomical_structure, biology.protein, Antidepressant, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. This compound, H2-cyanome, was tested in a rodent model of chronic depression induced by 7-week corticosterone exposure. In male mice, prolonged administration of H2-cyanome induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased ventral tegmental area dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome, like fluoxetine, also modulated several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.

Published
2019
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8. Antidepressive effects of targeting ELK-1 signal transduction

Author

Juan Pablo Lopez, Elsa Isingrini, Marie-Anne El Khoury, Naguib Mechawar, Chloé Guinaudie, Alejandro Orrico, Raphaele Mongredien, Jocelyne Caboche, Carlos Eduardo Macedo, Fabio Marti, Yiu C. Tse, Wojciech Jaworski, Bruno Giros, Severine Farley, Tak Pan Wong, Gustavo Turecki, Vincent Vialou, Kallia Apazoglou, Elise Morice, Ferah Yildirim, Franck Louis, Julien Grenier, Sophie Gautron, Laurent Groc, Ariane Bochereau, Sylvie Dumas, El Chérif Ibrahim, Raoul Belzeaux, Lenka Mikasova, Victor Gorgievski, Alexandre Barbé, Charbel Massaad, Eleni T. Tzavara, 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), Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), McGill University = Université McGill [Montréal, Canada], FondaMental Foundation, Fondation de Coopération Scientifique Hôpital, A. Chenevier, Douglas Mental Health University Institute [Montréal], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroplasticité et thérapie des addictions (ERL 3649), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Oramacell [Paris, France], Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Pôle de Psychiatrie Universitaire Solaris, Marseille, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Research Center of the Douglas Mental Health University Institute, PMSNC, Interdisciplinary Institute for Neuroscience, Régulation de la transcription et maladies génétiques (RTMG), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie et comportements = Neurophysiology and Behavior (NPS-06), Neurobiologie des processus adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), McGill University, 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), Pôle de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-CHU Marseille, Fondation FondaMental [Créteil], Université Paris Descartes - Paris 5 (UPD5)-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 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)-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), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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)-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 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and caboche, jocelyne

Subjects
Adult, Male, 0301 basic medicine, MAPK/ERK pathway, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Druggability, Hippocampus, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Elk-1, 0302 clinical medicine, Downregulation and upregulation, ELK1, Animals, Humans, Medicine, RNA, Messenger, dentate gyrus, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Transcription factor, ets-Domain Protein Elk-1, chronic stress, Neuronal Plasticity, Behavior, Animal, Depression, General Commentary, business.industry, Kinase, General Medicine, Middle Aged, Antidepressive Agents, adult neurogenesis, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Synaptic plasticity, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, business, Neuroscience, Stress, Psychological, 030217 neurology & neurosurgery, Signal Transduction
Abstract

International audience; Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.

Published
2018
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10. ÉTATS-UNIS

Author

Franck, Louis R.

Published
1939

13. IN MEMORIAM

Author

Rosenstock-Franck, Louis

Published
1937

19. Ctr9, a Protein in the Transcription Complex Paf1, Regulates Dopamine Transporter Activity at the Plasma Membrane

Author

Nicolas Pietrancosta, Bruno Giros, Stéphanie De Gois, Amaia M. Erdozain, Laurent Daviet, Caroline Bouvrais-Veret, Patrick Slama, Franck Louis, Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Canadian Institutes for Health Research Operating Grant [240843], INSERM/CNRS/Universite Pierre et Marie Curie funding, Fondation pour la Recherche Medicale, Basque Government, ``Schizo'Oui' association, Canadian Institutes for Health Research, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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 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)-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), 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)-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)-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)-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)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and 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)

Subjects
Synaptic cleft, Molecular Sequence Data, Biology, SH2 domain, Biochemistry, Cell Line, Reuptake, src Homology Domains, Neurobiology, parasitic diseases, mental disorders, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Molecular Biology, Transcription factor, Dopamine transporter, Dopamine Plasma Membrane Transport Proteins, Nuclear Proteins, Cell Biology, Membrane transport, Phosphoproteins, Rats, Cell biology, Molecular Docking Simulation, Protein Transport, Tetratricopeptide, nervous system, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nuclear localization sequence, Transcription Factors
Abstract

International audience; Dopamine (DA) is a major regulator of sensorimotor and cognitive functions. The DA transporter (DAT) is the key protein that regulates the spatial and temporal activity of DA release into the synaptic cleft via the rapid reuptake of DA into presynaptic termini. Several lines of evidence have suggested that transporter-interacting proteins may play a role in DAT function and regulation. Here, we identified the tetratricopeptide repeat domain-containing protein Ctr9 as a novel DAT binding partner using a yeast two-hybrid system. We showed that Ctr9 is expressed in dopaminergic neurons and forms a stable complex with DAT in vivo via GST pulldown and co-immunoprecipitation assays. In mammalian cells co-expressing both proteins, Ctr9 partially colocalizes with DAT at the plasma membrane. This interaction between DAT and Ctr9 results in a dramatic enhancement of DAT-mediated DA uptake due to an increased number of DAT transporters at the plasma membrane. We determined that the binding of Ctr9 to DAT requires residues YKF in the first half of the DAT C terminus. In addition, we characterized Ctr9, providing new insight into this protein. Using three-dimensional modeling, we identified three novel tetratricopeptide repeat domains in the Ctr9 sequence, and based on deletion mutation experiments, we demonstrated the role of the SH2 domain of Ctr9 in nuclear localization. Our results demonstrate that Ctr9 localization is not restricted to the nucleus, as previously described for the transcription complex Paf1. Taken together, our data provide evidence that Ctr9 modulates DAT function by regulating its trafficking.

Published
2015
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20. Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling

Author

Sophie Gautron, Bruno P. Guiard, Thomas Couroussé, Catherine Belzung, Alain M. Gardier, A-M Le Guisquet, Bruno Giros, L. Balasse, Franck Louis, A H Schinkel, A Bacq, Université Paris Descartes - Paris 5 (UPD5), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Universités (COMUE), Université Pierre et Marie Curie - Paris 6 (UPMC), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sérotonine et neuropharmacologie, Université Paris-Sud - Paris 11 (UP11)-IFR141, Université Paris-Sud - Paris 11 (UP11), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, McGill University = Université McGill [Montréal, Canada], This study was financially supported by the Institut National pour la Santé et la Recherche Médicale (INSERM), the Fondation de France and the Agence nationale de la recherche (ANR-13-SAMENTA-0003-01)., SENIOR investigators, ANR-13-SAMA-0003,ANTIDOCT,LES TRANSPORTEURS DE CATIONS ORGANIQUES, DE NOUVELLES CIBLES THERAPEUTIQUES POUR LA DEPRESSION(2013), 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), Division of Molecular Biology [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Department of Psychiatry [Montréal], French Ministry for Research, Societe Francaise de Pharmacologie et Therapeutique, Institut National pour la Sante et la Recherche Medicale (INSERM), Fondation de France, Agence nationale de la recherche [ANR-13-SAMENTA-0003-01], 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), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University, Gautron, Sophie, Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), 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)-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), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, UCMS, [SDV]Life Sciences [q-bio], vulnerability, Hippocampus, Action Potentials, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Norepinephrine, stress, Corticosterone, Hormone metabolism, Mice, Knockout, Organic cation transport proteins, biology, Pyramidal Cells, Uncertainty, Brain, Organic Cation Transporter 2, Resilience, Psychological, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Acute Disease, depression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, Psychology, medicine.medical_specialty, Serotonin, Organic Cation Transport Proteins, Adrenocorticotropic hormone, Cellular and Molecular Neuroscience, Internal medicine, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, GSK3B, Glycogen Synthase Kinase 3 beta, HPA axis, organic cation transporter, Hormones, Mice, Inbred C57BL, Endocrinology, chemistry, Chronic Disease, biology.protein, Proto-Oncogene Proteins c-akt, Stress, Psychological
Abstract

International audience; Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress and impaired HPA function without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2(-/-) mice were potently more sensitive to the action of unpredictable chronic mild stress (UCMS) on depression-related behaviors involving self-care, spatial memory, social interaction and stress-sensitive spontaneous behavior. The functional state of the glycogen synthase kinase-3 beta (GSK3 beta) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2(-/-) mice. In vivo pharmacology and western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3 beta signaling in OCT2(-/-) mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.

Published
2015
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21. Search for New Physics with the Atlas detector at LHC

Author

Franck, Louis, UFR Sciences et Technologies - Clermont-Ferrand (UFR ST - UBP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), and Julien Donini

Subjects
[PHYS]Physics [physics], Standard Model, Atlas detector, Modèle Standard, [PHYS.HPHE]Physics [physics]/High Energy Physics - Phenomenology [hep-ph], Grand Collisionneur de Hadrons (LHC), Détecteur Atlas, Large Hadron Collider (LHC)
Abstract

Despite its' 40 years of experimental success, the Standard Model, a theory which describes fundamental particles as well as three fundamental interactions, has theoretical and experimental limitations. These lead to the existence of theories beyond the Standard Model, called New Physics. This report presents the search for a new particle present in many theories beyond the Standard Model: the W' boson. This year, the Large Hadron Collider is entering run II, which will see proton-proton collisions take place at an unprecedented centre of mass energy of 13 TeV. This high energy will provide the mouth wateringprospect of fnding New Physics. Studies that have been made during this internship have used Monte Carlo simulations of events that we should see in the Atlas detector at LHC during run II. These studies are grouped into two main parts. The rst part consists in studies at the parton level, where we see the impact of physics aspects as parton distribution functions and gluon radiations by quarks on the reconstructed mass of the W' boson. We also see the increased potential for discovery of this new particle by comparing invariant mass distributions and cross-sections at centre of mass energies of 8 TeV and 13 TeV. The second part describes the step-by-step reconstruction of the W' boson in a detector simulation. The main difficulties in these steps are pointed out, as well as several ideas for improvements for run II. Background processes and the selection criteria that have been used to discriminate them from the signal are introduced, and optimisations of these criteria as well as efficiency tests for new ones are presented. This search is the sequel to a large number of studies made during run I, and will look to continue to improve the seek for beyond the Standard Model particles.; Malgré ses 40 ans de succès expérimentaux, le Modèle Standard, théorie décrivant les particules élémentaires et trois des interactions fondamentales, source de difficultés théoriques et expérimentales. Ces dernières mènent à l'existence de théories au-delà du Modèle Standard, dites de Nouvelle Physique. Ce rapport présente la recherche d'une nouvelle particule présente dans un grand nombre de théories au-delà du Modèle Standard : le boson W'. Cette année, le Grand Collisionneur de Hadrons (LHC) entame son run II, où l'on verra des collisions proton-proton à une énergie dans le centre de masse inédite de 13 TeV. Cette grande énergie nous apportera la perspective excitante de voir de la Nouvelle Physique. Les études menées durant ce stage ont été faites sur des simulations Monte Carlo d'évènements que l'on devrait voir au sein du détecteur Atlas au run II du LHC. Ces études sont groupées en deux grandes parties. La première partie consiste en des études au niveau partonique, où l'on voit l'impact d'aspects physiques tels que les fonctions de densité partonique et les émissions de gluons par les quarks sur la masse reconstruite du boson W'. On y voit aussi le potentiel accru de découverte de cette nouvelle particule en comparant des spectres de masse invariante ainsi que des sections efficaces aux énergies dans le centre de masse de 8 TeV et 13 TeV. La seconde partie décrit les étapes de la reconstruction du boson W' dans une simulation de détecteur. Les étapes présentant les plus grandes diffcultés sont mises en valeur, ainsi que quelques idées d'améliorations pour le run II. Les processus de bruit de fond et les critères de sélection utilisés pour les discriminer par rapport au signal sont introduits, et les optimisations de ces critères ainsi que les tests d'efficacité pour en trouver de nouveaux sont présentés. Cette recherche est la suite d'un grand nombre d'études faites durant le run I, elle cherchera à continuer d'améliorer la recherche de particules au-delà du Modèle Standard.

Published
2015

23. Ontogeny of reproductive abnormalities induced by deregulation of anti-müllerian hormone expression in transgenic mice

Author

Lionel Lyet, Nathalie Josso, Franck Louis, Maguelone G. Forest, Richard R. Behringer, and B. Vigier

Subjects
Anti-Mullerian Hormone, Male, medicine.medical_specialty, Freemartin, Mullerian Ducts, Ovary, Cell Count, Mice, Transgenic, Prophase, Mice, Aromatase, Ovarian Follicle, Internal medicine, Testis, medicine, Animals, Humans, RNA, Messenger, Promoter Regions, Genetic, Testosterone, Glycoproteins, biology, Leydig cell, Estradiol, Anti-Müllerian hormone, Cell Biology, General Medicine, Growth Inhibitors, Meiosis, Testicular Hormones, Seminiferous tubule, medicine.anatomical_structure, Endocrinology, Reproductive Medicine, Gene Expression Regulation, biology.protein, Oocytes, Female, Metallothionein, Germ cell
Abstract

Anti-mullerian hormone, normally responsible for the regression of mullerian ducts in male fetuses, induces stunting, germ cell loss, and seminiferous tubule formation in ovaries of bovine freemartin fetuses and of transgenic mice, which express the human anti mullerian hormone gene under the control of the metallothionein promoter. Because the latter have been studied only after birth, we undertook a detailed chronological study of their reproductive organs. Mullerian ducts of transgenic female fetuses regressed at the same time as those of normal or transgenic males. Maximal reduction of germ cell number occurred between 16 days postcoitus and birth, when most transgenic oocytes were still in the leptotene stage of the meiotic prophase, whereas normal oocytes had already reached the pachytene phase. Interference with progression of the meiotic prophase and germ cell loss in the fetal ovary are probably responsible for subsequent ovarian regression and retardation of follicle growth. Seminiferous tubule formation was not detectable prior to birth and occurred only rarely in postnatal ovaries. Aromatase activity of fetal transgenic ovaries was decreased, as well as serum concentration of testosterone in adult transgenic males, suggesting that high levels of anti-mullerian hormone may impair Leydig cell steroidogenesis.

Published
1995

35. Les paysans

Author

Reymont, Wladyrlaw, 1867-1925, Schoell, Franck Louis, 1889 - 1982, Payot (París), Imprimerie Crété, Reymont, Wladyrlaw, 1867-1925, Schoell, Franck Louis, 1889 - 1982, Payot (París), and Imprimerie Crété

Published
1925

36. Impressions d'Afrique

Author

Franck, Louis and Franck, Louis

Abstract

Conférence donnée dans la salle des fêtes du conservatoire de Liège, le mardi 22 février 1921, info:eu-repo/semantics/published

Published
1921

47. Digital rectilinear ultrasonic imaging system

Author

Franck Louis Lederman and Jerome Johnson Tiemann

Subjects
Transducer, Acoustics and Ultrasonics, Arts and Humanities (miscellaneous), Pulse (signal processing), Computer science, Acoustics, Line (geometry), Echo (computing), Ultrasonic sensor, Signal, Shift register, Ultrasonic imaging, Interpolation
Abstract

A B-scan ultrasonic imager produces a rectilinear image and has a linear transducer array with only one switch per element. Individual elements or overlapping transmit subarrays are selected sequentially to generate pulses of ultra-sound. Received echo signals are sequentially sent down a long shift register delay line, are tapped off at the pulse repetition rate, and delayed by different amounts in the several channels and summed to effect time delay focusing of the echoes. The video output signal is post-processed to improve the TV monitor picture; interpolated image lines are conveniently derived with this architecture.

Published
1979
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