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Neural Mechanisms of Oxytocin and Serotonin Interaction in Non-Human Primates and Patients with Autism Arthur Lefevre

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Neural Mechanisms of Oxytocin and Serotonin Interaction in Non-Human Primates and Patients with Autism Arthur Lefevre Neural mechanisms of oxytocin and serotonin interaction in non-human primates and patients with autism Arthur Lefevre To cite this version: Arthur Lefevre. Neural mechanisms of oxytocin and serotonin interaction in non-human primates and patients with autism. Neuroscience. Université de Lyon, 2016. English. NNT : 2016LYSE1323. tel-01508642 HAL Id: tel-01508642 https://tel.archives-ouvertes.fr/tel-01508642 Submitted on 14 Apr 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N°d’ordre NNT : xxx THESE de DOCTORAT DE L’UNIVERSITE DE LYON opérée au sein de l’Université Claude Bernard Lyon 1 Ecole Doctorale 476 (Neuroscience et Cognition) Spécialité de doctorat : Discipline : Neurosciences Soutenue publiquement le 13 Décembre 2016, par : Arthur LEFEVRE __________________________________________ Neural mechanisms of oxytocin and serotonin interaction in non- human primates and patients with autism __________________________________________ Thèse dirigée par Angela Sirigu (DRCE, CNRS) Devant le jury composé de : GERVAIS Rémi, Président, (Professeur à l’Université Lyon 1 Claude Bernard) CHINI BICE, Rapporteur, (Senior researcher at the Institute of Neuroscience, Milan) CHAKRABARTI Bhismadev, Rapporteur, (Associate Professor at university of Reading and Senior researcher at Cambridge university) KRAUS Christoph, Examinateur, (Senior researcher at the Medical university of Vienna) SIRIGU Angela, Directrice de thèse, (DRCE, Université de Lyon, CNRS) 1 UNIVERSITE CLAUDE BERNARD - LYON 1 Président de l’Université M. le Professeur Frédéric FLEURY Président du Conseil Académique M. le Professeur Hamda BEN HADID M. le Professeur Didier REVEL Vice-président du Conseil d’Administration M. le Professeur Philippe Vice-président du Conseil Formation et Vie Universitaire CHEVALIER Vice-président de la Commission Recherche M. Fabrice VALLÉE Directeur Général des Services M. Alain HELLEU COMPOSANTES SANTE Faculté de Médecine Lyon Est – Claude Bernard Directeur : M. le Professeur J. ETIENNE Directeur : Mme la Professeure C. Faculté de Médecine et de Maïeutique Lyon Sud – BURILLON Charles Mérieux Faculté d’Odontologie Directeur : M. le Professeur D. BOURGEOIS Directeur : Mme la Professeure C. Institut des Sciences Pharmaceutiques et Biologiques VINCIGUERRA Institut des Sciences et Techniques de la Réadaptation Directeur : M. X. PERROT Département de formation et Centre de Recherche en Directeur : Mme la Professeure A- Biologie Humaine M. SCHOTT 2 COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE Faculté des Sciences et Technologies Directeur : M. F. DE MARCHI Département Biologie Directeur : M. le Professeur F. THEVENARD Département Chimie Biochimie Directeur : Mme C. FELIX Département GEP Directeur : M. Hassan HAMMOURI Département Informatique Directeur : M. le Professeur S. AKKOUCHE Département Mathématiques Directeur : M. le Professeur G. TOMANOV Département Mécanique Directeur : M. le Professeur H. BEN HADID Département Physique Directeur : M. le Professeur J-C PLENET UFR Sciences et Techniques des Activités Physiques et Directeur : M. Y.VANPOULLE Sportives Directeur : M. B. GUIDERDONI Observatoire des Sciences de l’Univers de Lyon Directeur : M. le Professeur Polytech Lyon E.PERRIN Ecole Supérieure de Chimie Physique Electronique Directeur : M. G. PIGNAULT Institut Universitaire de Technologie de Lyon 1 Directeur : M. le Professeur C. VITON Ecole Supérieure du Professorat et de l’Education Directeur : M. le Professeur A. MOUGNIOTTE Institut de Science Financière et d'Assurances Directeur : M. N. LEBOISNE 3 Remerciements Je tiens en premier lieu à remercier Vendetta, Patch et Jimmy Jazz, les trois macaques ayant participé aux expériences de cette thèse. Evidemment, je suis très reconnaissant à Angela Sirigu de m’avoir offert l’opportunité de faire ce travail. A son contact, j’ai beaucoup appris sur le monde académique et le fonctionnement de la recherche. Je souhaite également remercier les personnes sans qui je n’aurais pu réaliser ce travail : Jean-René Duhamel et Manon Dirheimer pour m’avoir appris à manipuler et expérimenter sur des singes ; Nathalie Richard, Jérôme Redouté et Nicolas Costes pour leur aide précieuse dans l’analyse des données TEP. Beaucoup de collègues ont aussi ma gratitude pour le travail en collaboration que nous avons pu faire, Luc Zimmer et Sylvain Fieux pour l’autoradiographie, Miguel Pedroza pour la SPE, Raphaëlle Mottolese pour l’acquisition des TEP chez l’homme, Pierre-Aurélien Beuriat et Mina Jazayeri pour les TEP chez le singe, Sandra Duperrier pour l’histologie, Jean Luc Charieau et Fidji Francioly pour l’animalerie, Carmine Mottolese et le service de neurochirurgie pour les prélèvements de LCR, Véronique Berthier et le personnel du CERMEP pour leur flexibilité, Jennifer Beneyton pour son efficacité. De nombreuses personnes m’ont épaulé de manière diverses, merci à Didier Le Bars, Aicha Midouni, May Cha Li, les divers stagiaires de l’équipe, Laurence Chardon, Johan Pacquit et Sylvain Maurin. J’ai également une pensée pour les patients et leurs familles, qui nous permettent d’avancer, ainsi que l’ensemble des sujets ayant participé aux expériences. J’ai passé d’excellents moments à l’ISC grâce à la bonne ambiance qui règne entre étudiants, présents ou passés : Martina, Manuela, Song, Laure, Seongmin, David, Rémi, Mathilde, Romain, Sébastien, Augustin, Gustavo et tous les autres. Pour finir, merci à ma famille, qui m’a toujours soutenu ; à Emma, qui a partagé les hauts et les bas avec moi. 4 Résumé La neurohormone ocytocine (OT) est de plus en plus étudiée pour son potentiel thérapeutique dans les troubles du comportement social, comme l’autisme, qui sont associés à une dérégulation de plusieurs systèmes de neurotransmission, notamment l’OT et la sérotonine (5-HT). Dans ce cadre, une étape importante afin de développer des médicaments basés sur des mécanismes biologiques est de caractériser les interactions entre l’OT et les autres neurotransmetteurs. La littérature sur les rongeurs montre que la relation entre OT et 5-HT est fortement impliquée dans plusieurs aspects du comportement social. Par ailleurs, nous avons récemment montré chez le sujet sain que le fonctionnement du récepteur 5-HT 1A (5-HT1AR) est modifié suite à l’administration d’OT.neuro J’ai donc réalisé une première expérience chez des patients autistes en utilisant le scanner TEP avec le radiotraceur [18F]MPPF (spécifique du 5-HT1AR). Aucune différence n’est apparue, à l’état basal, entre 18 patients autistes et 24 sujets contrôles. Par ailleurs, l’OT n’a pas modifié le système 5-HT1AR. Enfin, alors qu’une corrélation entre la densité de 5- HT1AR et le volume de matière grise du striatum a été observé dans le groupe contrôle, cette relation était absente dans le groupe de patients. Ces résultats suggèrent une altération subtile du 5-HT1AR, ne pouvant être détectée qu’au niveau fonctionnel. Parce que le scanner TEP ne permet pas de dire si les changements observés sont dus à une libération de sérotonine ou à une modification directe du récepteur, j’ai réalisé une deuxième expérience chez 3 macaques rhésus, avec le [18F]MPPF et le [11C]DASB (marquant le transporteur de la 5-HT). Par rapport au placebo, l’OT injectée dans le ventricule latéral a significativement augmenté la liaison du [18F]MPPF dans l’amygdale et l’insula tandis que la liaison du [11C]DASB diminuait dans ces mêmes régions. Ainsi, nous pouvons dire que l’OT a provoqué la libération de 5-HT ainsi qu’une modification du 5-HT1AR dans ces régions importantes pour les comportements socio-émotionnels. Une étude par autoradiographie a confirmé cette interprétation. Ces expériences montrent qu’il existe une action régulatrice de l’OT sur la 5-HT chez le primate, mais que ce mécanisme est dérégulé chez les patients avec autisme. Cela ouvre donc la voie à l’investigation de traitements combinés exerçant un effet sur ces deux neurotransmetteurs. Mots clés : Ocytocine, sérotonine, Troubles du Spectre Autistique, Primate non- humain, scanner TEP 5 Abstract The neurohormone oxytocin (OT) is increasingly studied for its therapeutic potential in social disorders, like autism, which are associated with the deregulation of several neurotransmission systems, including OT and serotonin (5-HT). Hence investigating OT’s interactions with other neurotransmitters is a relevant step towards mechanism-based treatments. Studies in rodents demonstrated that the interaction between OT and 5-HT, is critical for several aspects of social behaviour. Moreover, using PET-scan in humans we have recently found that 5-HT 1A receptor (5-HT1AR) function is modified after intra-nasal oxytocin intake. Thus I performed a first experiment in which intra-nasal OT was administered to 18 patients with autism undergoing a [ F]MPPF (a 5-HT1AR radiotracer) PET scanner, in order to study their basal serotonergic system and to look if the oxytocin modulates the 5-HT1AR system. I found no differences of baseline 5-HT1AR concentration between 18 autistic subjects and 24 controls. Critically, in patients, OT did not induce changes on the
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