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Imaging of Camp/PKA Dynamics Induced by Catecholamines in the Neocortical Network Shinobu Nomura

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Imaging of Camp/PKA Dynamics Induced by Catecholamines in the Neocortical Network Shinobu Nomura Imaging of cAMP/PKA dynamics induced by catecholamines in the neocortical network Shinobu Nomura To cite this version: Shinobu Nomura. Imaging of cAMP/PKA dynamics induced by catecholamines in the neocortical network. Neurons and Cognition [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2014. English. NNT : 2014PA066440. tel-01374733 HAL Id: tel-01374733 https://tel.archives-ouvertes.fr/tel-01374733 Submitted on 1 Oct 2016 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. Thèse de doctorat de l’Université Pierre et Marie Curie, Paris 6 Spécialité : Neurosciences Ecole doctorale Cerveau-Cognition-Comportement (ED3C) Présentée par NOMURA Shinobu Pour obtenir le grade de Docteur de l’Université Paris 6 Sujet de la thèse : Imaging of cAMP/PKA dynamics induced by catecholamines in the neocortical network Soutenue le 26 septembre 2014 Devant le jury composé de : Dr Denis Hervé, Président Dr Emmanuel Valjent, Rapporteur Pr Philippe De Deurwaerdère, Rapporteur Dr Régine Hepp, Directeur de thèse Invités exceptionnels Dr Nicolas Gervasi Dr Thierry Gallopin Dr. Bertrand Lambolez 1 Remerciements Je voudrais tout d'abord remercier mon directeur de thèse, Bertrand Lambolez, pour m’avoira ccueilli pour mon stage de M2 puis de m’avoir proposé ce projet sur la transmission catécholaminergique pour poursuivre une thèse à l’UPMC. Je le remercie pour son encadrement et pour ses conseils avisés mais également pour ses encouragements. Grâce à Bertrand, j’ai eu la chance de suivre une formation de qualité et de profiter pleinement de la vie parisienne. Cette expérience a été déterminante pour mon avenir professionnel qui se poursuivra désormais à Okinawa. Je souhaite également remercier ma co-directrice de thèse Régine Hepp, pour avoir accepté de co-diriger ce travail, ainsi que pour ses remarques et son implication dans la rédaction de ce manuscrit. Je lui suis reconnaissante pour sa patience et sa générosité dans le travail qui ontpermis de surmonter les difficultés entre autres d’ordre linguistique. Merci à Bruno Cauli pour son aide, ses conseils, son très grand humour et surtout son filtre infra rouge ! Je remercie pour leur accueil dans leur unités respectives Danièle Tritsch et Jean Mariani, directeurs de l’unité UMR7102-NPA et Hervé Chneiweiss, directeur de l’UMR 8246-NPS. Je tiens à exprimer ma vive reconnaissance aux membres du jury Denis Hervé, Philippe De Deurwaerdère et Emmanuel Valjent qui ont accepté de juger mon travail et de faire ledéplacement pour la soutenance. Je remercie également Thierry Gallopin et Nicolas Gervasi pour leur présence à ma soutenance. Je voudrais remercier The Nakajima Foundation, pour son soutien financier pendant quatre ans. Cette aide m’a permis d’entreprendre mes études de manière sereine. J’adresse mes remerciements les plus sincères à Elvire Guiot et Ludovic Tricoire pour leur investissement à me former à la microscopie biphotonique et à l’optogénétique. Leur aide a été cruciale notamment quand cela ne fonctionnait pas. Merci à Ivan Cohen pour nous avoir aidé à donner une seconde vie à la photostimulation Merci à tous les autres membres de l’équipe pour leur gentillesse, pour m’avoir appris les gros mots en français et de m’avoir fait des blagues que je ne comprends toujours pas. Merci à Agnès, Audrey, Juliette Lim-Anna, Najate, Maud, Alexandre, Antoine, Matthieu, Xavier, Annastasios, Fabrice et puis ceux que j’oublie mais ce n’est pas exprès. Je remercie tous les membres des équipes du 5ème étage et du 6ème, pour le prêt de matériel, pour leur aide et leurs conseils mais surtout pour les moments de convivialité partagés au sein du laboratoire. Je voudrais aussi remercier tous les personnels des services généraux du laboratoire et le personnel de l’animalerie pour leur implication dans la vie quotidienne du laboratoire et le bien être des animaux. Le travail n’en a été que plus agréable. 2 Un grand merci au personnel de la plateforme d’imagerie pour leur disponibilité et leur gentillesse. Merci à tous les membres de NPA/NPS qui m’ont aidé de près ou de loin dans mon travail, en particulier Odile Poirel, Frank Louis et Salah El Mestikawi pour leur aide et leur collaboration. Merci à ma famille et mes proches au Japon pour leur soutien sans faille. Ils ont toujours encouragé mes grandes aventures à l’étranger. Merci également à mes amis en France pour leurs encouragements constants et pour tous ces bons moments passés ensemble. Un grand merci à tous, vous qui avez rendu mon séjour à Paris mémorable. 中島国際交流財団の皆様には四年という長期間に渡るご支援をいただき、ここに 博士学位論文としてまとめることが出来たことを心から感謝いたします。財団の 方々・審査員の先生方からは経済的支援のみならず、沢山の応援をいただきました。 重ねて御礼申し上げます。 最後に、私の選択を暖かく見守ってくれる家族へ。おかげさまで無事にフランス 研究留学を終えることができました。本当にどうもありがとう。 3 Abstract Neurotransmission mediated by the catecholamines dopamine (DA) and noradrenaline (NA) is critically involved in multiple brain functions and pathologies. NA and DA modulate neuronal excitability and synaptic transmission via Gs and Gi- coupled receptors and cAMP/PKA signaling. NA is released in the entire neocortex by axons of locus coeruleus (LC) neurons. In contrast, DA projections to the neocortex, which originate in the ventral tegmental area (VTA), are present in all layers of restricted medial and lateral areas but only in deep layers of other areas. According to binding assay and immunohistochemistry, dopamine receptors are nonetheless expressed in the entire cortex. The aim of this project is to characterize NA and DA effect using two-photon imaging of a PKA biosensor expressed in pyramidal neurons of cortical slice. We also aim to characterize cAMP/PKA signals elicited by the release of endogenous catecholamines in the neocortex. I have examined the cortical distribution of NA/DA-induced PKA signals in rat brain slices using bath application of NA (10μM), the β-adrenoceptor agonist Isoproterenol (1μM), DA (10μM) and the D1/D5 receptor agonist SKF 38393(1 μM). Responses to these drugs were observed in layers 2/3 and 5 pyramidal neurons throughout the entire rostro-caudal axis (i.e. in frontal, parietal and occipital cortices) of regions with scarce VTA fibers. Responses to these agonists were inhibited by their respective antagonists (β-adrenoceptor antagonist propranolol, 50μM; D1/D5 antagonist SCH 23390, 1 μM). The negative contribution of D2- like or α-adrenoceptor to responses elicited by DA or NA was also assessed using specific antagonists. The results show a widespread distribution of both NA and DA receptors in the neocortex that extends far beyond the territory of VTA fiber innervation. In order to investigate the PKA signals induced by the release of endogenous catecholamines, we combined optogenetics and 2-photon PKA imaging. Channelrhodopsin2 was expressed in LC neurons using conditional viral transfer in DBH Cre mice. The PKA sensor was also expressed by viral transfer in the cortex of the same mice. PKA activity in pyramidal cells was reversibly increased by photostimulation (470nm, 5ms pulse, 10Hz, for 5 seconds) and reproducible responses were obtained upon repetitive stimulation. Responses to photostimulation were inhibited by β-adrenoceptor antagonists. The NA transporter inhibitor Riboxetine (100 nM) increased responses to photostimulation. These results demonstrate that endogenous NA released from LC fibers by optogenetic stimulation activates the cAMP/PKA pathway in cortical slices, providing a means to characterize catecholaminergic transmission events. 4 Résumé La neurotransmission portée par les catécholamines dopamine (DA) et noradrénaline (NA) joue un rôle primordial dans de nombreuses fonctions cérébrales et est altérée dans de multiples pathologies. La NA et la DA modulent l’excitabilité neuronale et la transmission synaptique par l’intermédiaire de récepteurs couplés aux protéines Gs et Gi qui régulent la voie de signalisation cAMP/PKA. La NA est libérée dans l’ensemble du cortex cérébral par les axones issus des neurones du locus coeruleus (LC). Les projections DA sont originaires des neurones de l’aire tegmentale ventrale (VTA). Elles sont présentes dans toutes les couches de régions restreintes du cortex frontal, médian et latéral, mais uniquement dans les couches profondes des autres régions corticales. Pourtant, des expériences de liaison et d’immunohistochimie ont démontré la présence des récepteurs DA dans tout le cortex. Le but de ce projet de thèse est de caractériser les effets de l’application de NA et de DA exogènes, mais aussi de la libération de catécholamines endogènes sur la voie AMPc/PKA. J’ai réalisé ce travail en combinant l’utilisation de la channelrhodopsine, un canal ionique photosensible, à l’imagerie biphotonique de biosenseurs fluorescents de l’activité PKA exprimés dans les neurones pyramidaux du cortex. J’ai examiné les signaux PKA induits par l’application de la NA (10 μM), l’isoprotérénol (agoniste β-adrénergique, 1μM), la DA (10 μM) et le SKF 38393 (agoniste des récepteurs D1/D5 dopaminergiques, 1 μM) en tranches de cortex de rat. Toutes ces drogues ont stimulé l’activité PKA dans les cellules pyramidales des couches II/III et V du cortex, notamment dans les régions frontales, pariétales et occipitales peu innervées par les fibres DA. J’ai observé que les réponses NA et isoprotérénol sont inhibées par les antagonistes β - adrénergiques (propranolol, 50μM, CGP 20712 100 nM) et les réponses DA par un antagoniste des récepteurs D1/D5 (SCH 23390, 1 μM). La contribution inhibitrice des récepteurs de type D2 dopaminergiques et des récepteurs α2-adrénergiques a été également mise en évidence par des antagonistes spécifiques. Les résultats montrent que les récepteurs NA et DA sont fonctionnellement exprimés dans de vastes régions du cortex, bien au delà du territoire innervé par les fibres DA issue de la VTA.
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