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Dissecting Reward and Aversion in Addiction

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Dissecting Reward and Aversion in Addiction UNIVERSITÉ DE STRASBOURG and MCGILL UNIVERSITY École Doctorale des Sciences de la Vie et de la Santé Faculty of Medicine IGBMC, CNRS UMR 7104 Integrated Program in Neuroscience Joint PhD Degree to be defended by Laura-Joy BOULOS on the 19th of December, 2017 Mu opioid receptors in the habenula: Dissecting reward and aversion in addiction Supervisor: Dr. Brigitte KIEFFER (McGill) Co-Supervisor: Dr. Claire GAVÉRIAUX-RUFF (University of Strasbourg) Members of the Jury: Dr. Jean-Christophe CASSEL (University of Strasbourg) Dr. Catherine LE MOINE (University of Bordeaux) Dr. Marco LEYTON (McGill) Remerciements Je remercie d’abord la Pr. Brigitte Kieffer qui m’a accueillie dans son équipe à Strasbourg puis à Montréal. Merci de m’avoir montré ce qu’est la recherche et de m’avoir donné des conseils pour avancer dans le monde des neurosciences. Merci aussi de m’avoir fait confiance souvent. J’espère que nos projets et intérêts convergeront dans le futur. Je remercie aussi la Pr. Claire Gavériaux-Ruff. Merci Claire pour vos petites et vos grandes attentions. Pour votre présence malgré la distance, pour vos conseils scientifiques ou non tout au long de mon parcours d’étudiante et pour la soirée que vous avez organisée la veille de mon départ pour le Canada, je n’oublierai jamais. Je tiens enfin à remercier les professeurs/docteurs Jean-Christope Cassel, Catherine Le Moine et Marco Leyton qui ont accepté d’évaluer mon travail à Strasbourg, ainsi que les professeurs/docteurs Gabriella Gobbi, Alain Gratton et Marco Leyton qui ont évalué mon travail à McGill. Sami, ça va être difficile parce que la liste est longue et que tu n’aimes pas quand je te remercie. Merci de m’avoir encadrée, littéralement, aux deux moments les plus cruciaux de mon doctorat : le début et la fin. Merci de m’avoir appris à « maniper » et d’avoir pris l’initiative de m’aider quand tu as senti que j’en avais besoin. Merci aussi d’avoir écouté et accepté mon rythme pendant la rédaction. Merci surtout d’être quelqu’un avec qui je peux parler à la fois de « acquisition and maintenance of stimulus-reward association » ﻣﺎ ﻓﻲ ﻣﻧك .et de Haifa Wehbé Merci aux postdocs Manu en premier of course, Aliza (I was happy to share a room with you at #sfnsandiego2017), Taufiq (petit génie - ) et (postdoc by location) Jai! La student room, avec ses mouvements, son désordre, ses anciennes (Pauline, Gulebru), ses nouveaux (Lola, Dylan, Nathalie, Wei Ya, Amina, Ellie) et tous ceux qui l’ont traversée, de loin (Hélène, Sébastien, Michael, Stéphane) ou de très, très près (Léonie). Julie je ne sais pas où te ranger, écrire ton nom me fait penser à la belle époque où on était seules et organisées *sobs* et où nos inquiétudes se résumaient à trouver une cachette à notre stash de single malt *sobs again*. Good times. A special thanks to VECTOR for adding some manly testosterone to the mixture (we know you’re a softie deep down, a softie in leather boots). Mes réguliers du midi –avec qui on a bien plus souvent refait le monde que parlé Shampoing. Greg je ne vais pas te remercier, je t’en veux de m’avoir abandonnée avec les autres (merci d’avoir été une de mes plus belles rencontres à Montréal). Victor non plus, point de merci aux déserteurs (même si ces quelques paragraphes sont fortement inspirés des tiens et que moi aussi j’aimerais remercier Dostoïevski). Julie, petit chat ! Merci d’avoir débarqué juste quand il le fallait, avec ton humour, tes listes énoncées à voix haute, ton bon gout en whisky et en robes chères et, accessoirement, ta présence quand les choses ne vont pas très bien: merci merciii avec tout plein de i, pour mériter la danse. Chloé you little calisson you ! Tu es une personne merveilleuse et inspirante dans ta façon de de t’engager dans ce qui t’intéresse sans vouloir ressembler aux autres, avec un mélange d’angoisse et de légèreté. Lola, j’aurais aimé que nos chemins se croisent plus longuement ; mais j’aime aussi comme on a profité d’une anecdote hasardeuse pour se rapprocher et comme on a volé des bouts d’espace dans le temps pour construire notre amitié, entre nos longues discussions autour d’un verre oklm dans le parc et (je ne sais pas comment décrire les soirées de fête de manière politiquement correcte). Clément, merci essentiellement pour tes marinières qui te donnent un air de petit prince, ou de Tazio dans Mort à Venise de Visconti. Mais merci aussi pour nos beaux échanges dans tous les contextes, amicaux, professionnels and eveything in between ; j’espère habiter dans presque-ta-ville rien que pour pouvoir te demander des adresses et avoir une excuse de partager avec toi de nouveaux moments. Sébastien, merci pour ta douceur et nos belles conversations tard le soir en quittant le labo. Léonie je t’ai mis en dernier, près de Mathieu. Merci d’avoir amené un bout de Camille avec toi, merci pour tes belles réceptions, pour toutes nos sessions à la gym (hmmm) et, of course, merci de rendre Mathieu heureux. Et Mathieu : merci pour tout. Un petit chef que j’aime que j’aime : « Si le monde est à moi, le monde est à nous ». Alexa (la seule vraie petite chose), tu seras la transition de mes remerciements. Merci de rentrer dans pratiquement toutes les catégories (collègue, amie, « executive ») et merci de me donner envie de pousser plus loin les projets qu’on entreprend ensemble. Let’s go les filles… on lâche pas… Qui va me préparer un kit pour la soutenance ?? / J’ai franchement de la chance de t’avoir rencontrée. PS : j’en profite aussi pour remercier à travers toi ma famille Villeneuve d’adoption, qui me renie mais que j’aime ainsi que toutes mes sœurs. Les membres fondateurs du NeuroSymposium (Alexa, Robin, Elsa, Philippe-Antoine), vous êtes aussi magnifiques que notre projet et la perspective d’une suite me réjouit. Les membres de GSAN, avec un merci tout particulier au comité 2015-16 que j’ai présidé ainsi qu’aux présidents des comités avant (Rochelle) et après (Robin). Le soutien pour la co-tutelle : Joséphine Nalbantoglu, Joe Rochford, Serge Potier, Alex DeGuise, Katherine Vanka, Mélanie Muser, Géraldine Schverer, Myriam Rebetez. Le soutien à l’animalerie : Eve-Marie (t’es ben fine !), Geneviève, Eve, Gilles et Djémo Merci à mes NEURdz Marie-Julie pour tous nos délires, nos confidences, le magnifique dessin que tu m’as fait, les chaussures que tu acceptes de me voir porter, tu es juste géniale. Kim, the softest of us all. Thank you for being the perfect balance of “I accept and like you for who you are” “but this is how you could change”. Thank you for pushing me and empowering me. Thank you for all the snacks, in my pockets or at my doorstep. <3 Noor, with your pink hair, pink eye and necklace of Palestine that made me fall for you right away. Thank you for letting me be a step parent to old little something. I squish you strongly still, probably pour toujours. Merci à tous mes amis Yann Karl, merci d’être devenu la plus belle des constantes dans ma vie. Thank you Rochelle, strong as a pillar soft as a pillow (hihi), for showing me what love is. Merci mad’am (Mélissa) que j’ai hâte de pouvoir appeler comme ça à nouveau. Céline (depuis ton accueil avec bouteille de bulles et adaptateurs aux prises américaines jusqu’à chaque instant avec toi dans n’importe quelle ville du monde), thank you for making me happy in this city. Kess ekhta comme je t’aime !! Marwan, Mira, Bleu, Amandine, Zeina –b7ebbik-, Nael, Kelly, Jana, Farin, Carole, Robin. Merci à mes amants, mes amantes Merci Strasbourg qui m’a appris à vivre seule, comme une grande (et merci à Ramen qui s’est occupé de moi quand je redevenais petite). Merci Montréal, qui m’a radicalisée doucement (ce qui convient très bien aux limites de mon intellectualisme modéré et de mes goûts pour le luxe, l’esthétique et la volupté). Sans doute la ville la plus agréable du monde. Merci New York, pour la petite parenthèse grandiose, le regain de motivation, et un grand merci à Rita, qui se dessine une place dans ma vie. Merci Beyrouth, où je veux construire de belles choses, au bord de ta mer, pendant que le reste de la planète essaye de te privatiser ou de te détruire. En revanche, je ne remercie pas les petites gens, les bêtes et méchants (le pire mélange du monde) qui dirait-on ne sont là que pour vous mettre des bâtons dans les roues. Je leur souhaite de ne pas aller très loin et de faire le moins de mal possible autour d’eux. Plus que jamais et plus que tout, merci à mes 4 a, un à un et tous ensemble. “No matter how thoroughly you understood the physics of feathers, you wouldn’t have been able to predict a murmuration of starlings without first seeing it happen. So it is with the brain: you have to study the behavior first.” John Krakauer rephrasing David Marr Content General introduction I- The opioid system………………………………………………….…………….11 1. Overview 2. Anatomical distribution II- The mu opioid receptor………………………………………………………….12 1. Pharmacology 2. Cellular mechanisms 3. Anatomical distribution 4. Physiological functions III- Reward and aversion in addiction………………………………………………15 1. Reward and positive reinforcement 2. Aversion and negative reinforcement 3. Reward and aversion in addiction 4. Circuitry of addiction 5. The link with cognition and self-control disorders IV- The habenula…………………………………………………………………..…19 1.
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