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Data-Driven Computational Modelling for Some of the Implications of Dopamine in the Brain : from Subcellular Signalling to Area Networks Alexandre Foncelle

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Data-Driven Computational Modelling for Some of the Implications of Dopamine in the Brain : from Subcellular Signalling to Area Networks Alexandre Foncelle Data-driven computational modelling for some of the implications of dopamine in the brain : From subcellular signalling to area networks Alexandre Foncelle To cite this version: Alexandre Foncelle. Data-driven computational modelling for some of the implications of dopamine in the brain : From subcellular signalling to area networks. Quantitative Methods [q-bio.QM]. Université de Lyon, 2018. English. NNT : 2018LYSEI028. tel-02090797 HAL Id: tel-02090797 https://tel.archives-ouvertes.fr/tel-02090797 Submitted on 5 Apr 2019 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 : /<6(, THESE de DOCTORAT DE L’UNIVERSITE DE LYON opérée au sein de (INSA LYON) Ecole Doctorale N° 512 Mathématiques et Informatique (InfoMaths) Discipline de doctorat : Informatique et applications Soutenue publiquement le , par : Alexandre Foncelle Data-driven computational modelling for some of the implications of dopamine in the brain: from subcellular signalling to area networks. Devant le jury composé de : Tsaneva-Atanasova, Krasimira Professor University of Exeter Rapporteure Faure, Philippe Directeur de recherche Université Pierre et Marie Curie Rapporteur Soula, Hédi Professeur Université Pierre et Marie Curie Examinateur Beslon, Guillaume Professeur INRIA Examinateur Berry, Hugues Directeur de recherche INRIA Directeur de thèse Cette thèse est accessible à l'adresse : http://theses.insa-lyon.fr/publication/2018LYSEI028/these.pdf © [A. Foncelle], [2018], INSA Lyon, tous droits réservés Département FEDORA – INSA Lyon - Ecoles Doctorales – Quinquennal 2016-2020 SIGLE ÉCOLE DOCTORALE NOM ET COORDONNEES DU RESPONSABLE CHIMIE CHIMIE DE LYON M. Stéphane DANIELE Institut de recherches sur la catalyse et l’environnement de Lyon http://www.edchimie-lyon.fr IRCELYON-UMR 5256 Sec. : Renée EL MELHEM Équipe CDFA Bât. Blaise PASCAL, 3e étage 2 Avenue Albert EINSTEIN [email protected] 69 626 Villeurbanne CEDEX INSA : R. GOURDON [email protected] !"!"#" ! ÉLECTRONIQUE, M. Gérard SCORLETTI ÉLECTROTECHNIQUE, École Centrale de Lyon AUTOMATIQUE 36 Avenue Guy DE COLLONGUE 69 134 Écully http://edeea.ec-lyon.fr Tél : 04.72.18.60.97 Fax 04.78.43.37.17 Sec. : M.C. HAVGOUDOUKIAN [email protected] [email protected] !$%$ ! ÉVOLUTION, ÉCOSYSTÈME, M. Fabrice CORDEY MICROBIOLOGIE, MODÉLISATION CNRS UMR 5276 Lab. de géologie de Lyon Université Claude Bernard Lyon 1 http://e2m2.universite-lyon.fr Bât. Géode Sec. : Sylvie ROBERJOT 2 Rue Raphaël DUBOIS Bât. Atrium, UCB Lyon 1 69 622 Villeurbanne CEDEX Tél : 04.72.44.83.62 Tél : 06.07.53.89.13 INSA : H. CHARLES [email protected] [email protected] !&'(( ! INTERDISCIPLINAIRE Mme Emmanuelle CANET-SOULAS SCIENCES-SANTÉ INSERM U1060, CarMeN lab, Univ. Lyon 1 Bâtiment IMBL http://www.ediss-lyon.fr 11 Avenue Jean CAPELLE INSA de Lyon Sec. : Sylvie ROBERJOT 69 621 Villeurbanne Bât. Atrium, UCB Lyon 1 Tél : 04.72.68.49.09 Fax : 04.72.68.49.16 Tél : 04.72.44.83.62 [email protected] INSA : M. LAGARDE [email protected] ')*+%#,-( !INFORMATIQUE ET M. Luca ZAMBONI MATHÉMATIQUES Bât. Braconnier 43 Boulevard du 11 novembre 1918 http://edinfomaths.universite-lyon.fr 69 622 Villeurbanne CEDEX Sec. : Renée EL MELHEM Tél : 04.26.23.45.52 Bât. Blaise PASCAL, 3e étage [email protected] Tél : 04.72.43.80.46 Fax : 04.72.43.16.87 [email protected] %./012.34 ! MATÉRIAUX DE LYON M. Jean-Yves BUFFIÈRE INSA de Lyon http://ed34.universite-lyon.fr MATEIS - Bât. Saint-Exupéry Sec. : Marion COMBE 7 Avenue Jean CAPELLE Tél : 04.72.43.71.70 Fax : 04.72.43.87.12 69 621 Villeurbanne CEDEX Bât. Direction Tél : 04.72.43.71.70 Fax : 04.72.43.85.28 [email protected] [email protected] %!5# ! MÉCANIQUE, ÉNERGÉTIQUE, M. Philippe BOISSE GÉNIE CIVIL, ACOUSTIQUE INSA de Lyon Laboratoire LAMCOS http://edmega.universite-lyon.fr Bâtiment Jacquard Sec. : Marion COMBE 25 bis Avenue Jean CAPELLE Tél : 04.72.43.71.70 Fax : 04.72.43.87.12 69 621 Villeurbanne CEDEX Bât. Direction Tél : 04.72.43.71.70 Fax : 04.72.43.72.37 [email protected] [email protected] (6(7 ! ScSo * M. Christian MONTES Université Lyon 2 http://ed483.univ-lyon2.fr 86 Rue Pasteur Sec. : Viviane POLSINELLI 69 365 Lyon CEDEX 07 Brigitte DUBOIS [email protected] INSA : J.Y. TOUSSAINT Tél : 04.78.69.72.76 [email protected] *ScSo : Histoire, Géographie, Aménagement, Urbanisme, Archéologie, Science politique, Sociologie, Anthropologie Cette thèse est accessible à l'adresse : http://theses.insa-lyon.fr/publication/2018LYSEI028/these.pdf © [A. Foncelle], [2018], INSA Lyon, tous droits réservés ii Cette thèse est accessible à l'adresse : http://theses.insa-lyon.fr/publication/2018LYSEI028/these.pdf © [A. Foncelle], [2018], INSA Lyon, tous droits réservés R´esum´e Au cours de l’histoire, le cerveau a ´et´e´etudi´esous di ff´erents aspects. Du 5`eme au 17`eme si`ecle, le cerveau fut compar´eaux mod`eles hydrauliques, o`ules liquides ´etaient consid´er´es comme le support des pens´ees. Puis, durant le 18`eme si`ecle, le cerveau fut associ´e aux mod`eles´electriques, on venait de d´ecouvrir la sensibilit´edes muscles et des nerfs aux d´echarges ´electriques (Mein, 1988). De nos jours, le fonctionnement du cerveau est com- par´eaux calculs en parall`ele, aux statistiques bay´esiennes et aux dynamiques de r´eseau de neurones. Ce tr`es bref historique montre que nos repr´esentations du cerveau d´ependent largement de ce qui peut ˆetre mesur´eet des similitudes que l’on peut trouver avec des concepts d´ej`a connus. Ces moyens de repr´esentation simplifient notre compr´ehension du cerveau, c’est un objet tr`escomplexe comme l’illustre la diversit´ede sa composition, par exemple, la multitude de mol´ecules, de cellules, de tissus et la vari´et´ede leurs interactions et leurs effets multi´echelle. Dans le cerveau, il est di fficile de mettre au point des exp´eriences avec un niveau de contrˆole appropri´e`acause du haut niveau de connectivit´e. Pour traiter ce probl`eme, les mod`eles math´ematiques sont utilis´espour repr´esenter le cerveau d’une fa¸con plus compr´ehensible. En e ffet, les mod`eles math´ematiques peuvent ˆetre plus pratiques que les exp´eriences pour tester des hypoth`eseset chercher `aextraire l’essence mˆeme du principe ´etudi´e,en le simplifiant. De plus, la mod´elisation computationnelle forme une branche sp´ecifique de la mod´elisation math´ematique, permettant de r´esoudre de gros cal- culs num´eriques. Dans cette th`ese, j’ai utilis´ela mod´elisation computationnelle `atravers di ff´erentes approches pour ´etudier certaines r´egions c´er´ebrales. Nous avons collabor´eavec des neu- robiologistes en appliquant nos mod`eles `ades donn´ees exp´erimentales pour contribuer `a mieux comprendre l’action de la dopamine, un neuromodulateur. J’ai ´etudi´ela diversit´e de l’action de la dopamine `atrois ´echelles: la r´egion c´er´ebrale, le niveau cellulaire et le niveau mol´eculaire. La dopamine a un gros impact sur le cerveau et elle est princi- palement connue pour son implication dans le syst`eme de r´ecompense. En e ffet, c’est une mol´ecule associ´ee`ala pr´ediction de r´ecompense et de punition. Peu de r´egions produisent de la dopamine et ces r´egions sont alt´er´eespar la maladie de Parkinson ou perturb´eespar la d´epression. Pour la maladie de Parkinson, j’ai con¸cu un mod`ele de type taux de d´echarge pour reproduire l’activit´eneuronale des ganglions de la base. Ce mod`ele montre des r´eponses neuronales significativement di ff´erentes, entre la condition t´emoin et la condition parkinsonienne. Par ailleurs, avec un mod`ele de type Hodgin-Huxley prenant en compte la dynamique de l’ion potassium, j’ai pu appuyer l’hypoth`ese que la r´egion c´er´ebrale appel´ee l’habenula, lorsqu’elle est hyperactive, induirait la d´epression. Cette d´epression serait due `aun d´es´equilibre de la concentration en potassium `acause d’une dysfonction de l’astrocyte (surexpression des canaux Kir4.1). Enfin, la dopamine est aussi impliqu´eedans la plasticit´esynaptique, un ph´enom`ene `ala base de la m´emoire. Je l’ai ´etudi´eavec un troisi`eme mod`ele, prenant en compte plusieurs r´esultats exp´erimentaux relatifs `ala plasticit´een fonction du timing des potentiels d’action et de sa modulation. iii Cette thèse est accessible à l'adresse : http://theses.insa-lyon.fr/publication/2018LYSEI028/these.pdf © [A. Foncelle], [2018], INSA Lyon, tous droits réservés iv La maladie de Parkinson Dans le contexte de la maladie de Parkinson, nous avons collabor´eavec des exp´erimentateurs (l’´equipe de Laurent Venance au Coll`ege de France, Paris) pour ´etudier les ganglions de la base, une r´egion du cerveau connue pour ˆetre alt´er´ee chez les malades parkinsoniens. La maladie de Parkinson est caract´eris´ee, aux premiers stades, par des symptˆomes moteurs, comme des tremblements et une rigidit´edes muscles, puis des di fficult´es`aun plus haut niveau cognitif, comme la planification ou la r´esolution de probl`emes, enfin, si elle n’est pas trait´ee,de l’apathie et de l’anxi´et´e.C’est une maladie neurod´eg´en´erative, ce qui signifie que des neurones sp´ecifiques deviennent dysfonctionnels, en particulier les neurones des ganglions de la base, la r´egion c´er´ebrale impliqu´ee dans le contrˆole de la motricit´eet les fonctions ex´ecutives.
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