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SUMMARY:Thesis defense - Léa Tochon
DESCRIPTION: Venue: Amphi E – ENSEIRB-MATMECA\, Talence (Bâtiment Bordeaux INP\, Avenue des Facultés\, 33400 Talence; arrêt du tram B “Arts & Métiers”). \nDefense in french \n\n\nLéa Tochon \nINCIA \nThesis supervisor :\nVincent David \n\nTitle\nMechanisms of vulnerability to alcohol use disorders induced by a single nucleotide polymorphism of the gene encoding the alpha5 nicotinic acetylcholine receptor subunit \nAbstract\nHuman genetic studies have implicated gene variants in the CHRNΑ5 gene\, encoding for the α5 nicotinic acetylcholine receptor subunit (α5-nAChR)\, as high risk factors for developing alcohol use disorders (AUDs). The single nucleotidic polymorphism (SNP) D398N is highly represented in Western population (in ~35% of individuals). Yet\, mechanisms through which they may influence this risk remain unknown. In this context\, the aim of my PhD was to understand how the α5-SNP modify behavioral processes and neural circuits involved in the vulnerability to AUDs. To this aim\, I used male and female transgenic mice expressing either the human α5-SNP (α5KI mice)\, or a deletion of the CHRNA5 gene (α5KO mice)\, and organized my research work around the three following questions: \n(1) How are these α5 subunit mutations modifying alcohol-drinking behaviour? \n(2) What is the neural substrate of these modifications? Focusing on regions carrying the highest density of α5-nAChR in the brain: the ventral tegmental area (VTA)\, a key component of the reward system and the interpeduncular nucleus (IPN)\, which may mediate a regulation/aversion signal. \n(3) Do α5-subunit mutations modify the preconsummatory traits related to alcohol abuse? Which unfortunately are still poorly assessed in preclinical addiction studies. \nBy combining models of alcohol self-administration and in-vitro electrophysiological recordings of the VTA dopaminergic and the IPN GABAergic neurons\, we found that the lack of α5 subunit results in a functional imbalance in the VTA-IPN circuit\, shifting the alcohol consumption toward high doses in both males and females\, with nevertheless some sex-dependent effects. Using viral neurospecific reexpression\, we obtained further evidence that α5-expressing IPN GABAergic neurons play a critical role in the control of alcohol intake. \nBy testing the α5KI mice\, we found that\, as for the α5 subunit deletion\, the α5-SNP deregulates alcohol consumption: both α5KI and α5KO mice drink larger amount of alcohol at high doses. However\, prior any alcohol exposition\, these two mutant strains display opposite socio-emotional phenotypes. Strickingly\, these are highly consistent with two human alcoholic profiles established by Cloninger and colleagues\, with: the Type I = female\, risk and novelty ‘avoidant’ displaying high anxiety; versus the Type II = male\, ‘sensation seeker’. These data suggest that preclinical models expressing human genetic variants can help to identify different motivations to consume and thus different AUDs subtypes while exploring their neurobiological basis. These could represent a major step toward the development of personalized and thus more effective treatments. \nKeywords: α5 nicotinic acetylcholine receptor subunit; ventral tegmental area; interpeduncular nucleus; transgenic mice; alcohol use disorders; preconsummatory traits. \nPublications\nPublished:\n \nHusson M\, Harrington L\, TOCHON L\, Cho Y\, Ibañez-Tallon I\, Maskos U\, David V (2020).\nβ4-nicotinic receptors are critically involved in reward-related behaviors and self-regulation of nicotine reinforcement. J. Neurosci. 40 (12): 0356.\nhttps://doi.org/10.1523/JNEUROSCI.0356-19.2020\nArticle of exceptional importance (F1000 recommendation): https://facultyopinions.com/prime/737584784 \nSubmitted: \nTOCHON L\, Vouimba RM\, Corio M\, Béracochéa D\, Guillou JL\, David V (2021).\nChronic alcohol consumption and withdrawal shift learning and synaptic plasticity from hippocampus- to striatum-dependant pathways. eLife. \nLakosa A\, Rahimian A\, Tomasi F\, Tahraoui S\, Marti F\, David V\, Canonne C\, Danckaert A\, TOCHON L\, De Chaumont F\, Forget B\, Maskos U\, Besson M (2021).\nThe gut microbiome influences nicotine rewarding properties and glial cells in the ventral tegmental area. Microbiome. \nIn preparation: \nTOCHON L\, Allain AE\, Caillé-Garnier S\, Bertrand S\, David V.\nLack of α5*nAChRs increases ethanol self-administration and reverses ethanol induced neuronal activity in VTA and IPN. In preparation for Molecular Psychiatry. \nTOCHON L\, Henkous N\, Besson M\, Dominique N\, Maskos U\, David V.\nMice expressing allelic variant or deletion of CHRNA5 show increased alcohol consumption but opposite motivational profiles : preclinical support for Cloninger’s alcoholism typology. In preparation for Biological Psychiatry.  \nTOCHON L\, Pageze C\, Guillou JLG\, David V.\nAlcohol-prone α5-nicotinic receptor mutant mice display sex-dependent opposite social-emotional profiles in emotion recognition and pro-social tasks. In preparation for Genes\, Brain and Behavior. \nJury\nMr François Georges (DR\, CNRS UMR 5293\, Univ. de Bordeaux). Président du jury\nMr Mickaël Naassila (PR\, Inserm UMRS 1247\, Univ. d’Amiens). Rapporteur\nMme Sylvie Granon (PR\, CNRS UMR 9197\, Univ. Paris-Saclay). Rapporteur\nMme Mélina FATSEAS (PU-PH\, CNRS UMR 5287\, Univ. de Bordeaux). Membre invité\nMr Vincent DAVID (CR\, CNRS UMR 5287\, Univ. de Bordeaux). Directeur de thèse\n
URL:https://www.bordeaux-neurocampus.fr/en/event/soutenance-de-these-lea-tochon/
CATEGORIES:Thesis
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