Venue: Centre Broca
Defense in french
Pauline Couty
Team: FoodCircus (Ferreira / Trifilieff)
NutriNeuro
Thesis supervisor: Katia Touyarot
Title
Vulnérabilité anatomofonctionnelle de la transmission dopaminergique à des manipulations du statut en vitamine A.
Abstract
Vitamin A deficiency during the perinatal period, caused by a vitamin A-deficient diet, remains a major public health issue, especially in developing countries. Retinoic acid (RA), the active metabolite of vitamin A, is essential for the brain development of the fetus and newborn, and plays a very important role in brain function in adulthood. By binding to its nuclear receptors, which act as transcription factors, RA regulates the expression of numerous genes, notably those involved in dopaminergic transmission within the striatum. On the other hand, reduced maternal vitamin A status during gestation or genetic polymorphisms in the retinoid signaling pathway have been associated with certain neurodevelopmental psychiatric diseases, such as schizophrenia, although the underlying mechanisms remain to be established.
This is the background to this thesis, with the aim of studying the consequences of vitamin A deficiency initiated during gestation in mice on the modulation of vitamin A metabolism and its impact on the functionality of dopaminergic transmission in adult offspring. We hypothesize that hypoactivity of retinoid signaling could lead to dysfunction of dopaminergic transmission in the striatum, characteristic of certain neurodevelopmental pathologies.
In this study, we show that perinatal vitamin A deficiency in mice induces hypoactivity of retinoid signaling associated with alterations in dopaminergic transmission in adult offspring, which are more pronounced in the nucleus accumbens (NAc) than in the dorsal striatum. More specifically, decreased expression of dopamine transporter (DAT) and dopamine receptor 3 (D3R) mRNA is observed in vitamin A-deficient offspring in the ventral tegmental area (VTA) and NAc, respectively. These neurobiological alterations in the mesolimbic dopaminergic transmission pathway are accompanied in deficient male offspring by an increase in motivational processes and impulsivity assessed in operant conditioning tasks, in contrast to deficient female offspring who appear to be protected. To further investigate mesolimbic transmission, we studied mesolimbic dopaminergic activity in vivo in our model, combining the dLight dopaminergic biosensor with fiber photometry. We have shown that perinatal vitamin A deficiency alters dopaminergic dynamics in vivo, leading to an increase in phasic dopamine release in the NAc during operant conditioning tasks. Finally, the causal link between alterations in mesolimbic dopaminergic transmission and the behavioral changes observed in vitamin A-deficient offspring was investigated using viral approaches (DREADDs) to manipulate the activity of dopaminergic neurons.
In conclusion, this thesis demonstrates the importance of retinoid signaling, during and after the perinatal period, in maintaining the integrity of mesolimbic dopaminergic transmission. This study suggests that reduced vitamin A status in several neurodevelopmental psychiatric disorders may play a role in certains aspects of the symptomatology of these pathologies, such as motivational or impulsive disorders. Thus, nutritional supplementation with vitamin A could be envisaged as a nutritional strategy to prevent cognitive processes altered by vitamin A deficiency, in the context of these pathologies, and enable normal brain development in children.
Keywords : Vitamin A, retinoic acid, nucleus accumbens, striatum, dopamine, mesolimbic, motivation.
Publication
Couty, I. Dulapt, L. Berger, A. Santoro, K. Lard, S. Alfos, J.C. Helbling, M.F. Angelo, C. Halimi, P. Borel, C. Bosch-Bouju, P. Trifilieff, K. Touyarot. Vitamin A deficiency started during gestation impaired reward processing by affecting the integrity of mesolimbic transmission. En préparation pour soumission.
Jury
Dr. Francis CHAOULOFF, Directeur de recherche, Université de Bordeaux, Président
Dr. Corinne BEURRIER, Chargé de recherche, Aix-Marseille Université, Rapportrice
Dr. Wojciech KREZEL, Directeur de recherche, Université de Strasbourg, Rapporteur
Dr. Élodie FINO, Chargé de recherche, Aix-Marseille Université, Examinatrice
Dr. Patrick BOREL, Directeur de recherche, Aix-Marseille Université, Examinateur
Dr. Katia TOUYAROT, Maître de conférences, Bordeaux INP, Directrice de thèse
Dr. Pierre TRIFILIEFF, Directeur de recherche, Université de Bordeaux, Invité