Defense in french
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Supervisor : Bruno GUIARD
Committee members :
- Pr. Céline CRUCIANI-GUGLIELMACCI – Reviewer – Université de Paris – CNRS UMR 8251Unité BFA – Equipe REGLYS “Régulation de la glycémie par le système nerveux central”
- Dr. Sebastian FERNANDEZ – Reviewer – Université Côte D’Azur – Institut de Pharmacologie Moléculaire et Cellulaire – CNRS UMR7275
- Dr. Guillaume FERREIRA – Reviewer – Université de Bordeaux – Laboratoire Nutrition et de Neurobiologie intégrée
- Pr. Isabelle CASTAN-LAURELL, Examinator – Université de Toulouse III – UMR 1301 INSERM – 5070 CNRS – RESTORE/Metabolink
- Dr. Amandine GAUTIER-STEIN, Examinator – Université Lyon 1 – U1213 Nutrition
- Pr. Bruno GUIARD (**), Thesis Supervisor – Université Toulouse III – UMR5169 – Centre de Recherches sur la Cognition Animale
Epidemiological studies estimate a higher risk of developing major depression (MD) among diabetic patients compared to the general population. More specifically, human studies highlighted correlations between impairments of metabolic parameters and depressive symptoms. Peripheral insulin resistance could be determinant in this relationship since defect in insulin signaling positively correlates with the severity of MD. However, brain insulin resistance consequences on depressive disorders in humans and pre-clinical models are yet to be deeply investigated. Because the brain is endowed with a high density of insulin receptor, it has been proposed that insulin could directly (or indirectly) modulates monoaminergic systems and more particularly serotonergic (5-HT) neuronal activity in the dorsal raphe nucleus (DRN). In agreement with the latter hypothesis, previous findings indicate that insulin influences the dopaminergic system and related feeding behaviors but only few studies have focused on the impact of this hormone on the 5-HT system yet indisputably involved in MD.
During this thesis, we were able to show that insulin receptor is expressed in DRN 5-HT neurons. Interestingly, although in-vitro patch-clamp experiments emphasize a direct excitatory effect of insulin on DRN 5-HT neuronal activity, in vivo electrophysiological and neurochemical data are consistent with a net inhibitory effect on this system leading to a decreased 5-HT tone in the hippocampus. These results led us to test whether insulin modulates neurobehaviors. Doing so, we demonstrated that acute intra-DRN or intra-nasal insulin injection produces anxiolytic-like effects in healthy mice. In a second part, we studied the activity of the 5-HT system and anxio-depressive-like behaviors in mouse models of type 1 or type 2 diabetes (T1D/T2D) thereby providing insight into the relationship between insulin signaling impairment and emotionality. In a context of insulinopenia (T1D) or insulin resistance (T2D), mice displayed apparent anxious behaviors accompanied by a significant reduction of 5-HT firing rate. Then, we tried to identify the implication of apelin, an adipokine known for its insulin-sensitizing properties, in T2D-induced behavioral anomalies. Our results showed that Apelin knock-out mice are more prone to develop insulin resistance in response to a diabetogenic diet but also marked behavioral disturbances reminiscent of anxiety. Interestingly, although chronic metformin treatment, an oral antidiabetic drug, did not improve peripheral metabolic parameters, it exerted anxiolytic-like effects in these mutant mice.
Thus far, this work highlights the existence of anatomic and functional interactions between insulinergic and serotonergic systems and their importance in anxiety, a psychiatric disorder often predictive of depressive episodes. Furthermore, we identified apelin as a potential actor implicated in the comorbidity between diabetes and depression anticipating putative pharmacological strategies targeting this adipokine. Indeed, this work strengthens the hypothesis in which insulin-sensitizers could alleviate anxio-depressive symptoms in patients displaying (or not) metabolic syndrome. It also paves the way for the development of potentiation strategies based on the use of insulin or antidiabetic treatments to reinforce antidepressant efficacy. However, the mechanisms underpinning such effects warrant further investigations for future studies.