Hugo Martin PhD

Abstract

Type-2 Diabetes (T2D) is mainly characterized by insulin-resistance and accompanied by comorbidities such as Major Depressive Disorder (MDD). Indeed, patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance was positively correlated with the severity of depressive symptoms. As the serotoninergic (5-HT) system in the brain is one of the major neurotransmission involved in the pathophysiology of depression, we hypothesized that insulin resistance at the level of 5-HT neurons participates in the development of mood disorders during T2D. Supporting this hypothesis, we first show that mice fed a high fat diet (HFD) for 16 weeks display both hallmarks of T2D (including insulin resistance) and anxio/depressive-like behavior that is associated with decreased serotonin levels and alterations of Dorsal Raphe nucleus (DR) 5-HT neurons. Another point of the project aimed at studying brain insulin’s action onto the 5-HT system and emotional behavior. Using patch-clamp electrophysiology, we show that insulin increases firing activity of DR 5-HT neurons. Our results also show that intranasal insulin administration elicits anxiolytic-like effect associated with decreased 5-HT levels in areas related to anxiety processing. Finally, using an original transgenic mouse model, we show that the selective ablation of the IR in 5-HT neurons decreases the activity of DR 5-HT neurons and leads to diminished innate anxiety-like behavior. Altogether, this study suggests that insulin modulates emotional behavior in acting onto the 5-HT system. Such findings would help improving treatment for T2D patients suffering from comorbid mood disorders.

Jury

Pr. Pascal FOSSAT, Professeur, CNRS, Université de Bordeaux Président 

Dr. Nasser HADDJERI, Directeur de recherche, INSERM, Université de Lyon Rapporteur 

Dr. Amandine GAUTIER-STEIN, Chargé de recherche, INRAE, Université de Lyon Rapporteur 

Pr. Christophe MAGNAN, Professeur, CNRS, Université Paris-Diderot Examinateur 

Pr. Catherine BELZUNG, Professeure, INSERM, Université de Tours Examinateur 

Pr. Bruno GUIARD, Professeur, CNRS, Université Toulouse III- Paul Sabatier Invité