Type 2 DiabetesAssociated Mood Disorders: Role of Insulin Resistance in Serotonergic Neurons

Type-2 Diabetes mellitus (T2DM) is mainly characterized by insulin-resistance and often accompanied by comorbidities such as major depressive disorders (MDD). Indeed, patients with T2DM are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. In preclinical studies, we and others showed that mice fed a High Fat Diet (HFD) for 16 weeks display both hallmarks of T2DM including increased basal blood glucose level and impaired glucose tolerance and anxio-depressive-like behaviors. We also showed that the insulin-sensitizing agent metformin reverses HFD-induced impaired glucose homeostasis and emotional alterations. As the serotonergic (5-HT) system in the brain is one of the major neuronal networks involved in the pathophysiology of MDD, we hypothesized that insulin resistance at the level of 5-HT neurons contributes to the development of mood disorders in a context of T2DM. Using patch-clamp electrophysiology, we show that HFD feeding impairs the excitability of dorsal Raphe 5-HT neurons while this effect is reversed by metformin treatment. Our data also show that local application of insulin increases firing rate of 5-HT neurons in chow fed animals and this is consistent with our histochemical observations indicating that the dorsal Raphe is endowed with a high density of insulin positive cells. Additionally, preliminary data suggest that intranasal or intra-Raphe insulin injection decreases anxiety in the elevated plus maze test. Our current work aims at evaluating the intranasal and intra-Raphe insulin injection in mice lacking the insulin receptor specifically in 5-HT neurons on emotional behaviors. Altogether, this study suggests that insulin action onto dorsal Raphe 5-HT neurons is important to control emotional behaviors and that insulin-resistance in these neurons is critical in the development of T2DM-associated mood disorders. Disclosure H. Martin: None. S. Bullich: None. F. Ducrocq: None. M. Graland: None. C. Olivry: None. S. Laye: None. B. Guiard: None. X. Fioramonti: None. Funding Societe Francophone du Diabete; INRAE-Region Nouvelle Aquitaine