Major Depressive Disorder (MDD) and Type-2 Diabetes (T2D) are diseases of major health concern. Recent epidemiological studies indicate that MDD is a comorbidity of T2D with serious detrimental health outcomes. Despite this, the mechanisms linking these two pathologies remain largely unknown. As the brain's serotoninergic (5-HT) system is involved in the pathophysiology of depression, we hypothesized that T2D can affect this network. Thus, we aimed to determine whether emotional behavior, serotoninergic neurotransmission and electric properties of 5-HT neurons are altered in a nutritional model of T2D-associated mood disorders, and if the insulin-sensitizing agent metformin can rescue these alterations. We assessed depressive-like and anxiety-like behavior in mice fed a high fat diet (HFD) for 16 weeks and treated for 4 weeks with metformin (300mg/kg; p.o) or vehicle control. The electrical activity of Dorsal Raphe Nucleus 5-HT neurons was assessed by patch clamp electrophysiology on brain slices from Pet1-cre-mcherry mice to specifically visualize 5-HT neurons. We observed depressive-like and anxiety-like behaviors in HFD-fed mice. Moreover, we observed that intrinsic properties of 5-HT neurons were altered by HFD feeding. In both cases, electrophysiological and behavioral alterations were reversed in part by the metformin treatment. In conclusion, these results show that HFD-induced mood disorders are associated with impaired 5-HT neuronal excitability. Interestingly, improving metabolic outcomes with the insulin-sensitizing agent metformin is sufficient to reduce emotional disorders and rescue 5-HT neuronal excitability, supporting the hypothesis that impairment in 5-HT neuronal activity in response to HFD-induced T2D is underlying associated mood disorders.< Réduire