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Insulin modulates emotional behavior through a serotonin-dependent mechanism

Abstract

Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D 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. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.

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Fig. 1: Insulin increases DR 5-HT neurons firing frequency by direct activation of insulin receptor expressed onto that neuronal population.
Fig. 2: Insulin decreases DR 5-HT neurons in vivo through a 5-HT1A receptor-dependent mechanism.
Fig. 3: The anxiolytic like effect of intranasal insulin delivery relies on the central serotonergic system.
Fig. 4: HFD feeding impairs the insulin response of the 5-HT system.
Fig. 5: Schematic representation of the putative action of insulin onto DR 5-HT neurons and related control of emotional behaviors.

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Acknowledgements

XF and HM thank Région Nouvelle-Aquitaine and INRAE for their support. XF has been supported by the Société Française du Diabète and the Fondation Université de Bordeaux. Authors are thankful to the Fondation pour la Recerche Médicale (FRM, SL) and for the RRI Food4BrainHealth (HM, SL, XF). We thank INSERM (SJ, DC), ANR-17-CE14–0007 BABrain (to DC), and ANR-18-CE14-0029 MitObesity (to DC) for their support. AK has been supported by the Deutsche Forschungsgemeinschaft grant project and by grants from the German Ministry of Education and Research (BMBF grant 031B0569) and the State of Brandenburg (DZD grant 82DZD00302). Authors are grateful to Pr. Vanessa H. Routh (Rutgers University, NJ, USA) and Pr. Thierry Alquier (University of Montreal, Canada) for their insightful comments on the manuscript.

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HM, and SB designed and performed experiments. MM, MC, MDM, VS, SJ, JB, MS, and SC performed experiments. FC, AK, DC, PDD, LP, and SL edited the manuscript. BG and XF designed the project and wrote the manuscript.

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Correspondence to Xavier Fioramonti.

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Martin, H., Bullich, S., Martinat, M. et al. Insulin modulates emotional behavior through a serotonin-dependent mechanism. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01812-3

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