Insulin modulates emotional behavior through a serotonin-dependent mechanism

Hugo Martin, Sébastien Bullich, Maud Martinat, Mathilde Chataigner, Mathieu Di Miceli, Vincent Simon, Samantha Clark, Jasmine Butler, Mareike Schell, Simran Chopra, Francis Chaouloff, Andre Kleinridders, Daniela Cota, Philippe De Deurwaerdere, Luc Pénicaud, Sophie Layé, Bruno P. Guiard, Xavier Fioramonti
Mol Psychiatry. 2022-10-07; :
DOI: 10.1038/S41380-022-01812-3

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Martin H(#)(1), Bullich S(#)(2), Martinat M(1), Chataigner M(1), Di Miceli M(1)(3), Simon V(4), Clark S(4), Butler J(5), Schell M(6), Chopra S(6), Chaouloff F(4), Kleinridders A(6), Cota D(4), De Deurwaerdere P(5), Pénicaud L(7), Layé S(1), Guiard BP(#)(2), Fioramonti X(#)(8).

Author information:
(1)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France.
(2)Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Toulouse, France.
(3)Worcester Biomedical Research Group, University of Worcester, WR2 6AJ, Worcester, UK.
(4)University of Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France.
(5)INCIA, UMR CNRS, Bordeaux University, Neurocampus, Bordeaux, France.
(6)University of Potsdam, Institute of Nutritional Science, Molecular and Experimental Nutritional Medicine, Nuthetal, Germany.
(7)RESTORE, UMR INSERM 1301/CNRS 5070/Université Paul Sabatier/EFS/ENVT, Toulouse, France.
(8)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France. .
(#)Contributed equally

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 -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.

© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

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