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Insulin modulates emotional behavior through a serotonin-dependent mechanism

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Martin, H., Bullich, S., Martinat, M., Chataigner, M., Di Miceli, Mathieu ORCID: https://orcid.org/0000-0003-3713-0370, Simon, V., Clark, S., Butler, J., Schell, M., Chopra, S., Chaouloff, F., Kleinridders, A., Cota, D., De Deurwaerdere, P., Pénicaud, L., Layé, S., Guiard, B. and Fioramonti, X. (2022) Insulin modulates emotional behavior through a serotonin-dependent mechanism. Molecular Psychiatry. ISSN Print: 1359-4184 Online: 1476-5578

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Official URL: https://doi.org/10.1038/s41380-022-01812-3

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.

Item Type:	Article
Additional Information:	This version of the article has been accepted for publication, after peer review (when applicable) but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41380-022-01812-3. Use of this Accepted Version is subject to the publisher’s Accepted Manuscript terms of use https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
Subjects:	Q Science > QH Natural history > QH301 Biology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry R Medicine > RM Therapeutics. Pharmacology
Divisions:	College of Health, Life and Environmental Sciences > School of Science and the Environment
Copyright Info:	© The Author(s), under exclusive licence to Springer Nature Limited 2022
Depositing User:	Mathieu Di Miceli
Date Deposited:	27 Sep 2022 12:34
Last Modified:	02 Jun 2023 14:18
URI:	https://eprints.worc.ac.uk/id/eprint/12492

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