Insulin modulates emotional behavior through a serotonin-dependent mechanism

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 s...

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Published in:Molecular psychiatry Vol. 29; no. 6; pp. 1610 - 1619
Main Authors: Martin, Hugo, Bullich, Sébastien, Martinat, Maud, Chataigner, Mathilde, Di Miceli, Mathieu, Simon, Vincent, Clark, Samantha, Butler, Jasmine, Schell, Mareike, Chopra, Simran, Chaouloff, Francis, Kleinridders, Andre, Cota, Daniela, De Deurwaerdere, Philippe, Pénicaud, Luc, Layé, Sophie, Guiard, Bruno P., Fioramonti, Xavier
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.06.2024
Nature Publishing Group
Subjects:
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Administration, Intranasal
Animals
Anxiety
Anxiolytics
Behavioral Sciences
Biological Psychology
Comorbidity
Depressive Disorder, Major
Diabetes mellitus
Diabetes Mellitus, Type 2
Diet, High-Fat
Dorsal Raphe Nucleus
Emotional behavior
Emotional disorders
Emotions
High fat diet
Insulin
Insulin Resistance
Life Sciences
Male
Medicine
Medicine & Public Health
Mental disorders
Mice
Mice, Inbred C57BL
Mood
Mood disorders
Neuromodulation
Neurons
Neurons and Cognition
Neurosciences
Neurotransmission
Pharmacotherapy
Psychiatry
Receptor, Serotonin, 5-HT1A
Serotonergic Neurons
Serotonin
Serotonin S1 receptors
Synaptic Transmission
ISSN:1359-4184, 1476-5578, 1476-5578
Online Access:Get full text
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Summary: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-HT 1A 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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ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/s41380-022-01812-3