MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression

This is the authors' abstract. We don't add key points for this paper.

Major depressive disorder is associated with weight loss and decreased appetite; however, the signaling that connects these conditions is unclear. Here, we show that MC 4 R signaling in the dorsal raphe nucleus (DRN) affects feeding, anxiety, and depression. DRN infusion of α-MSH decreases DRN neuronal activation and feeding. DRN MC 4 R is expressed in GABAergic PRCP-producing neurons. DRN selective knockdown of PRCP ( Prcp DRNKD ), an enzyme inactivating α-MSH, decreases feeding and DRN neuronal activation. Interestingly, Prcp DRNKD mice present lower DRN serotonin levels and depressive-like behavior. Similarly, PRCP-ablated MC 4 R mice ( Prcp MC4RKO ) show metabolic and behavioral phenotypes comparable to those of Prcp DRNKD mice. Selective PRCP re-expression in DRN MC 4 R neurons of Prcp MC4RKO mice partially reverses feeding, while fully restoring mood behaviors. Chemogenetic inhibition of DRN MC 4 R neurons induces anxiety, depression, and reduced feeding, whereas chemogenetic activation reverses these effects. Our results indicate that MC 4 R signaling in DRN plays a role in feeding, anxiety, and depression.