Major depressive disorder is associated with weight loss and decreased appetite; however, the signaling that connects these conditions is unclear. Here, we show that MC4R signaling in the dorsal raphe nucleus (DRN) affects feeding, anxiety, and depression. DRN infusion of a-MSH decreases DRN neuronal activation and feeding. DRN MC4R is expressed in GABAergic PRCP-producing neurons. DRN selective knockdown of PRCP (PrcpDRNKD), an enzyme inactivating a-MSH, decreases feeding and DRN neuronal activation. Interestingly, PrcpDRNKD mice present lower DRN serotonin levels and depressive-like behavior. Similarly, PRCP-ablated MC4R mice (PrcpMC4RKO) show metabolic and behavioral phenotypes comparable to those of PrcpDRNKD mice. Selective PRCP re-expression in DRN MC4R neurons of PrcpMC4RKO mice partially reverses feeding, while fully restoring mood behaviors. Chemogenetic inhibition of DRN MC4R neurons induces anxiety, depression, and reduced feeding, whereas chemogenetic activation reverses these effects. Our results indicate that MC4R signaling in DRN plays a role in feeding, anxiety, and depression.

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