Prefrontal cortex melanocortin 4 receptors (MC4R) mediate food intake behavior in male mice

•MC4R-expressing neurons in the infralimbic (IL) region of the mouse cortex (ILMC4R) are glutamatergic and project to multiple regions that coordinate the appetitive response to food stimuli.•ILMC4R are functionally responsive to melanocortinergic input.•ILMC4R are important to maintain body weight and food intake.•ILMC4R are relevant to food-seeking, but not general exploratory behavior, and may be involved in behavior inhibition. Melanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making. Using viral techniques in genetically modified male mice combined with molecular techniques, we identify and define the effects on feeding behavior of a novel population of MC4R expressing neurons in the infralimbic (IL) region of the cortex. Here, we describe a novel population of MC4R-expressing neurons in the IL of the mouse prefrontal cortex that are glutamatergic, receive input from melanocortinergic neurons, and project to multiple regions that coordinate appetitive responses to food-related stimuli. The neurons are stimulated by application of MC4R-specific peptidergic agonist, THIQ. Deletion of MC4R from the IL neurons causes increased food intake and body weight gain and impaired executive function in simple food-related behavior tasks. Together, these data suggest that MC4R neurons of the IL play a critical role in the regulation of food intake in male mice.