The central melanocortin (MC) system mediates its effects on food intake via MC3 (MC3R) and MC4 receptors (MC4R). Although the role of MC4R in meal size determination, satiation, food preference, and motivation is well established, the involvement of MC3R in the modulation of food intake has been less explored. Here, we investigated the role of MC3R on the incentive motivation for food, which is a crucial component of feeding behavior. Dopaminergic neurons within the ventral tegmental area (VTA) have a crucial role in the motivation for food. We here report that MC3Rs are expressed on VTA dopaminergic neurons and that pro-opiomelanocortinergic (POMC) neurons in the arcuate nucleus of the hypothalamus (Arc) innervate these VTA dopaminergic neurons. Our findings show that intracerebroventricular or intra-VTA infusion of the selective MC3R agonist γMSH increases responding for sucrose under a progressive ratio schedule of reinforcement, but not free sucrose consumption in rats. Furthermore, ex vivo electrophysiological recordings show increased VTA dopaminergic neuronal activity upon γMSH application. Consistent with a dopamine-mediated effect of γMSH, the increased motivation for sucrose after intra-VTA infusion of γMSH was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. Taken together, we demonstrate an Arc POMC projection onto VTA dopaminergic neurons that modulates motivation for palatable food via activation of MC3R signaling.

Objective The lateral hypothalamus (LH) is known for its role in feeding, and it also regulates other aspects of energy homeostasis. How genetically defined LH neuronal subpopulations mediate LH effects on energy homeostasis remains poorly understood. The behavioral effects of chemogenetically activating LH gamma‐aminobutyric acid (GABA) and the more selective population of LH GABA neurons that coexpress the leptin receptor (LepR) were compared. Methods LepR‐cre and VGAT‐cre mice were injected with AAV5‐hSyn‐DIO‐hM3DGq‐mCherry in the LH. The behavioral effects of LH GABA or LH LepR neuronal activation on feeding, locomotion, thermogenesis, and body weight were assessed. Results The activation of LH GABA neurons increased body temperature (P ≤ 0.008) and decreased body weight (P ≤ 0.01) despite decreased locomotor activity (P = 0.03) and transiently increased chow intake (P ≤ 0.009). Also, similar to other studies, this study found that activation of LH GABA neurons induced gnawing on both food and nonfood (P = 0.001) items. Activation of LH LepR neurons decreased body weight (P ≤ 0.01) and chow intake when presented on the cage floor (P ≤ 0.04) but not when presented in the cage top and increased locomotor activity (P = 0.002) and body temperature (P = 0.03). Conclusions LH LepR neurons are a subset of LH GABA neurons, and LH LepR activation more specifically regulates energy homeostasis to promote a negative energy balance.

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Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.