Alpha‐melanocyte stimulating hormone increases the activity of melanocortin‐3 receptor‐expressing neurons in the ventral tegmental area

Abstract

Key points Alpha‐melanocyte stimulating hormone (α‐MSH) is an anorexigenic peptide. Injection of the α‐MSH analog MTII into the ventral tegmental area (VTA) decreases food and sucrose intake and food reward. Melanocortin‐3 receptors (MC3R) are highly expressed in the VTA, suggesting that the effects of intra‐VTA α‐MSH may be mediated by α‐MSH changing the activity of MC3R‐expressing VTA neurons. α‐MSH increased the firing rate of MC3R VTA neurons in acute brain slices from mice, although it did not affect the firing rate of non‐MC3R VTA neurons. The α‐MSH induced increase in MC3R neuron firing rate is probably activity‐dependent, and was independent of fast synaptic transmission and intracellular Ca2+ levels. These results help us to better understand how α‐MSH acts in the VTA to affect feeding and other dopamine‐dependent behaviours. Abstract The mesocorticolimbic dopamine system, the brain's reward system, regulates multiple behaviours, including food intake and food reward. There is substantial evidence that the melanocortin system of the hypothalamus, an important neural circuit controlling feeding and body weight, interacts with the mesocorticolimbic dopamine system to affect feeding, food reward and body weight. For example, melanocortin‐3 receptors (MC3Rs) are expressed in the ventral tegmental area (VTA) and our laboratory previously showed that intra‐VTA injection of the MC3R agonist, MTII, decreases home‐cage food intake and operant responding for sucrose pellets. However, the cellular mechanisms underlying the effects of intra‐VTA alpha‐melanocyte stimulating hormone (α‐MSH) on feeding and food reward are unknown. To determine how α‐MSH acts in the VTA to affect feeding, we performed electrophysiological recordings in acute brain slices from mice expressing enhanced yellow fluorescent protein in MC3R neurons to test how α‐MSH affects the activity of VTA MC3R neurons. α‐MSH significantly increased the firing rate of VTA MC3R neurons without altering the activity of non‐MC3R expressing VTA neurons. In addition, the α‐MSH‐induced increase in MC3R neuron activity was independent of fast synaptic transmission and intracellular Ca2+ levels. Finally, we show that the effect of α‐MSH on MC3R neuron firing rate is probably activity‐dependent. Overall, these studies provide an important advancement in the understanding of how α‐MSH acts in the VTA to affect feeding and food reward.

Whole‐brain efferent and afferent connectivity of mouse ventral tegmental area melanocortin‐3 receptor neurons

“…Every 5th section was then analyzed for the presence of eYFP+ axons using standard epifluorescence microscopy. In all mice, eYFP+ cells bodies were largely restricted to the VTA and were present in all VTA subnuclei, similar to the previously reported distribution of VTA MC3R neurons (Lippert et al, 2014; West et al, 2019). YFP+ axons were observed in efferent target regions between +1.78 and −6.24 mm relative to bregma, with no labeling identified in brain regions rostral or caudal to these regions (see examples of labeling in sagittal sections in Figure 1).…”

“…VTA MC3R axons and retrogradely labeled neurons were concentrated in the medial aspects of the ventromedial striatum (Figure 3d) consistent with the ventromedial position of VTA MC3R neurons (Lippert et al, 2014; West et al, 2019) and the previously characterized mediolateral topographic organization of VTA neuron projections and inputs (Ikemoto, 2007; Yang et al, 2018). Overall, the brain regions providing input to VTA MC3R neurons were more widely distributed across the brain than the efferent projections of these cells, and some areas showed reciprocal connections, whereas other areas only received projections or provided input (Figure 11).…”

“…Although VTA MC3R neurons are present in all subnuclei of the VTA, they are highly concentrated in the ventromedial region including PN, IF, RLi, and CLi (Figures 3a–c and 6b; Lippert et al, 2014). Both the ventromedial location of the VTA MC3R neurons and their electrophysiological properties (West et al, 2019) are consistent with a unique population of medial neurons identified by Lammel et al (2008) which project to the mPFC, NAcc medial shell and core, and basolateral amygdala. VTA MC3R neurons differed from the population identified by Lammel et al (2008), however, in that their cortical projections were very sparse.…”

“…Male and female transgenic mice expressing Cre recombinase in MC3R neurons (MC3R‐Cre mice) on a mixed C57/129 background were used for tracing VTA MC3R neuron projections and inputs, and for the synaptophysin‐based synaptic connectivity confirmation. MC3R‐Cre mice were generously provided by David Olson (University of Michigan, Ann Arbor), and have been previously characterized and validated (Pei et al, 2019; West, Lu, Olson, & Roseberry, 2019). C57/129 mice (stock no.…”

The Melanocortin System behind the Dysfunctional Eating Behaviors

“…The melanocortin system interacts with several nuclei of the brain and neural circuits, among which, one of the most relevant in the control of food intake and body weight is the mesocorticolimbic dopamine system [ 93 ], connecting the VTA with the Nac, amygdala and PFC, regions particularly involved in reward, motivational processes and food consumption [ 94 , 95 , 96 ]. Dopamine has an essential role in food intake and reward, and thus, it is supposed that the melanocortin system can also influence feeding by modulating dopamine transmission in areas that are implicated in eating behaviors, satiety perception and reward processes.…”