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

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.Key pointsAlpha‐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.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149572/1/tjp13547.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149572/2/tjp13547_am.pd

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

The mesolimbic dopamine (DA) system is involved in the regulation of multiple behaviors, including feeding, and evidence demonstrates that the melanocortin system can act on the mesolimbic DA system to control feeding and other behaviors. The melanocortin‐3 receptor (MC3R) is an important component of the melanocortin system, but its overall role is poorly understood. Because MC3Rs are highly expressed in the ventral tegmental area (VTA) and are likely to be the key interaction point between the melanocortin and mesolimbic DA systems, we set out to identify both the efferent projection patterns of VTA MC3R neurons and the location of the neurons providing afferent input to them. VTA MC3R neurons were broadly connected to neurons across the brain but were strongly connected to a discrete set of brain regions involved in the regulation of feeding, reward, and aversion. Surprisingly, experiments using monosynaptic rabies virus showed that proopiomelanocortin (POMC) and agouti‐related protein (AgRP) neurons in the arcuate nucleus made few direct synapses onto VTA MC3R neurons or any of the other major neuronal subtypes in the VTA, despite being extensively labeled by general retrograde tracers injected into the VTA. These results greatly contribute to our understanding of the anatomical interactions between the melanocortin and mesolimbic systems and provide a foundation for future studies of VTA MC3R neurons and the circuits containing them in the control of feeding and other behaviors.VTA MC3R neurons are a likely site of interaction between homeostatic and hedonic feeding circuits.VTA MC3R neurons send efferent projections to, and receive afferent input from, multiple brain regions involved in feeding, reward, and aversion.Very few POMC and AgRP neurons were labeled by monosynaptic rabies from multiple VTA neuron subtypes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166395/1/cne25013.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166395/2/cne25013_am.pd

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

The mesolimbic dopamine (DA) system is involved in the regulation of multiple behaviors, including feeding, and evidence demonstrates that the melanocortin system can act on the mesolimbic DA system to control feeding and other behaviors. The melanocortin‐3 receptor (MC3R) is an important component of the melanocortin system, but its overall role is poorly understood. Because MC3Rs are highly expressed in the ventral tegmental area (VTA) and are likely to be the key interaction point between the melanocortin and mesolimbic DA systems, we set out to identify both the efferent projection patterns of VTA MC3R neurons and the location of the neurons providing afferent input to them. VTA MC3R neurons were broadly connected to neurons across the brain but were strongly connected to a discrete set of brain regions involved in the regulation of feeding, reward, and aversion. Surprisingly, experiments using monosynaptic rabies virus showed that proopiomelanocortin (POMC) and agouti‐related protein (AgRP) neurons in the arcuate nucleus made few direct synapses onto VTA MC3R neurons or any of the other major neuronal subtypes in the VTA, despite being extensively labeled by general retrograde tracers injected into the VTA. These results greatly contribute to our understanding of the anatomical interactions between the melanocortin and mesolimbic systems and provide a foundation for future studies of VTA MC3R neurons and the circuits containing them in the control of feeding and other behaviors.VTA MC3R neurons are a likely site of interaction between homeostatic and hedonic feeding circuits.VTA MC3R neurons send efferent projections to, and receive afferent input from, multiple brain regions involved in feeding, reward, and aversion.Very few POMC and AgRP neurons were labeled by monosynaptic rabies from multiple VTA neuron subtypes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166395/1/cne25013.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166395/2/cne25013_am.pd