Role of feeding-related peptides on brain reward pathways

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Feeding is a motivated survival behavior, and like other motivated behaviors (e.g., procreation and drug taking) is heavily regulated by dopamine neurotransmission. Motivation to eat is conditional and is regulated by allostatic processes that are driven by metabolic requirements. Receptors for several peptides that regulate food intake, ghrelin, orexin, insulin and leptin are abundantly expressed in the dopamine-containing cells in the ventral tegmental area (VTA) that project to forebrain targets involved in motivation, such as the nucleus accumbens, prefrontal cortex and dorsal striatum. The experiments outlined in this proposal aim to investigate the role of orexigenic (orexin, ghrelin) and satiety (insulin, leptin) peptides on dopamine neurons of the mesolimbic reward pathway. Dopamine neurons can encode the salience of rewards in relation to de novo presented rewards or to reward predicting cues. Consistent with this, dopamine neurons alter their synaptic efficacy in correlation with the experience-dependent learning of cues that predict rewards. Our overall hypothesis is that peptides that signal hunger or satiety can alter the synaptic efficacy of dopamine neurons and resultant dopamine release. We predict that this enhanced dopamine neuronal signaling underlies a heightened salience to the environmental cues that predict reward. In the current proposal, we will measure the effects of orexigenic peptides, orexin and ghrelin, and anorexigenic peptides, insulin and leptin, on excitatory synaptic transmission of VTA dopamine neurons. We will then compare the effects of orexin, ghrelin and insulin on somatodendritic and terminal dopamine release. Finally, we will determine how endogenous activation of orexin neurons (via photostimulation) alters DA neuronal activity and the effects of ghrelin or insulin signaling in the VTA.