Role of feeding-related peptides on brain reward pathways

进食是一种有动机的生存行为，与其他有动机的行为（如繁殖和吸毒）一样，多巴胺神经传导对其进行了严格的调节。进食的动机是有条件的，受代谢需求驱动的适应过程的调节。调节食物摄入、饥饿素、食欲素、胰岛素和瘦素的几种多肽受体在腹侧被盖区（VTA）含有多巴胺的细胞中大量表达，这些细胞投射到涉及动机的前脑目标，如伏隔核、前额叶皮层和背纹状体。本实验旨在探讨促食肽（食欲素、饥饿素）和饱腹肽（胰岛素、瘦素）在中脑边缘奖赏通路多巴胺神经元中的作用。多巴胺神经元可以编码与新呈现的奖励或奖励预测线索相关的奖励显著性。与此一致的是，多巴胺神经元改变其突触效能，与预测奖励的线索的经验依赖学习相关。我们的总体假设是，发出饥饿或饱腹信号的肽可以改变多巴胺神经元的突触效能，从而改变多巴胺的释放。我们预测，这种增强的多巴胺神经元信号是对预测奖励的环境线索的高度突出的基础。在目前的提案中，我们将测量厌氧肽，食欲素和胃饥饿素，以及厌氧肽，胰岛素和瘦素对VTA多巴胺神经元兴奋性突触传递的影响。然后，我们将比较食欲素、胃促生长素和胰岛素对体树突和终末多巴胺释放的影响。最后，我们将确定食欲素神经元的内源性激活（通过光刺激）如何改变DA神经元的活性以及胃饥饿素或胰岛素信号在VTA中的作用。

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.