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（例如，生殖和药物服用）受到多巴胺神经传递的严重调节。 进食的动机是有条件的，受代谢需求驱动的非稳态过程的调节。调节食物摄入的几种肽、生长激素释放肽、食欲素、胰岛素和瘦素的受体在腹侧被盖区（VTA）中的含多巴胺细胞中大量表达，所述细胞投射到与动机有关的前脑靶点，例如前额叶皮层、背侧纹状体和背侧被盖区。在这个提议中概述的实验旨在研究食欲（食欲素，生长激素释放肽）和饱腹感（胰岛素，瘦素）肽对中脑边缘奖励通路的多巴胺神经元的作用。 多巴胺神经元可以编码与从头呈现奖励或奖励预测线索有关的奖励的显着性。与此相一致的是，多巴胺神经元改变了它们的突触功效，这与预测奖励的线索的经验依赖性学习有关。我们的总体假设是，发出饥饿或饱腹感信号的肽可以改变多巴胺神经元的突触功效和由此产生的多巴胺释放。我们预测，这种增强的多巴胺神经元信号的基础是一个高度的显着性的环境线索，预测奖励。在目前的建议中，我们将测量食欲肽，食欲素和ghrelin，和食欲肽，胰岛素和瘦素，对腹侧被盖区多巴胺神经元的兴奋性突触传递的影响。然后，我们将比较食欲素，生长激素释放肽和胰岛素对体树突和终端多巴胺释放的影响。最后，我们将确定如何内源性激活食欲素神经元（通过光刺激）改变DA神经元的活动和腹侧被盖区的生长激素释放肽或胰岛素信号的影响。

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.