Role of feeding-related peptides on brain reward pathways

进食是一种有动机的生存行为，和其他有动机的行为(如生育和吸毒)一样，受多巴胺神经传递的严格调控。进食的动机是有条件的，由代谢需求驱动的异位平衡过程调节。胃促生长素、食欲素、胰岛素和瘦素等调节食物摄取的多肽受体在腹侧被盖区(VTA)的多巴胺细胞中大量表达，这些细胞投射到与动机有关的前脑靶点，如伏隔核、前额叶皮质和背侧纹状体。这些实验旨在研究食欲素(食欲素，Ghrelin)和饱腹感(胰岛素，瘦素)肽对中脑边缘奖赏通路中的多巴胺神经元的作用。多巴胺神经元可以编码与新出现的奖赏或奖赏预测线索相关的奖赏的显著程度。与此一致的是，多巴胺神经元改变了它们的突触效能，与预测奖励的线索的经验相关学习相关。我们的总体假设是，发出饥饿或饱腹感信号的多肽可以改变多巴胺神经元的突触效能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是对预测奖励的环境线索的高度重视的基础。在目前的方案中，我们将测量食欲素和Ghrelin，以及厌食肽，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，我们将比较增食欲素、胃促生长素和胰岛素对躯体树突状细胞和终末多巴胺释放的影响。最后，我们将确定内源性增食欲素神经元的激活(通过光刺激)如何改变DA神经元的活动，以及Ghrelin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.