Diet, Insulin, Dopamine, and Reward

项目摘要 多巴胺(DA)是大脑奖赏通路中一种公认的神经调节剂。人们越来越认识到 纹状体内的调节因子促进局部DA的释放，补充中脑DA的作用 向靶区供应多巴胺的神经元活动。我们已经报道，葡萄糖诱导的血管紧张素水平升高 代谢激素胰岛素在伏隔核(NAC)起到奖赏信号的作用。利用体外纹状体 切片，我们发现胰岛素促进了NAc和背侧纹状体中DA的释放，并且胰岛素 在因高脂肪、高糖(HF-HS)饮食而肥胖的啮齿动物中，反应性丧失。我们的同伴 行为学研究表明，胰岛素在NAC中的作用对于通过葡萄糖学习风味营养是必要的。 含有溶液，以及在训练期间出现的葡萄糖摄入量增加。虽然对 这种奖赏途径还远未完成，我们已经确定了纹状体微回路的关键作用，包括 DA轴突和纹状体胆碱能中间神经元(CHI)均表达胰岛素受体(INSR)。一个 大量文献表明，CHIS中的乙酰胆碱(ACh)通过β2-亚基促进DA的释放 DA轴突上的烟碱型ACh受体(β_2-nAChRs)。我们之前已经证明作用于InsRs的胰岛素增加 β2-nAChR选择性拮抗可阻止胰岛素的DA增强作用； 在缺乏纹状体ACh合成的小鼠(Chat KO小鼠)中不存在。然而，需要了解的关键要素 并利用这一途径，包括：1)胰岛素增加CHI活性的细胞机制； 2)味道-营养学习的特定成分受胰岛素的影响以及它们是否被β-2-阻断- NAChR拮抗剂和HF-HS饮食的损害；3)胰岛素依赖的突触可塑性模式。 NAC中的刺状输出神经元(MSN)是味觉-营养学习的基础。这些缺失的元素将是 在三个具体目标中加以解决，以利用私营部门主管的互补专门知识。总体而言，我们之前的 初步数据显示，NAC胰岛素信号对于学习风味-营养是必要的，它指导着食物的选择 以及基于预测的营养产量的消费量。这种依赖胰岛素的奖赏学习在 HF-HS喂养导致InsR亚敏感，导致不适应消费。通过识别 驱动营养学习的细胞机制和特定于路径的可塑性，这个项目将不仅回答 关于NAC胰岛素的关键问题，但也指出了可能绕过亚敏感NAC InsRs并恢复的靶点 健康饮食。

Project Summary Dopamine (DA) is an established neuromodulator in brain reward pathways. It is increasingly recognized that regulatory factors acting within the striatum sculpt local DA release, complementing the role of midbrain DA neuron activity in supplying DA to target regions. We have reported that glucose-induced increases in levels of the metabolic hormone insulin acts as a reward signal in the nucleus accumbens (NAc). Using ex vivo striatal slices, we discovered that insulin enhances DA release in the NAc and dorsal striatum, and that insulin responsiveness is lost in rodents that are obese from a high-fat high-sugar (HF-HS) diet. Our companion behavioral studies show that insulin action in the NAc is necessary for flavor-nutrient learning with glucose- containing solutions, and for the escalation of glucose intake seen during training. Although understanding of this reward pathway is far from complete, we have established the pivotal role of a striatal microcircuit involving DA axons and striatal cholinergic interneurons (ChIs), both of which express insulin receptors (InsRs). An abundant literature indicates that acetylcholine (ACh) from ChIs promotes DA release via β2-subunit containing nicotinic ACh receptors (β2-nAChRs) on DA axons. We showed previously that insulin acting at InsRs increases ChI excitability, and that the DA-boosting effect of insulin is prevented by β2-nAChR-selective antagonism, and is absent in mice that lack striatal ACh synthesis (ChAT KO mice). However, key elements required to understand and harness this pathway are missing, including: 1) cellular mechanisms by which insulin increases ChI activity; 2) specific components of flavor-nutrient learning influenced by insulin and whether they are blocked by β2- nAChR antagonists and impaired by a HF-HS diet; and 3) patterns of insulin-dependent synaptic plasticity in NAc medium spiny output neurons (MSNs) that underlie flavor-nutrient learning. These missing elements will be addressed in three specific aims that capitalize on the complementary expertise of the PIs. Overall, our previous and pilot data show that NAc insulin signaling is necessary for flavor-nutrient learning, which guides food choice and consumption based on predicted nutritive yield. This insulin-dependent reward learning is impaired in subjects with InsR subsensitivity induced by HF-HS feeding, leading to maladaptive consumption. By identifying cellular mechanisms and pathway-specific plasticity that drive nutritive learning, this project will not only answer key questions about NAc insulin, but also indicate targets that might bypass subsensitive NAc InsRs and restore healthy eating.