Diet, Insulin, Dopamine, and Reward

项目摘要 多巴胺（DA）是脑奖赏通路中的一种神经调质。人们日益认识到 纹状体内的调节因子塑造局部DA释放，补充中脑DA的作用 在向靶区域供应DA中的神经元活动。我们已经报道了葡萄糖诱导的 代谢激素胰岛素在脑桥核（NAc）中充当奖赏信号。使用离体纹状体 我们发现，胰岛素可以增强NAc和背侧纹状体中DA的释放， 在因高脂高糖（HF-HS）饮食而肥胖的啮齿动物中丧失了反应性。我们的同伴 行为研究表明，NAc中的胰岛素作用对于葡萄糖的风味营养学习是必要的， 含有溶液，并用于训练期间观察到的葡萄糖摄入量的增加。虽然了解 虽然这种奖赏途径还远未完成，但我们已经确定了纹状体微回路的关键作用， DA轴突和纹状体胆碱能中间神经元（ChIs），两者都表达胰岛素受体（InsRs）。一个 大量文献表明ChIs中的乙酰胆碱（Ach）通过含有β2-亚基的β2-亚基促进DA的释放， DA轴突上的烟碱型ACh受体（β2-nAChRs）。我们之前已经证明，作用于InsRs的胰岛素增加， ChI兴奋性，胰岛素的DA增强作用被β2-nAChR选择性拮抗作用阻止， 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 和利用这一途径的缺失，包括：1）胰岛素增加ChI活性的细胞机制; 2)受胰岛素影响的风味-营养学习的特定成分以及它们是否被β2- nAChR拮抗剂和HF-HS饮食损害;和3）胰岛素依赖性突触可塑性的模式， NAc中等多刺输出神经元（MSN）是味觉-营养学习的基础。这些缺失的元素将 在三个具体目标中解决了这些问题，这些目标利用了PI的互补专长。总的来说，我们以前的 试验数据表明，NAc胰岛素信号传导对于指导食物选择的风味-营养学习是必要的 和基于预测的营养产量的消耗。这种依赖胰岛素的奖励学习在 HF-HS喂养诱导InsR亚敏感性的受试者，导致适应不良的消费。通过识别 细胞机制和特定途径的可塑性，驱动营养学习，这个项目不仅将回答 关于NAc胰岛素的关键问题，但也指出了可能绕过亚敏感NAc InsR并恢复 吃健康

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.