Dopamine neurons in the zona incerta regulate feeding motivation

项目摘要 位于腹侧丘脑和下丘脑之间的脑区未定带（Zona incerta，ZI）已被发现 根据最新研究结果调节食物摄入量。我们报道了在ZI的g-氨基丁酸（GABA）神经元调节 通过抑制投射到室旁丘脑（PVT）的食物摄入。除了GABA神经元， 多巴胺（DA）神经元已经在ZI中发现了几十年。然而，很少有人知道他们的功能， 行为规范。在我们的初步研究中，我们使用TH-Cre小鼠靶向ZI DA神经元，发现 化学发生激活的ZIDA神经元有力地增加了获得食物奖励的动机。基于我们 初步数据，我们假设：1）ZI DA神经元调节摄食动机，以控制食物消耗。（二） ZI DA神经元编码进食行为并响应代谢饥饿信号。3)PVT作为 ZIDA神经元对摄食进行功能控制的重要突触后区。来测试我们 假设，我们将使用腺相关病毒载体（AAV）诱导Cre依赖性兴奋性表达， hM3Dq、抑制性hM4Di或ChR2选择性地在TH-Cre小鼠的ZI DA神经元中。化学发生激活和 沉默将被用来选择性地操纵ZI DA神经元，以测试它们在食物控制中的作用。 使用强化的累进比率（PR）时间表和实时食物消耗和膳食的激励 使用喂养实验装置（FED）的模式。我们还将使用光遗传学来选择性地激活ZI DA 投射，以确定PVT神经元在ZI DA神经元诱导的摄食调节中的作用。除了 在行为学研究中，我们将进行切片电生理学结合光遗传学来解剖 功能性ZIDA途径。在体内的纤维光度法将被应用于研究ZI DA神经元如何编码进食 行为，包括食物寻求和消费和切片电生理学将用于研究活动 ZIDA神经元对代谢饥饿信号的反应。总之，本申请中的拟议研究将 揭示了新的ZIDA途径在喂养控制。拟议研究的预期成果将 显著地扩展了我们关于ZI和中枢DA信号如何调节进食动机和食物的观点 消费

PROJECT SUMMARY Zona incerta (ZI), a brain region located between the ventral thalamus and the hypothalamus, has been revealed to regulate food intake by latest findings. We reported that g-aminobutyric acid (GABA) neurons in the ZI regulate food intake through inhibitory projections to paraventricular thalamus (PVT). In addition to GABA neurons, dopamine (DA) neurons have been found in the ZI for decades. However, little is known about their function in the behavioral regulation. In our pilot studies, we used TH-Cre mice to target ZI DA neurons and found that chemogenetic activation of ZI DA neurons potently increased motivation to obtain food reward. Based on our pilot data, we hypothesize that: 1) ZI DA neurons regulate feeding motivation to control food consumption. 2) ZI DA neurons encode feeding behaviors and respond to metabolic hunger signals. 3) the PVT serves as one of the important postsynaptic areas for ZI DA neurons to exert the functional control on feeding. To test our hypothesis, we will use adeno-associated viral vectors (AAVs) to induce Cre-dependent expression of excitatory hM3Dq, inhibitory hM4Di, or ChR2 selectively in ZI DA neurons of TH-Cre mice. Chemogenetic activation and silencing will be employed to selectively manipulate ZI DA neurons for testing their role in the control of food motivation using progressive ratio (PR) schedule of reinforcement and real-time food consumption and meal pattern using Feeding Experimental Devices (FED). We will also use optogenetics to selectively activate ZI DA projections to determine the role of PVT neurons in feeding regulation induced by ZI DA neurons. In addition to the behavioral studies, we will perform slice electrophysiology in combination with optogenetics to dissect functional ZI DA pathways. In vivo fiber photometry will be applied to examine how ZI DA neurons encode feeding behaviors including food seeking and consumption and slice electrophysiology will be used to study the activity response of ZI DA neurons to metabolic hunger signals. Together, the proposed studies in this application will reveal novel ZI DA pathways in feeding control. The expected outcome from the proposed studies will significantly expand our view of how ZI and central DA signaling regulate feeding motivation and food consumption.