Dopamine neurons in the zona incerta regulate feeding motivation

未定带中的多巴胺神经元调节进食动机

基本信息

批准号：
10585604
负责人：
Xiaobing Zhang
金额：
$ 41.38万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585604
关键词：
Affect Aminobutyric Acids Amygdaloid structure Area Behavioral Behavioral Mechanisms Brain Brain region Calcium Signaling Calories Consummatory Behavior Consumption Cues Data Development Devices Dopamine Dopamine Antagonists Dopamine D2 Receptor Eating Eating Disorders Electrophysiology (science)Emotions Fatty acid glycerol esters Feeding behaviors Fiber Food Food Intake Regulation Food deprivation (experimental)Genetic Glucose Goals Hunger Hyperphagia Hypothalamic structure Limbic System Mediating Metabolic Monitor Motivation Mus Neural Pathways Neurons Nucleus Accumbens Nutrient Obesity Outcome Pathway interactions Pattern Peripheral Photometry Physiological Pilot Projects Play Prefrontal Cortex Public Health Regulation Reinforcement Schedule Reporting Rewards Role Schedule Signal Transduction Site Slice Source Subthalamic structure System Testing Thalamic structure Time Ventral Tegmental Area Work adeno-associated viral vector behavioral study dopaminergic neuron experimental study feeding food consumption frontal lobe hedonic in vivo inducible Cre innovation mind control neural novel obesity risk optogenetics patch clamp postsynaptic response transmission process zona incerta

项目摘要

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.

项目概要未定带 (ZI) 是位于腹侧丘脑和下丘脑之间的大脑区域根据最新发现调节食物摄入量。我们报道了ZI中的g-氨基丁酸（GABA）神经元调节通过对室旁丘脑（PVT）的抑制性投射来控制食物摄入。除了 GABA 神经元之外，几十年来，人们在 ZI 中发现了多巴胺 (DA) 神经元。然而，人们对它们的功能知之甚少行为调节。在我们的试点研究中，我们使用 TH-Cre 小鼠来靶向 ZI DA 神经元，并发现 ZI DA 神经元的化学遗传学激活有效增加了获得食物奖励的动机。基于我们的根据试点数据，我们假设：1）ZI DA 神经元调节进食动机以控制食物消耗。 2） ZI DA 神经元编码进食行为并对代谢性饥饿信号做出反应。 3) PVT 作为其中之一 ZI DA 神经元发挥摄食功能控制的重要突触后区域。来测试我们的假设，我们将使用腺相关病毒载体（AAV）来诱导兴奋性的 Cre 依赖性表达 TH-Cre 小鼠的 ZI DA 神经元中选择性地存在 hM3Dq、抑制性 hM4Di 或 ChR2。化学遗传学激活和沉默将用于选择性地操纵 ZI DA 神经元，以测试它们在控制食物中的作用使用渐进比例 (PR) 强化计划和实时食物消耗和膳食来激励使用喂养实验装置（FED）的模式。我们还将利用光遗传学选择性激活ZI DA 预测以确定 PVT 神经元在 ZI DA 神经元诱导的摄食调节中的作用。此外行为研究，我们将进行切片电生理学结合光遗传学来剖析功能性 ZI DA 途径。体内光纤光度测定法将用于检查 ZI DA 神经元如何编码进食包括食物寻找和消费以及切片电生理学在内的行为将用于研究活动 ZI DA 神经元对代谢饥饿信号的反应。总之，本申请中提出的研究将揭示了饲喂控制中新的 ZI DA 途径。拟议研究的预期结果将显着扩展了我们对 ZI 和中央 DA 信号如何调节进食动机和食物的认识消耗。