Identification of a dopamine circuit mediating day eating and diet-induced obesity in mice

介导小鼠日间饮食和饮食诱导肥胖的多巴胺回路的鉴定

基本信息

批准号：
10730567
负责人：
Andrew David Steele
金额：
$ 44.1万
依托单位：
CALIFORNIA STATE POLY U POMONA
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：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730567
关键词：
Ablation Acute Adult American Anatomy Animal Model Automobile Driving Biological Rhythm Body Weight decreased Body fat Brain Calories Cardiovascular Diseases Caring Circadian Dysregulation Circadian Rhythms Consumption Diabetes Mellitus Diet Disease Dopamine Dopamine Receptor Eating Eating Behavior Energy Intake Energy consumption FOXP2 gene Fatty acid glycerol esters Feeding Patterns Feeding behaviors Food Genetic Genetic Identity Health Human Hunger Hyperphagia Hypothalamic structure Incentives Individual Injections Intervention Knockout Mice Knowledge Link Malignant Neoplasms Maps Mediating Mediator Medical Metabolic Diseases Metabolic syndrome Metabolism Midbrain structure Motivation Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Nucleus Accumbens Obesity Obesity Epidemic Overweight Pathologic Pathway interactions Phase Phenotype Physiological Population Predisposition Production Resistance Resting Phase Retrieval Rewards Risk Signal Transduction Site Syndrome System Testing Therapeutic Time Transgenic Mice Tyrosine 3-Monooxygenase United States Ventral Tegmental Area Viral Weight Gain Work calbindin circadian circadian pacemaker circadian regulation conditional knockout cost designer receptors exclusively activated by designer drugs diet-induced obesity dopaminergic neuron experimental study feeding food consumption hedonic human model innovation mouse genetics mutant neural circuit novel pleasure prevent recombinase response restoration retrograde transport reward circuitry sensory integration sugar suprachiasmatic nucleus tool trend

项目摘要

Project Summary Excess body fat significantly increases the risk for a range of maladies including diabetes, cancer, and cardiovascular diseases. An estimated 45 million adult Americans go on diets and spend over $30 billion on weight loss products each year. Most of these interventions fail, leaving individuals overweight and susceptible to metabolic disorders like type 2 diabetes. This trend is likely due to the easy availability of palatable, energy-rich foods which incentivizes food consumption for pleasure regardless of the energy need (hedonic feeding). Dopaminergic neurons of the ventral tegmental area (VTA) compute the potential value of food reward and release dopamine (DA) to tune the activity of downstream targets. One of the results of this reward computation is the encoding of the necessary drive for retrieval and consumption of food. Uncoupling food consumption from energy need guided by the reward circuitry leads to continuous snacking rather than a meal-based pattern of feeding. Mounting evidence suggests that in addition to increased caloric intake, this type of irregular meal timing promotes desynchrony of precisely timed metabolic processes, which further contributes to the maladaptive effects of overeating. Indeed, disorganization of mealtimes by manipulation of circadian rhythms is correlated with weight gain and metabolic syndrome in humans and animal models. How do rewarding foods influence meal timing? The suprachiasmatic nucleus (SCN) is the primary regulator of circadian rhythms and integrates sensory and physiologic information to synchronize homeostatic functions to the day/night cycles. The basis for how reward, feeding and circadian circuitry interact to promote normal and pathological feeding represents a significant gap in our knowledge. Here, we propose to test the hypothesis that dopaminergic input from a select group of VTA-DA neurons to the SCN is an integral part of the hedonic feeding neurocircuitry. We will genetically and anatomically define the subpopulation of VTA neurons that releases DA in the SCN in response to palatable foods. We will ablate DA production in these select neurons to validate their direct functional SCN input. This proposal employs innovative approaches while leveraging our expertise in mouse genetics, stereotaxic viral delivery, and functional neural circuitry mapping strategies. Using these tools, we will identify the group of DA neurons that govern feeding behavior by modulating the activity of central circadian clock neurons. This work will have broad implications for understanding how reward circuitry overcomes homeostatic control while providing unique avenues for therapeutic approaches against the obesity epidemic.

项目概要体内脂肪过多会显着增加患一系列疾病的风险，包括糖尿病、癌症、心血管疾病。据估计，有 4500 万美国成年人正在节食并每年在减肥产品上花费超过 300 亿美元。大多数干预措施都失败了，导致超重且易患代谢性疾病（如 2 型糖尿病）的人。这个趋势是可能是因为容易获得美味且富含能量的食物，从而刺激了食物无论能量需求如何，为了快乐而消费（享乐性喂养）。多巴胺能神经元腹侧被盖区 (VTA) 计算食物奖励和释放的潜在价值多巴胺 (DA) 调节下游靶点的活性。本次奖励的成果之一计算是对获取和消费食物的必要驱动力的编码。将食物消耗与由奖励电路引导的能量需求分开会导致持续的吃零食而不是以正餐为主的喂养方式。越来越多的证据表明，此外为了增加热量摄入，这种不规则的进餐时间会导致精确的不同步定时的代谢过程，进一步加剧了暴饮暴食的适应不良效应。事实上，通过控制昼夜节律来打乱进餐时间与体重相关人类和动物模型中的增益和代谢综合征。奖励性食物如何影响吃饭时间？视交叉上核（SCN）是昼夜节律的主要调节者整合感觉和生理信息，使稳态功能与昼/夜循环。奖励、喂养和昼夜节律电路如何相互作用以促进的基础正常和病理性喂养代表了我们知识上的巨大差距。在此，我们建议检验以下假设：从一组选定的 VTA-DA 神经元到 SCN 的多巴胺能输入是享乐喂养神经回路的一个组成部分。我们将从遗传学和解剖学上定义 VTA 神经元亚群，在 SCN 中释放 DA，以响应美味的食物。我们将消除这些选定神经元中的 DA 产生，以验证其直接功能性 SCN 输入。这该提案采用创新方法，同时利用我们在小鼠遗传学方面的专业知识，立体定位病毒传递和功能神经回路映射策略。使用这些工具，我们将识别通过调节 DA 神经元的活动来控制摄食行为的组中枢生物钟神经元。这项工作将对理解如何奖励电路克服了稳态控制，同时提供了独特的治疗途径对抗肥胖流行的方法。