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

• 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
• 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

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.

项目摘要 过多的体脂显著增加了患包括糖尿病在内的一系列疾病的风险， 癌症和心血管疾病。据估计，有4500万美国成年人在节食和 每年在减肥产品上的花费超过300亿美元。大多数干预措施都失败了，留下了 超重和易患代谢紊乱的人，如2型糖尿病。这一趋势是 可能是因为容易获得美味的、富含能量的食物，这会刺激食物 为了享乐而消费，而不考虑能量需求(享乐式喂养)。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)调节下游靶标的活性。这项奖励的结果之一 计算是对获取和消费食物的必要驱动力的编码。 在奖励回路的引导下，将食物消耗与能量需求分离导致持续 吃零食，而不是以餐为基础的喂养模式。越来越多的证据表明，除了 为了增加卡路里的摄入量，这种不规律的进餐时间会促进 限时的代谢过程，这进一步加剧了过量进食的不适应效应。 事实上，通过操纵昼夜节律来打乱进餐时间与体重有关。 人类和动物模型中的增重和代谢综合征。有奖励的食物如何影响 就餐时间？视交叉上核(SCN)是昼夜节律的主要调节器。 整合感觉和生理信息，使体内平衡功能与 昼夜循环。奖赏、摄食和昼夜节律如何相互作用以促进 正常和病态喂养代表着我们知识上的一大鸿沟。在这里，我们建议 为了检验这样一种假设，即从一组精选的VTA-DA神经元向SCN输入的多巴胺是 享乐式喂养神经回路的一个组成部分。我们将从基因和解剖学上定义 VTA神经元的一个亚群，它对美味的食物作出反应，在SCN中释放DA。我们 将消融这些精选神经元中DA的产生，以验证其直接的功能性SCN输入。这 Proposal采用了创新的方法，同时利用了我们在老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 将确定通过调节神经元的活动来控制摄食行为的DA神经元群 中枢昼夜节律时钟神经元。这项工作将对理解 奖励电路克服了体内平衡控制，同时为治疗提供了独特的途径 对抗肥胖症流行的方法。