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

项目摘要 过多的身体脂肪会显著增加患一系列疾病的风险，包括糖尿病， 癌症和心血管疾病。估计有4500万美国成年人节食， 每年在减肥产品上花费超过300亿美元。这些干预措施大多失败， 超重且容易患2型糖尿病等代谢疾病的人。这一趋势 这可能是由于容易获得可口的、富含能量的食物， 为了快乐而消费，而不考虑能量需求（享乐喂养）。多巴胺能神经元 腹侧被盖区（VTA）的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。这项奖励的结果之一 计算是获取和消耗食物的必要驱动力的编码。 将食物消耗与奖励回路引导的能量需求脱钩， 吃零食，而不是以膳食为基础的喂养模式。越来越多的证据表明，此外， 增加热量摄入，这种类型的不规则的用餐时间促进精确的 定时代谢过程，这进一步导致了过度饮食的适应不良影响。 事实上，通过控制昼夜节律来打乱进餐时间与体重有关 在人类和动物模型中的增益和代谢综合征。奖励食物如何影响 用餐时间？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，以使体内平衡功能与 日/夜循环。奖励、进食和昼夜节律回路如何相互作用以促进 正常和病理性进食在我们的知识中代表了一个显著的差距。在这里，我们建议 为了检验从一组选定的腹侧被盖区-多巴胺能神经元到SCN的多巴胺能输入是 享乐进食神经回路的一部分我们将从基因和解剖学上定义 腹侧被盖区神经元亚群，在SCN中释放DA以响应美味食物。我们 将消融这些选定神经元中的DA产生，以验证它们的直接功能性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， 立体定位病毒递送和功能性神经回路映射策略。利用这些工具，我们 将确定一组DA神经元，通过调节 中枢生物钟神经元这项工作将对理解如何 奖励回路克服了自我平衡控制，同时为治疗提供了独特的途径。 对抗肥胖症流行的方法。

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.