Unraveling the homeostatic and hedonic circuits underlying feeding behavior and obesity

项目摘要 肥胖症及其相关的个人和公共健康后果的惊人流行突出了 了解为什么人们吃得过多和体重增加的重要性。人们普遍认为暴饮暴食 由自我平衡（即，营养需求，饥饿）和享乐（即，快乐，奖励）驱动。 虽然这些稳态（例如，下丘脑的）和享乐的[例如，中脑多巴胺（DA）系统已被 虽然这些系统被描述为食物摄入的离散驱动因素，但有相当多的证据表明，这些系统是重叠的。为 例如，对食物做出反应的DA信号被饥饿增强，在饥饿期间增加食物的奖励价值。 时间的自我平衡需要。我们最近在啮齿动物模型中的发现揭示了这种相互作用的神经相关性 平衡系统和享乐系统之间的区别饥饿敏感的下丘脑刺豚鼠相关蛋白的活性 （AgRP）表达神经元增强DA对食物的反应。相反，DA信号增强了 稳态AgRP神经元对食物的反应。AgRP和DA神经元通过什么回路相互作用 对食物的反应？它们是否有助于解释为什么有些人更容易暴饮暴食和体重增加？这 该提案将测试总体假设，即不同的AgRP和DA神经元亚群介导了 内稳态和奖赏信号相互作用与AgRP和DA反应的个体差异 食物预测未来的体重增加。目的本实验将确定AgRP神经元投射亚群 增强多巴胺对食物的反应我们将利用AgRP神经元的解剖组织，以及 光遗传学和化学遗传学技术，以单独测试每个AgRP投射亚群 影响食物诱发的DA信号传导。目的II实验将确定DA调节AgRP的作用位点 神经元活动我们将使用遗传学和药理学方法来研究DA预测和 神经递质信号传导影响AgRP神经元活性。目标III将确定AgRP和DA活性如何 预测未来的暴饮暴食和体重增加。利用体重增加的可变性， 高脂肪，高糖饮食，我们将确定是否在瘦小鼠神经活动的个体差异预测未来 暴饮暴食和肥胖的发展。总的来说，这些实验采取了一种独特的方法来理解 体重增加（1）确定神经交叉的稳态和享乐电路，具有经典的 被认为是摄入量的离散驱动因素，以及（2）识别神经活动生物标志物以预测暴饮暴食， 肥胖倾向最终，拟议研究的结果将揭示细胞和分子靶点 可以用来开发肥胖预防和更有效的减肥策略。

PROJECT SUMMARY The striking prevalence of obesity and its associated personal and public health consequences highlights the importance of understanding why individuals overeat and gain weight. It is widely recognized that overeating results from a combination of homeostatic (i.e., nutrient need, hunger) and hedonic (i.e., pleasure, reward) drives. While these homeostatic (e.g., hypothalamic) and hedonic [e.g., midbrain dopamine (DA)] systems have been characterized as discrete drivers of food intake, there is considerable evidence that these systems overlap. For example, DA signaling in response to food is potentiated by hunger, increasing the reward value of food during times of homeostatic need. Our recent findings in rodent models revealed a neural correlate for the interaction between homeostatic and hedonic systems. Activity in hunger-sensitive, hypothalamic agouti-related protein (AgRP)-expressing neurons potentiates the DA response to food. Conversely, DA signaling enhances the homeostatic AgRP neuron response to food. What are the circuits through which AgRP and DA neurons interact in response to food? Do they help explain why some individuals are more likely to overeat and gain weight? This proposal will test the overarching hypotheses that distinct AgRP and DA neuron subpopulations mediate the interaction between homeostatic and reward signaling and that individual differences in AgRP and DA responses to food predict future weight gain. Aim I experiments will determine the AgRP neuron projection subpopulations that potentiate DA responses to food. We will leverage the anatomical organization of AgRP neurons, as well as optogenetic and chemogenetic technologies, to individually test how each AgRP projection subpopulation influences food-evoked DA signaling. Aim II experiments will determine sites of action for DA modulation of AgRP neuron activity. We will use genetic and pharmacological approaches to examine how DA projections and neurotransmitter signaling influence AgRP neuron activity. Aim III will determine how AgRP and DA activity predicts future overeating and weight gain. Taking advantage of the variability in weight gain in response to a high-fat, high-sugar diet, we will determine if individual differences in neural activity in lean mice predict future overeating and the development of obesity. Overall, these experiments take a unique approach to understanding weight gain by (1) determining the neural intersection of homeostatic and hedonic circuits that have classically been considered discrete drivers of intake and (2) identifying neural activity biomarkers to predict overeating and obesity predisposition. Ultimately, results from the proposed studies will reveal cellular and molecular targets that can be leveraged to develop obesity prevention and more effective weight loss strategies.