Unraveling the homeostatic and hedonic circuits underlying feeding behavior and obesity

项目总结 肥胖的惊人流行及其对个人和公共健康的影响突显了 了解个人暴饮暴食和体重增加的重要性。人们普遍认为，暴饮暴食 这是动态平衡(即营养需求、饥饿)和享乐(即愉悦、回报)驱动力共同作用的结果。 虽然这些动态平衡(例如，下丘脑)和享乐[例如，中脑多巴胺(DA)]系统 以食物摄取的离散驱动因素为特征，有相当多的证据表明这些系统重叠。为 例如，DA信号对食物的反应因饥饿而增强，从而增加了食物的奖励价值 需要动态平衡的时候。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关联 在动态平衡和享乐系统之间。饥饿敏感的下丘脑刺鼠相关蛋白的活性 (AgRP)表达神经元增强DA对食物的反应。相反，DA信令增强了 动态平衡AgRP神经元对食物的反应。AgRP和DA神经元相互作用的回路是什么 作为对食物的回应？它们是否有助于解释为什么有些人更有可能暴饮暴食和体重增加？这 该提案将检验主要假设，即不同的AgRP和DA神经元亚群介导 动态平衡和奖赏信号相互作用与AgRP和DA反应个体差异 预测未来体重增加的食物。目的I实验将确定AgRP神经元投射亚群 这增强了DA对食物的反应。我们将利用AgRP神经元的解剖组织，以及 光遗传和化学遗传技术，以单独测试每个AgRP亚群如何投射 影响食物诱导的DA信号。AIM II实验将确定AgRP的DA调节作用部位 神经元活性。我们将使用遗传学和药理学方法来研究DA预测和 神经递质信号影响AgRP神经元的活性。AIM III将确定AgRP和DA活动如何 预测未来的暴饮暴食和体重增加。利用体重增加的可变性来响应 高脂肪、高糖饮食，我们将确定瘦小鼠神经活动的个体差异是否可以预测未来 暴饮暴食与肥胖的发展。总体而言，这些实验采取了一种独特的方法来理解 体重增加通过(1)确定体内平衡和享乐回路的神经交叉点，这些回路具有经典的 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记物来预测过量饮食和 肥胖倾向。最终，拟议研究的结果将揭示细胞和分子靶标。 这可以被用来制定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.