Deconstructing the Neural Control of Food Seeking

总结。 美国肥胖症和相关合并症的急剧增加是一个主要的公共健康问题 担忧。虽然减肥改善了这些条件，但在实施成功的节食方面普遍存在困难 高复发率是有效治疗肥胖症的主要障碍。这项建议的目的是 确定神经元亚群并确定阻碍体重减轻的神经机制。刺鼠相关蛋白 能量缺乏激活下丘脑弓状核(AgRP)阳性神经元 刺激食物的寻觅和消费。我们已经证明了AgRP神经元传递负性信号 通常与饥饿和减肥有关的负面影响背后的价态信号。因此，在那里 迫切需要确定AgRP神经元如何与大脑其他区域沟通以驱动负性反应 价格、寻找食物和消费。AgRP神经元可以分为不同的亚群， 投射到几个靶区之一，但我们对不同的AgRP投射的理解 调节AgRP神经活动的生理和情感后果的亚群仍然存在 不完整。为此，本提案中的补充目标使用最先进的技术来 以前所未有的详细程度描述AgRP神经元投射亚群和回路 驱动食物摄取的机制。具体地说，我们的实验将(1)识别不同的AgRP投影 调节与饥饿相关的负价态的亚群(S)，(2)决定内源性 AgRP亚群在生理状态由饱足向匮乏过渡过程中的活性模式 国家，(3)检查AgRP亚群活动如何随肥胖而变化，以及(4)确定AgRP 预测有助于促进为食物而工作的动机的亚群。总体而言，这些结果 实验将确定AgRP神经元生理和功能上招募的大脑区域 活性，提供新的神经底物靶点，可用于开发有效的肥胖症疗法。

Summary. The dramatic increase in obesity and associated comorbidities in the United States is a major public health concern. While weight loss improves these conditions, widespread difficulty in implementing successful diets and high recidivism are major barriers to effective obesity treatments. The objective of this proposal is to identify neuron subpopulations and define neural mechanisms that impede weight loss. Agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus are activated by energy deficit and motivate food seeking and consumption. We have demonstrated that AgRP neurons transmit a negative valence signal that may underlie the negative affect often associated with hunger and weight loss. Thus, there is a critical need to identify how AgRP neurons communicate with other brain regions to drive negative valence, food seeking, and consumption. AgRP neurons can be divided into distinct subpopulations that project to one of several target brain regions, but our understanding of the distinct AgRP projection subpopulations that mediate the physiological and affective consequences of AgRP neural activity remains incomplete. To this end, the complementary aims in this proposal use state-of-the-art techniques to characterize, with unprecedented levels of detail, the AgRP neuron projection subpopulations and circuit mechanisms that drive food intake. Specifically, our experiments will (1) identify the distinct AgRP projection subpopulation(s) that mediate the negative valence associated with hunger, (2) determine the endogenous activity patterns of AgRP subpopulations during the transition between replete and deprived physiological states, (3) examine how AgRP subpopulation activity changes with obesity, and (4) determine the AgRP projection subpopulations that contribute to the motivation to work for food. Overall, results from these experiments will identify brain regions that are physiologically and functionally recruited by AgRP neuron activity, providing novel neural substrate targets that can be leveraged to develop potent therapies for obesity.