Neural Mechanisms that Underlie Eating in the Absence of Hunger

肥胖症在世界各地的流行程度不断上升，这是对 21世纪。尽管几种新疗法似乎有可能获得批准，但最有效的长期疗法 对肥胖的治疗是外科手术，而目前专注于饮食的行为干预90%的时间都失败了。一位少校 节食的挑战是控制食物的摄入量，以面对我们丰富的感官环境，包括许多 与食物相关的感官暗示。这些感官提示会引起渴望和寻食。 行为即使在没有生理需要的情况下也是如此。杏仁核和相关的脑结构，如 眼眶前额叶皮质调节联想学习过程以及这些区域的感觉线索的处理 可以调节食物的消耗。然而，线索调制的精确神经电路机制 消费仍然知之甚少，它们与限制食物摄入量的动态平衡信号的相互作用是 完全未知。事实上，研究感官暗示如何在动态平衡的情况下促进进食 信号限制消费一直很难研究。在这里，我们建议通过以下方法来研究电路和机制 在没有饥饿的情况下，即在进食后的极度饱腹期，哪些感官线索会驱动进食行为 当小鼠吃得过多而导致低噬时。我们训练小鼠将特定的感觉线索联系起来，例如 一种语气，带有奖励的食物，然后使用提示增加食物消耗。我们利用这种行为 测试感觉线索挑战以下发生的基线体重的能力的范式 过量进食，也是为了测试这是否会导致较高的体重设定点。我们将使用最先进的 神经科学工具，包括病毒介导的电路追踪，依赖活性的基因重组表达， 钙成像、全脑组织学和光遗传学来验证杏仁核相关回路的假说 通过下丘脑外侧核驱动线索诱导的摄食行为，并可以在没有提示的情况下驱动摄食 饥饿。在目标1中，我们将在杏仁核相关回路中表达钙指示物，以研究感觉的编码 线索诱导喂食过程中的刺激。然后，我们使用光遗传学来测试这些区域是否有必要 足以调节线索诱导的摄食行为。在目标2中，我们将结合线索诱导的喂养和 过度摄食以测试线索诱导的摄食导致体重增加的能力，以及参与其中的电路元件 进程。了解神经机制，其中感觉线索可以驱动摄食行为在 缺乏生理需求将帮助我们理解环境因素对肥胖的贡献，以及为什么长期 成功的节食和减肥是很少见的。这些研究最终可能有助于确定治疗和治疗的目标 预防肥胖。

The rising prevalence of obesity throughout the world represents a major public health challenge for the 21st century. Although several new therapies seem likely to be approved, the most effective long-term treatments for obesity are surgical, while current behavioral interventions focused on diet fail 90% of the time. A major challenge in dieting is controlling food intake in the face of our rich sensory environment that includes many sensory cues that have become associated with foods. These sensory cues elicit cravings and food-seeking behavior even in the absence of physiologic need. The amygdala and related brain structures such as orbitofrontal cortex mediate associative learning processes, and the processing of sensory cues in these areas can modulate food consumption. However, the precise neural circuit mechanisms through which cues modulated consumption remain poorly understood, and their interaction with homeostatic signals that limit food intake are completely unknown. Indeed, studying how sensory cues promote feeding in circumstances when homeostatic signals limit consumption has been difficult to study. Here, we propose to study the circuits and mechanism by which sensory cues drive feeding behavior in the absence of hunger, i.e. during acute satiety following a meal and when mice have been overfed to induce hypophagia. We train mice to associate specific sensory cues, e.g. a tone, with rewarding foods, and later use the cue to increase food consumption. We use this behavioral paradigm to test the ability of sensory cues to challenge the return to baseline body weight that occurs following over-feeding, and also to test whether this leads to a higher body weight set-point. We will use state-of-the art neuroscience tools including viral-mediated circuit tracing, activity-dependent recombinant expression of genes, calcium imaging, whole-brain histology, and optogenetics to test the hypothesis that amygdala-related circuits drive cue-induced feeding behaviors via the lateral hypothalamus, and can drive feeding during the absence of hunger. In Aim 1, we will express calcium indicators in amygdala related circuits to study the encoding of sensory stimuli during cue-induced feeding. We then use optogenetics to test whether these areas are necessary and sufficient to modulate cue-induced feeding behaviors. In Aim 2, we will combine cue-induced feeding with overfeeding to test the ability of cue-induced feeding to cause weight gain, and circuit-elements involved in this process. Understanding the neural mechanisms whereby sensory cues can drive feeding-behavior in the absence of physiologic need will help us understand environmental contributors to obesity, and why long-term success in dieting and weight-loss is rare. These studies may ultimately help identify targets for treatment and prevention of obesity.