Non-Homeostatic Neural Controls of Food Intake

描述(申请人提供)：新陈代谢和非新陈代谢因素共同决定了摄食行为的启动和维持。在后者中，环境线索以及奖励、认知和情感因素发挥着重要作用，特别是在现代世界的人类食物摄入量中。这些非稳态因子主要在前额叶、杏仁核和腹侧纹状体等皮质-边缘结构中处理。一个重要的问题是了解新陈代谢和非新陈代谢因素如何以及在哪里整合起来，以推动食物的摄入。拟议的工作集中在这一问题的一个方面，通过研究腹侧纹状体和下丘脑肽能回路之间的解剖、神经化学和功能关系，这些环路涉及能量平衡的动态平衡调节。 在目标1中，我们利用Fos表达、神经元追踪、免疫组织化学和原位杂交的方法，确定了下丘脑腹侧纹状体投射的靶点，这些投射与伏隔核或腹侧苍白球内化学操作诱导的特定食物的强劲摄取有关。在目标2中，我们假设伏隔核中的化学操作通过作用于食欲增加和/或食欲减退的下丘脑信号系统，刺激充分饱足大鼠的进一步食物摄取，并推翻正常的体内平衡控制。我们通过使用选择性的拮抗剂和激动剂来测试这一点，这些实验包括针对“喂食”多肽受体的选择性拮抗剂和激动剂，解剖定位的免疫毒性损伤，以及小鼠基因敲除模型。在目标3中，我们假设腹侧纹状体D下丘脑投射在对美味食物的急性高吞噬反应和长期接触美味食物的肥胖的发展中发挥重要作用。为此，我们使用了两种不同的慢性损伤模型，这两种模型中断了腹侧纹状体-下丘脑回路的特定组件，并测量了食物摄入的“喜欢”和“想要”的方面，以及肥胖和体重。这些结果对于(1)从解剖学和神经化学角度详细了解奖励和体内平衡神经系统之间的关系，(2)建立一个概念框架，说明食物奖励中涉及的不同心理过程是如何在神经学上组织起来的，以及(3)开发药物和行为治疗工具来对抗“普遍的”肥胖，这些结果将是重要的。

DESCRIPTION (provided by applicant): The initiation and maintenance of ingestive behavior is co-determined by metabolic and non-metabolic factors. Among the latter, environmental cues as well as reward, cognitive and emotional factors play an important role, particularly in human food intake in the modern world. These non-homeostatic factors are processed mainly in cortico-limbic structures such as the prefrontal cortex, amygdala, and ventral striatum. An important issue is to understand how and where metabolic and non-metabolic factors are integrated to drive food intake. The proposed work focuses on one aspect of this issue by examining the anatomical, neurochemical, and functional relationship between the ventral striatum and the hypothalamic peptidergic circuits implicated in the homeostatic regulation of energy balance. In Aim 1, we identify hypothalamic targets of ventral striatal projections involved in the robust intake of specific foods induced by chemical manipulations within the nucleus accumbens or ventral pallidum, using Fos expression, neuronal tracing, immunohistochemistry, and in situ hybridization. In Aim 2 we hypothesize that chemical manipulations in the nucleus accumbens stimulate further food intake and override normal homeostatic controls in fully satiated rats by acting on orexigenic and/or anorexigenic hypothalamic signaling systems. We test this by using pharmacological experiments with selective antagonists and agonists against "feeding" peptide receptors, anatomically localized immunotoxic lesions, and murine knockout models. In Aim 3 we hypothesize that ventral striatum D hypothalamus projections play an important role in the acute hyperphagic response to palatable foods and in the development of obesity with chronic exposure to palatable diets. To this end, we use two different chronic lesion models that interrupt specific components of ventral striatal-hypothalamic circuitry, and measure both "liking" and "wanting" aspects of food intake as well as adiposity and body weight. The results will be important for (1) gaining detailed anatomical and neurochemical insight into the relationship between reward and homeostatic neural systems, (2) the development of a conceptual framework of how the different psychological processes involved in food reward are neurologically organized, and (3) the development of pharmacological and behavioral therapeutic tools to counteract "common" obesity in a world of plenty