Neural determinants on meal size in invertebrate models of obesity

项目摘要 在进食过程中，动物通过将感官线索与食物的有益品质联系起来来调节食物的大小。 食物这一过程是控制食物摄入的核心，在暴露于以下物质的人类和动物中受到损害： 高脂肪和高糖饮食。通过食物协会的神经机制1）调节膳食大小和2） 被这种饮食环境所困扰，然而，仍然知之甚少。这种知识的缺乏， 阻碍了揭示肥胖症根本原因的进展，从而抑制了代谢性疾病的传播。 疾病在这里，我们建议使用D。黑腹模型，以解决机制研究的需要， 神经对膳食量的调节和放松。高糖饮食会促进高摄入量和肥胖， 但与脊椎动物模型不同的是，涉及食物关联的神经回路集中在一个单一的神经回路上。 此外，操纵和可视化这些回路的转基因工具是公开可用的，这要归功于 几十年的研究和连接体我们的长期目标是利用飞模的独特优势 揭示高糖和高脂肪的食物环境如何促进肥胖和代谢疾病。我们的中央 一种假设是，饮食驱动的多巴胺传递变化是观察到的膳食量增加的基础， 喂食高热量食物的动物。这一假设是基于我们已发表和未发表的数据， 味觉的多巴胺能加工与营养品质、食物的形成之间的因果关系 协会和摄入量。为了验证这个想法，我们将使用钙和多巴胺信号的体内成像， 行为测定、代谢测量和多巴胺能、相关神经元和神经元的光遗传学操作。 学习和前运动回路，以确定受损的食物联想的原因（目标1）及其 对膳食量的影响（目标2）。成功完成拟议的研究将确定食物 协会控制摄入量和程度，通过饮食依赖性改变DA信号影响这一点， 过程;这将阐明调节膳食大小的神经机制，并揭示它们是如何被调节的。 解除对食品环境的管制。总之，这将有助于我们进一步了解 肥胖，这是NIDDK降低代谢疾病负担和传播的使命的关键。

PROJECT SUMMARY During eating animals modulate the size of meals by associating sensory cues with rewarding qualities of food. This process is central to the control of food intake and is impaired in humans and animals exposed to high fat and sugar diets. The neural mechanisms through which food associations 1) regulate meal size and 2) are perturbed by this dietary environment, however, remain poorly understood. This lack of knowledge has hindered progress in uncovering the underlying causes of obesity and, thus, in curbing the spread of metabolic disease. Here we propose to use the D. melanogaster model to address the need for mechanistic studies on the neural regulation and deregulation of meal size. A diet high in sugar promotes higher intake and obesity in flies, but unlike vertebrate models, the neural circuits involved in food associations converge onto a single brain region; further, transgenic tools to manipulate and visualize these circuits are publicly available, thanks to decades of research and the connectome. Our long term goal is to use the unique advantages of the fly model to uncover how food environments high in sugar and fat promote obesity and metabolic disease. Our central hypothesis is that diet-driven changes in dopamine transmission underlie the increase in meal size observed in animals fed high-calorie diets. This hypothesis is based on our published and unpublished data showing a causal link between the dopaminergic processing of taste and nutrient qualities, the formation of food associations, and intake. To test this idea we will use in vivo imaging of calcium and dopamine signals, behavioral assays, metabolic measurements, and optogenetic manipulations of dopaminergic, associative learning, and premotor circuits to define both the causes of impaired food associations (Aim 1) and their consequences on meal size (Aim 2). The successful completion of the proposed studies will define how food associations control intake and the extent through which diet-dependent alterations in DA signaling impact this process; this will illuminate the neural mechanisms that regulate meal size and uncover how they are deregulated by the food environment. Together, this will help advance our understanding of the causes of obesity, which is key to the NIDDK mission of decreasing the burden and spread of metabolic disease.