Hypothalamic-Striatal Control of Motivation for Obesogenic Food

项目摘要 肥胖是一种令人震惊的慢性健康危机，目前影响着39.8%的成年人口(2015-2016) 美国。肥胖者是一个具有挑战性的公共卫生问题，因为他们处于 增加了几种危及生命和代价高昂的并存疾病的风险，包括糖尿病、代谢综合征、 心血管疾病和癌症。由于肥胖带来的经济和健康负担是如此有害， 更机械性地欣赏导致肥胖的喂食行为(S)对于理解 这种疾病的病因学和用于确定可用药靶点。一种有助于 肥胖是指过度食用非常美味的食物。非常可口的食物，包括高脂肪食物，是一种 是肥胖的重要驱动力，并已在啮齿动物中显示出强化价值。增援是通过 伏隔核壳(NAcSh)是调节享乐性的关键神经解剖学底物 喂食。另一个控制食物摄取的底物是下丘脑室旁核(PVN)。 PVN在生理能量需求的水平上调节食物的摄入量，促进体内平衡 进食行为。下丘脑室旁核神经元投射到NacSh(Pvn→NAcSh)并协调社会奖赏，但它们的 对于高脂肪食物的动机，其作用尚不清楚。初步数据表明，神经递质 谷氨酸(Glu)在PVN→NAcSh传递中起着不可或缺的作用。药物遗传刺激 下丘脑室旁核→NAcSh神经元可导致NAcSh突触前谷氨酸的持续释放。另外， 直接给NAcSh注射Glu激动剂会减少摄食，而给予Glu拮抗剂则会减少摄食 引发消费行为的即时和持续增长。尽管有相当多的Glu证据 在参与消费行为方面，谷氨酸在高脂肪食物动机中的作用尚未被探索。我们 推测下丘脑室旁核→NAcSh神经元内的谷氨酸信号是一种重要的神经调节因子 高脂肪食物。本研究的目的是：(1)建立谷氨酸信号转导的神经解剖学基础 在下丘脑室旁核→NAcSh和(2)操纵下丘脑室旁核→NAcSh中突触前谷氨酸的释放以检验特定的假设 关于谷氨酸在调节高脂肪食物的动机中的作用。完成这些目标将 为申请者提供新概念和新方法方面的培训，包括肥胖的神经生物学， 设计和解释行为实验，神经药理学的原理和方法，以及 基因技术的应用。这些研究的结果将对以下方面产生持续、强大的影响 我们的领域通过确定在PVN→NAcSh介导的动机中谷氨酸传递的关键调节作用 高脂肪食物，这将极大地促进改善肥胖和代谢治疗结果的努力 监管失调。

PROJECT ABSTRACT Obesity is an alarming chronic health crisis that currently affects 39.8% of the adult population (2015-2016) in the United States. Obese individuals present a challenging public health problem because they are at increased risk for several life-threatening and costly co-morbidities including diabetes, metabolic syndrome, cardiovascular disease, and cancer. Because the financial and health burdens of obesity are so pernicious, a more mechanistic appreciation of the feeding behavior(s) that contribute to obesity is critical to understanding the etiology of this disease and for identifying druggable targets. One feeding behavior that contributes to obesity is overconsumption of highly palatable food. Highly palatable food, including high-fat food, is an important driver of obesity and has demonstrated reinforcement value in rodents. Reinforcement is mediated in part by the nucleus accumbens shell (NAcSh), a key neuroanatomical substrate that regulates hedonic feeding. Another substrate governing food intake is the paraventricular nucleus of the hypothalamus (PVN). The PVN regulates food intake at the level of physiological energy requirements, and facilitates homeostatic feeding behavior. PVN neurons project to the NAcSh (PVN→NAcSh) and orchestrate social reward, but their role in motivation for high-fat food remains unknown. Preliminary data indicate that the neurotransmitter Glutamate (Glu) plays an integral role in PVN→NAcSh transmission. Pharmacogenetic stimulation of PVN→NAcSh neurons results in robust and sustained presynaptic Glu release in the NAcSh. Additionally, administration of Glu agonists directly to the NAcSh decrease feeding, while administration of Glu antagonists evoke an immediate and sustained increase in consumption behavior. Despite considerable evidence of Glu involvement in consumption behavior, the role of Glu in motivation for high fat food has not been explored. We propose that Glu signaling within PVN→NAcSh neurons is a critical neuromodulator of motivation for high-fat food. The objectives of this proposal are to (1) establish the neuroanatomical basis for Glu signaling in PVN→NAcSh and (2) manipulate presynaptic Glu release in PVN→NAcSh to test specific hypotheses concerning the role of Glu in the regulation of motivation for high-fat food. Completion of these objectives will provide the applicant with training in new concepts and methodologies, including the neurobiology of obesity, the design and interpretation of behavioral experiments, principles and methods of neuropharmacology, and the application of genetic technology. The outcomes of these studies will have a sustained, powerful impact on our field by identifying a key regulatory role for Glu transmission in PVN→NAcSh mediated motivation for highfat food, which will critically advance efforts to improve treatment outcomes in obesity and metabolic dysregulation.