Integration of Hypothalamic and Limbic Pathways to Regulate Motivation for Food

 描述(由申请人提供)：需要安全有效的肥胖治疗方法来应对这种疾病的巨大负担，如糖尿病、心血管疾病，甚至一些癌症。尽管几十年来一直被作为不同的途径进行研究，但现在人们认为，调节饮食和动机的过程是由重叠的神经回路驱动的。研究这种重叠可能会对过量热量摄入的基础提供重要的见解，并导致确定治疗代谢性疾病的新药理靶点，这是我们研究的长期目标。在这方面的一个潜在的新的和创新的靶点是神经介素U(NMU)，一种被证明可以抑制食物摄取和导致减肥的多肽。NMU的这些作用与其作用于下丘脑的NMU受体2(NMUR2)有关，特别是在富含NMUR2的室旁核(PVN)。我们之前已经发现，选择性地耗尽大鼠PVN中的NMUR2会增加高脂肪饮食的摄入量，增加体重增加，并增强对脂肪而不是蔗糖的饮食偏好。本项目的目标是探索NMUR2信号作为下丘脑和中脑边缘系统之间的关键接口，并进一步评估NMUR2激动剂对摄食行为的作用。我们的初步数据表明，下丘脑中的NMUR2神经元与伏隔核直接相连，伏隔核是中脑边缘系统的一个关键区域，负责调节奖励和动机行为。我们首次在体内评估了小分子NMUR2激动剂。我们的初步数据表明，这些化合物抑制了高脂肪饮食的进食。为了实现我们的目标，我们的具体目标是1)评估下丘脑和中脑边缘回路之间的结构联系，2)建立脑啡肽和阿片信号转导之间的功能联系，3)确定NMUR2是否是抑制高脂肪食物的动机和代谢生理调节的靶点。这些目标将通过使用诸如病毒载体示踪剂来绘制大脑中的神经路径的创新技术来实现，在澄清的、完整的大脑中以清晰的光学清除来可视化这些路径，以及通过病毒介导的RNA干扰来研究NMUR2基因对食物摄入量、体重和食物动机的影响。总体而言，这些研究将为理解调节食物动机的神经通路奠定基础，并为未来开发基于NMUR2的肥胖症治疗方法奠定基础。

 DESCRIPTION (provided by applicant): Safe and effective approaches for the treatment of obesity are needed to address the tremendous burdens of this disease such as diabetes, cardiovascular disease, and even some cancers. Although studied as distinct pathways for decades, processes regulating eating and motivation are now thought to be driven by overlapping neural circuits. Studying this overlap may provide important insights into the basis of excess caloric intake and lead to the identification of novel pharmacological targets for treating metabolic diseases, the long-term goal of our research. A potential novel and innovative target in this regard is neuromedin U (NMU), a peptide shown to suppress food intake and cause weight loss. These effects of NMU are related to its actions at the NMU receptor 2 (NMUR2) in the hypothalamus, particularly in the paraventricular nucleus (PVN), which is enriched for NMUR2. We have previously found that selective depletion of NMUR2 in the PVN of rats potentiates the intake of a high-fat diet, increases weight gain, and enhances a dietary preference specifically for fat but not sucrose. The goals of the present project are to explore NMUR2 signaling as a key interface between the hypothalamic and mesolimbic systems, and to further evaluate the action of NMUR2 agonists on feeding behavior. Our preliminary data indicate that NMUR2 neurons in the hypothalamus are directly connected to the nucleus accumbens, a key region of the mesolimbic system that regulates reward and motivated behavior. We have, for the first time, evaluated small-molecule NMUR2 agonists in vivo. Our preliminary data indicate that these compounds suppress feeding on a high-fat diet. To accomplish our goals, our Specific Aims are 1) To evaluate the structural link between the hypothalamic and mesolimbic circuits, 2) To establish a functional link between these areas involving enkephalins and opioid signaling, and 3) To determine if NMUR2 is a target to inhibit motivation for high-fat food and regulation of metabolic physiology. These aims will be achieved using such innovative technologies as viral-vector tracers to map neural pathways in the brain, optical clearing with CLARITY visualize these pathways in clarified, intact brains, and virus-mediated RNA interference study the effects of the NMUR2 gene on food intake, body weight, and motivation for food. Overall, these studies will lay the foundation for understanding neural pathways that regulate motivation for food, and for future work developing NMUR2-based therapeutics for the treatment of obesity.