Melanin-concentrating hormone and the neural regulation of feeding

项目总结/摘要 肥胖及其相关的合并症对公共卫生造成了重大负担，现有的治疗方法 只有最低限度的效果或具有重大的不利后果。大脑在调节 能量平衡黑色素浓集激素（MCH）是一种主要在外侧皮质产生的神经肽， 下丘脑区（LHA）增加能量摄入和体重增加，因此最近有兴趣 在开发肥胖症的治疗方法，阻断MCH的吞噬作用。初步数据表明， 除了一般增加食物摄入量外，MCH还通过调节食物摄入量， 食欲机制，如食物冲动和可口食物的条件性位置偏好。 此外，这些机制可以归因于MCH神经元回路的特定节点，例如 腹侧海马（vHP），一个含有高水平MCH受体的区域，但MCH的功能 关于进食行为，以前没有研究过。通过对妇幼保健体系的研究， 它的贡献，中央调节摄食行为，主要目标，拟议的5年 研究职业发展计划是为了方便申请人从研究助理教授的过渡 终身制助理教授与独立的R 01资金。拟议的研究将使 申请人掌握几种基于病毒的神经解剖学和化学遗传学技术，啮齿动物行为学 范例，高分辨率全脑映射与功能连接分析。使用这些 技术，她将确定MCH到vHP神经元回路在介导进食行为中的作用， 这一途径与肥胖的相关性，并将确定侧支投射，功能连接， 下游目标Specific Aim 1利用双重病毒化学遗传学技术选择性激活MCH 神经元投射到vHP，以研究vHP à MCH神经元回路在介导 喂养行为的几个方面。Specific Aim 2使用基于病毒的神经追踪、免疫组织化学和 原位杂交，以进一步表征这些神经元的侧支投射和表型 基因/蛋白质表达谱。目的3使用双病毒化学遗传学与全 脑灌注映射，以确定通过激活MCH神经元参与的下游区域， VHP。此外，目标3中的实验将确定MCH到vHP神经元回路如何增强 食物冲动时的大脑区域活动这种新颖的方法组合允许调查 激活特定回路的特定节点与即时行为效应之间的相互作用。 这些实验的结果将作为申请人提交的R 01的试验数据， 为摄食行为研究做出重大贡献，并将为申请人提供 为她的独立研究生涯提供了一套独特的技能。

Project Summary/Abstract Obesity and its associated comorbidities pose a major burden to public health, and existing therapeutics are only minimally effective or have major adverse consequences. The brain plays a central role in mediating energy balance. Melanin-concentrating hormone (MCH), a neuropeptide produced primarily in the lateral hypothalamic area (LHA) increases energy intake and body weight gain, and therefore there is recent interest in developing obesity therapeutics that block the hyperphagic effects of MCH. Preliminary data herein suggest that in addition to generally increasing food intake, MCH contributes to excessive feeding via conditioned appetitive mechanisms, such as food impulsivity and conditioned place preference for palatable food. Furthermore, these mechanisms can be attributed to specific nodes of MCH neuronal circuitry such as the ventral hippocampus (vHP), a region that contains high levels of MCH receptor but where the function of MCH with regard to feeding behavior has not previously been investigated. Through studying the MCH system and its contributions to the central regulation of ingestive behavior, the principal goal of the proposed 5-year research career development plan is to facilitate the applicant's transition from Research Assistant Professor to Tenure-track Assistant Professor with independent R01 funding. The proposed research will enable the applicant to master several virus-based neuroanatomical and chemogenetic techniques, rodent behavioral paradigms, high- resolution whole brain mapping with functional connectivity analyses. Using these techniques, she will determine the role of MCH to vHP neuronal circuitry in mediating feeding behavior, the relevance of this pathway to obesity, and will identify collateral projections, functional connections, and downstream targets. Specific Aim 1 utilizes dual virus chemogenetic techniques to selectively activate MCH neurons that project to the vHP in order to study the role of vHPà MCH neuronal circuitry in mediating several aspects of feeding behavior. Specific Aim 2 uses viral-based neural tracing, immunohistochemistry and in situ hybridization to further characterize these neurons by their collateral projections and phenotypic gene/protein expression profiles. Aim 3 uses the novel combination of dual virus chemogenetics with whole brain perfusion mapping to determine downstream regions engaged by activating MCH neurons that project to the vHP. Additionally, experiments in Aim 3 will determine how MCH to vHP neuronal circuitry augments regional brain activity during food impulsivity. This novel combination of approaches allows for investigation of the interaction between activating specific nodes of a defined circuit and immediate behavioral effects. Results from these experiments will be generative as pilot data for an R01 submission by the applicant, will provide significant contributions to ingestive behavior research, and will overall provide the applicant with a unique set of skills for her independent research career.