Melanin-concentrating hormone and the neural regulation of feeding

项目摘要/摘要 肥胖及其相关的合并症是公共卫生的主要负担，现有的治疗方法 只有最小的效果或有重大的不良后果。大脑在中介中起着中心作用。 能量平衡。黑色素浓缩激素(MCH)是一种主要在大脑外侧区产生的神经肽。 下丘脑区(LHA)增加能量摄入和体重增加，因此最近引起了人们的兴趣。 在开发肥胖治疗方法以阻断MCH的肥大效应方面。这里的初步数据表明 除了普遍增加食物摄入量外，妇幼保健还会通过条件化的方式导致过度喂养 食欲机制，如食物冲动和对美味食物的条件性地点偏好。 此外，这些机制可以归因于MCH神经元电路的特定节点，如 腹侧海马区(VHP)，含有高水平的MCH受体，但MCH的功能 关于摄食行为，以前还没有进行过调查。通过对妇幼保健院制度的研究， 它对中央调节摄入行为的贡献，这是拟议的5年期的主要目标 研究职业发展计划是为申请者从研究助理教授过渡提供便利 到终身教席的助理教授，由独立的R01资助。拟议的研究将使 申请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 范例，高分辨率全脑地形图和功能连接分析。使用这些 技术，她将确定MCH到VHP神经元回路在调节摄食行为中的作用， 这一途径与肥胖的相关性，并将确定侧支投射、功能联系和 下游目标。特异性目标1利用双重病毒化学发生技术选择性地激活MCH 投射到VHP的神经元，以研究VHP？MCH神经元回路在调节 摄食行为的几个方面。特定目标2使用基于病毒的神经追踪，免疫组织化学和 原位杂交通过侧支投射和表型进一步确定这些神经元的特征 基因/蛋白质表达谱。AIM 3使用双病毒化学遗传学和全病毒的新组合 脑灌注图确定下游区域，通过激活MCH神经元投射到 VHP。此外，AIM 3中的实验将确定MCH到VHP的神经元回路如何增强 食物冲动时的局部大脑活动。这种新颖的方法组合允许进行调查 激活已定义电路的特定节点与即时行为效果之间的相互作用。 这些实验的结果将作为申请人提交R01的试点数据，Will 对摄食行为研究做出重大贡献，并将全面为申请者提供 为她的独立研究事业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.