Control of feeding behavior by melanin-concentrating hormone

黑色素浓缩激素控制进食行为

基本信息

批准号：
10152596
负责人：
Scott Edward Kanoski
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-23 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152596
关键词：
3-Dimensional Affect Amygdaloid structure Anatomy Anti-Obesity Agents Appetite Stimulants Behavior Behavior Therapy Behavioral Behavioral Mechanisms Biological Body Weight Brain Brain Mapping Brain region Cerebral Ventricles Cerebrospinal Fluid Chronic Communication Consumption Cues Data Detection Eating Feeding behaviors Fluorescent in Situ Hybridization Food Food Intake Regulation Health Care Costs High Fat Diet Histologic Image Immunohistochemistry Impulsivity In Situ Hybridization Injections Intake Lateral Hypothalamic Area Medial Mediating Messenger RNA Methods Mus Neural Pathways Neurobiology Neuromodulator Neurons Neuropeptides Nucleus Accumbens Obesity Output Palate Pathway interactions Peptides Pharmacology Pharmacotherapy Phenotype Population Prefrontal Cortex Prevalence Rattus Regional Blood Flow Research Resolution Rest Rewards Rodent Role Route Signal Pathway Signal Transduction Slice Structure Sucrose Synapses System Techniques Testing Transgenic Organisms United States Ventricular Viral Virus adverse outcome awake bariatric surgery base brain pathway circadian conditioned place preference diet-induced obesity experimental study feeding hormonal signals hormone deficiency increased appetite innovation insight interest melanin-concentrating hormone melanin-concentrating hormone receptor multimodality neural circuit neural network neurochemistry neuroimaging novel obesogenic overexpression receptor relating to nervous system success

项目摘要

7. Project Summary: Melanin-concentrating hormone is an neuropeptide produced primarily in the lateral hypothalamic area of the brain that potently increases appetite, food intake, and body weight 1,2. Importantly, chronic central pharmacological blockade of MCH receptors (MCH1Rs) reverses diet-induced obesity in mice 3,4 and therefore there is recent interest in developing obesity pharmacotherapies targeting the MCH system 5-8. While MCH-producing neurons extensively project throughout the brain 9 and central MCH1Rs are widely distributed 10, very little is presently known about the neuronal pathways and behavioral mechanisms mediating the potent orexigenic effects of MCH. Our preliminary data reveal that central MCH signaling in rats increases both normal chow intake as well as conditioned reward-based feeding behaviors, including impulsive responding and conditioned place preference for palatable food. We further identify two novel signaling targets through which MCH neurons promote orexigenic effects: [1] “bulk flow” signaling through the cerebral ventricles following MCH release into the cerebral spinal fluid (CSF), and [2] synaptic signaling to the nucleus accumbens shell (ACBsh), a brain substrate critically associated with learned aspects of food reward 11,12. We hypothesize that MCH CSF- and ACBsh-signaling pathways differentially regulate normal vs. reward-based feeding, respectively. This hypothesis is supported by our preliminary data showing that chemogenetic activation of ACBsh-projecting MCH neurons increases palatable food (sucrose, high fat diet) intake without affecting intake of bland chow, whereas CSF MCH injections equally increase intake of a less- and more- preferred food (chow vs. sucrose), and endogenous MCH CSF levels are elevated prior to regular nocturnal chow intake. Our hypothesis will be examined in Aim 1, where we investigate the effects of chemogenetic activation of specific MCH neuronal populations that project to either the CSF or the ACBsh on various feeding behaviors (e.g., habitual, circadian, conditioned reward-based). Conditional virus-based neural pathway tracing strategies are used in Aim 2 in order to identify the collateral projections of CSF- and MCH-projecting MCH neurons, as well as the 2nd-order targets of MCH neurons that receive input from the medial prefrontal cortex and the basolateral amygdala, two brain regions that are critically involved in reward-based feeding 13. In conjunction with retrograde neural pathway tracing, neurochemical phenotyping of these populations of MCH neurons will be done using fluorescence in situ hybridization and immunohistochemistry techniques. Finally, Aim 3 utilizes a [14C]-iodoantipyrine-based autoradiographic brain mapping method to identify functional downstream neural systems through which MCH neurons elevate feeding. Results will reveal brain networks engaged by chemogenetic activation of ACBsh-projecting MCH neurons at resting state, during intake of palatable sucrose, and during presentation of a sucrose-conditioned cue. Neural networks engaged by activating CSF-projecting MCH neurons will also be identified, at resting state and during chow consumption. Overall, results from this proposal will identify the neurobiological pathways and behavioral mechanisms whereby MCH engages normal and reward-based feeding, thus contributing critical insight into feeding behavior, and advancing toward strategies to reverse excessive feeding.

7。项目摘要：黑色素浓缩马酮是一种神经肽，主要在后来产生大脑的下丘脑区域可能会增加食欲，食物摄入量和体重1,2。重要的是， MCH受体（MCH1R）的慢性中央药物阻断逆转小鼠饮食诱导的肥胖症 3,4因此，最近有兴趣开发针对MCH系统的肥胖药物治疗5-8。虽然产生MCH的神经元在整个大脑中广泛发射，而中央MCH1R则广泛地发射分布式10，几乎没有关于神经元途径和行为机制的介绍介导MCH的潜在侵蚀性作用。我们的初步数据表明，大鼠中央MCH信号传导增加正常的食物摄入量和条件奖励的喂养行为，包括冲动响应和条件的地方偏爱可口的食物。我们进一步确定了两个新的信号目标 MCH神经元通过其促进侵入性作用：[1]通过大脑的“大量流动”信号传导 MCH释放到大脑脊髓液（CSF）和[2]突触信号转导向细胞核之后，心室 Accumbens Shell（ACBSH），这是一种与食品奖励的学术方面至关重要的11,12。我们假设MCH CSF和ACBSH信号途径不同地调节了正常与奖励基于奖励分别喂食。我们的初步数据证明了这一假设 ACBSH预测的MCH神经元的激活增加了可口食品（蔗糖，高脂饮食）摄入量没有影响淡淡的食物的摄入量，而CSF MCH注射也同样增加了较少和更多的摄入量首选的食物（食物与蔗糖）和内源性MCH CSF水平在常规夜间之前升高食用。我们的假设将在AIM 1中进行检查，我们研究化学发生的作用在各种喂养的情况下激活将CSF或ACBSH投射到CSF或ACBSH的激活行为（例如习惯，昼夜节律，基于条件奖励）。基于条件病毒的神经途径 AIM 2使用跟踪策略，以确定CSF和MCH项目的附带项目 MCH神经元以及MCH神经元的二阶靶标，这些靶标的是从介质前额叶接收输入的皮层和基底外侧杏仁核，这两个大脑区域与奖励基于奖励的进食13。与逆行神经通道追踪结合在一起，这些种群的神经化学表型 MCH神经元将使用荧光原位杂交和免疫组织化学技术进行。最后，AIM 3利用[14C] - 碘antipyrine的基于碘的放射自显影脑映射方法来识别 MCH神经元升高进食的功能性下游神经元系统。结果将显示大脑在摄入期间，通过在静止状态下ACBSH预测的MCH神经元的化学发生激活参与的网络可口的蔗糖，以及在蔗糖条件的提示期间。由在静止状态和食用期间，还将确定激活CSF投射MCH神经元。总体而言，该提案的结果将确定神经生物学途径和行为机制 MCH可以参与正常和奖励的喂养，从而有助于喂养饲料行为，并朝着逆转过量喂养的策略前进。