Control of feeding behavior by melanin-concentrating hormone

黑色素浓缩激素控制进食行为

• 批准号: 9923654
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-23 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923654
• 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; Diet; 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; 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

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. 项目概要：黑色素浓缩激素是一种主要在侧脑室产生的神经肽 大脑下丘脑区域，可有效增加食欲、食物摄入量和体重 1,2。重要的是， 慢性中枢药理学阻断 MCH 受体 (MCH1R) 可逆转小鼠饮食诱导的肥胖 3,4 因此，最近人们对开发针对 MCH 系统的肥胖药物疗法产生了兴趣 5-8。 虽然产生 MCH 的神经元广泛投射到整个大脑 9 并且中枢 MCH1R 广泛分布在整个大脑中。 分布10，目前对神经元通路和行为机制知之甚少 介导 MCH 的有效促食欲作用。我们的初步数据显示大鼠中枢 MCH 信号传导 增加正常的食物摄入量以及条件性奖励喂养行为，包括冲动 对可口食物的反应和条件偏好。我们进一步确定了两个新的信号传导目标 MCH 神经元通过其促进食欲产生作用：[1] 通过大脑的“大量流”信号传导 MCH 释放到脑脊液 (CSF) 后的脑室，以及 [2] 向细胞核发出突触信号 伏隔核壳 (ACBsh)，一种与食物奖励的学习方面密切相关的大脑基质 11,12。我们 假设 MCH CSF 和 ACBsh 信号通路对正常与基于奖励的信号通路有不同的调节作用 分别喂食。我们的初步数据支持了这一假设，表明化学遗传学 激活 ACBsh 投射的 MCH 神经元可增加可口食物（蔗糖、高脂肪饮食）的摄入量，而无需 影响清淡食物的摄入量，而脑脊液 MCH 注射同样会增加较少和较多食物的摄入量 首选食物（食物与蔗糖），并且内源性 MCH CSF 水平在常规夜间活动前升高 食物摄入量。我们的假设将在目标 1 中得到检验，我们将研究化学遗传学的影响 激活特定的 MCH 神经元群，这些神经元群在不同的进食情况下投射到 CSF 或 ACBsh 行为（例如习惯、昼夜节律、基于条件奖励的行为）。基于条件病毒的神经通路 目标 2 中使用追踪策略来识别 CSF 和 MCH 预测的附带预测 MCH 神经元，以及从内侧前额叶接收输入的 MCH 神经元的二阶目标 皮质和基底外侧杏仁核，这两个大脑区域在基于奖励的喂养中发挥着至关重要的作用 13. 结合逆行神经通路追踪，这些群体的神经化学表型分析 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 利用基于 [14C]-碘安替比林的放射自显影脑图方法来识别 MCH 神经元通过功能性下游神经系统提高摄食。结果将揭示大脑 在静息状态、摄入期间，由 ACBsh 投射的 MCH 神经元的化学遗传学激活参与的网络 美味的蔗糖，以及在呈现蔗糖条件提示期间。神经网络参与 在静息状态和进食期间，激活 CSF 投射的 MCH 神经元也将被识别。 总的来说，该提案的结果将确定神经生物学途径和行为机制 MCH 参与正常和基于奖励的喂养，从而为喂养提供重要的见解 行为，并制定扭转过度喂养的策略。