Control of feeding behavior by melanin-concentrating hormone

7.项目总结：黑色素浓缩激素是一种主要在大脑外侧区产生的神经肽 大脑下丘脑区域，能有效增加食欲、食物摄入量和体重1，2。 慢性中枢药物阻断MCH受体逆转饮食诱导的小鼠肥胖 3，4，因此最近有兴趣开发针对MCH系统5-8的肥胖药物疗法。 而产生MCH的神经元广泛投射到整个大脑9和中枢MCH1Rs广泛 分布10，目前对神经元通路和行为机制知之甚少 介导了MCH的强烈促食欲作用。我们的初步数据显示，大鼠的中枢MCH信号 增加正常食物摄入量以及基于条件奖赏的喂养行为，包括冲动 对美味食物的反应和条件性的地点偏好。我们进一步确定了两个新的信号靶标 MCH神经元通过其促进食欲效应：[1]大脑中的“体流”信号 脑室后的MCH释放到脑脊液(CSF)，和[2]突触信号到核 伏隔膜(ACBsh)，一种大脑底物，与学习的食物奖励11，12密切相关。 假设MCH、CSF和ACBsh信号通路对正常和基于奖赏的信号通路有不同的调节作用 分别取食。这一假设得到了我们的初步数据的支持，这些数据表明，化学发生 激活ACBsh投射的MCH神经元增加美味食物(蔗糖、高脂饮食)的摄入量 影响平淡食物的摄入量，而注射脑脊液MCH同样增加了摄入量-和更多-更少- 更喜欢的食物(食物与蔗糖)和内源性MCH-CSF水平在正常夜间活动之前升高 进食量。我们的假设将在目标1中得到检验，在那里我们将研究化学发生的影响 在不同的摄食过程中投射到脑脊液或ACBsh的特定MCH神经元群的激活 行为(例如，习惯性的、昼夜节律的、基于条件奖励的)。基于条件病毒的神经通路 在目标2中使用跟踪策略以识别投射脑脊液和母婴的侧支投射 MCH神经元以及接受内侧前额叶输入的MCH神经元的二级靶点 大脑皮层和基底外侧杏仁核，这两个大脑区域与基于奖励的喂养密切相关13。 结合逆行神经通路追踪，这些人群的神经化学表型 将利用荧光原位杂交和免疫组织化学技术对MCH神经元进行研究。 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 功能性下游神经系统，MCH神经元通过该系统提升摄食。结果将揭示大脑 摄食时ACBsh投射的MCH神经元在静息状态下的化学激活所参与的网络 可口的蔗糖，以及在呈现蔗糖条件的提示时。所使用的神经网络 在静息状态和进食期间，也将发现激活脑脊液投射的MCH神经元。 总体而言，这项提议的结果将确定神经生物学途径和行为机制 因此，妇幼保健院从事正常的和基于奖励的喂养，从而有助于对喂养的关键洞察力 行为，并朝着扭转过度进食的策略前进。

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.