Control of feeding behavior by melanin-concentrating hormone

7.项目概述：黑色素浓集激素是一种神经肽，主要产生于外侧 大脑的下丘脑区域，有效地增加食欲，食物摄入量和体重1，2。重要的是， 慢性中枢药物阻断MCH受体（MCH 1 Rs）可逆转小鼠饮食诱导的肥胖 3，4，因此最近人们对开发靶向MCH系统的肥胖药物疗法感兴趣5-8。 虽然产生MCH的神经元广泛地投射到整个大脑9和中央MCH 1 R广泛地投射到大脑9和中央MCH 1 R。 由于神经元的分布，目前对神经元通路和行为机制知之甚少 介导MCH的强有力的促食欲作用。我们的初步数据显示，大鼠中枢MCH信号 增加正常的食物摄入量以及有条件的奖励为基础的喂养行为，包括冲动 对可口食物的反应性和条件性位置偏好。我们进一步确定了两个新的信号转导靶点 MCH神经元通过其促进食欲作用：[1]通过大脑的“整体流”信号传导 MCH释放到脑脊髓液（CSF）后的心室，[2]突触信号传递到核 贝壳（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 分别喂食。这一假设得到了我们初步数据的支持，这些数据表明， ACBsh投射MCH神经元的激活增加了可口食物（蔗糖、高脂肪饮食）的摄入， 影响清淡食物的摄入，而CSF MCH注射同样增加了较少和较多的 首选食物（食物vs.蔗糖）和内源性MCH CSF水平在定期夜间给药前升高 食物摄入量。我们的假设将在目标1中进行检验，在那里我们研究了化学遗传学的影响。 激活特定的MCH神经元群体，这些神经元群体在各种喂养下投射到CSF或ACBsh 行为（例如，习惯性的、昼夜节律的、基于条件性奖励的）。条件性病毒神经通路 在目标2中使用追踪策略，以识别CSF和MCH投射的侧支投射 MCH神经元，以及MCH神经元的二阶目标，其接收来自内侧前额叶的输入 皮质和基底外侧杏仁核，这两个大脑区域与基于奖励的进食密切相关13。 结合逆行神经通路追踪，这些人群的神经化学表型， 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，目标3利用基于[14 C]-碘安替比林的放射自显影脑成像方法来识别 MCH神经元通过其提升进食的功能下游神经系统。结果将揭示大脑 网络从事化学发生激活ACBsh投射MCH神经元在静息状态下，在摄入 可口的蔗糖，并在介绍蔗糖条件的线索。神经网络参与了 在静息状态和进食期间，也将鉴定激活的CSF投射MCH神经元。 总的来说，这项建议的结果将确定神经生物学途径和行为机制 借此，妇幼保健从事正常和奖励为基础的喂养，从而有助于关键的洞察喂养 行为，并朝着扭转过度喂养的战略前进。

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.