Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor

Melanocortin-3 受体的性别二态性表达和功能

• 批准号: 10468942
• 负责人: Roger D. Cone
• 金额: $ 35.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468942
• 关键词: Androgen Receptor; Animals; Anorexia; Anorexia Nervosa; Axon; Behavior; Behavior Control; Biological Assay; Brain region; Candidate Disease Gene; Cell Nucleus; Cells; Cues; Data; Defect; Dependence; Disease; Eating; Electrophysiology (science); Estrogen Receptors; Estrogens; Event; Exhibits; Exposure to; Fasting; Feeding behaviors; Female; Food; Foundations; Functional disorder; GNRH1 gene; Gene Expression; Gestational Diabetes; Glutamates; Gonadal Steroid Hormones; Gonadotropins; Homeostasis; Hormones; Human; Image Analysis; Immunohistochemistry; In Situ Hybridization; Lateral; Lentivirus; Leptin; Masculine; Mediating; Medical; Melanocortin 3 Receptor; Metabolic; Metabolic Control; Metabolism; Methods; Mus; Neurons; Nutritional; Pattern; Phenotype; Population; Pregnancy; Regulation; Reproduction; RiboTag; Role; Sensory; Sex Differences; Signal Transduction; Slice; Steroids; Stress; Structure of nucleus infundibularis hypothalami; Structure of paraventricular nucleus of thalamus; System; Testing; Three-Dimensional Image; Time; Tracer; Ventral Tegmental Area; Woman; alpha-Melanocyte stimulating hormone; fascinate; feeding; hypothalamic pituitary gonadal axis; knock-down; leptin receptor; male; parabrachial nucleus; paraventricular nucleus; postnatal; postnatal development; receptor expression; relating to nervous system; reproductive; response; restoration; restraint stress; sexual dimorphism; small hairpin RNA; transcriptomics

Neural systems regulating feeding behavior and reproduction communicate bidirectionally to gate reproductive events and to regulate energy stores for changes in reproductive states, such as pregnancy. The melanocortin-3 receptor (MC3R) is expressed in multiple nuclei that regulate reproduction and energy homeostasis such as the AgRP neurons of the arcuate nucleus, and exhibits a large sexual dimorphism in its level of expression in both humans and mice. Loss of the MC3R has particularly profound consequences for female animals. First, we demonstrate that MC3R is essential for fasting-induced suppression of the HPG axis in females. Second, we have identified fascinating sexual dimorphisms in feeding behavior in the absence of MC3R. For example, In the novelty suppressed feeding (NSF) assay in which fasted animals must enter an open field to retrieve food, MC3RKO males eat equivalent amounts to WT mice, while female MC3RKO fail to explore, and cease feeding entirely. In contrast, male but not female mice exhibit enhanced anorexia in response to restraint stress. AgRP neurons, the majority of which express MC3R, send information regarding nutritional state directly to reproductive and metabolic control centers, like the PVH and AVPV, and to behavioral control centers like the ventral tegmental area (VTA), paraventricular nucleus of the thalamus (PVT), and lateral parabrachial nucleus (PBl), and project indirectly to the insular cortex, involved in sensory interpretation of food cues and implicated in the pathophysiology of anorexia nervosa. This proposal will conduct the first systematic mapping and characterization of the MC3R neurons involved in the coordination of energy homeostasis, reproduction and feeding behavior, determine the mechanism(s) underlying the requirement of MC3R for fasting-induced suppression of the HPG axis, and identify the MC3R neurons and circuits mediating sexually dimorphic feeding behaviors.

调节摄食行为和生殖的神经系统与 控制生殖事件并调节能量储备以应对生殖状态的变化，如 就像怀孕一样。黑素皮质素-3受体(MC3R)在多个核中表达，调节 生殖和能量平衡，如弓状核的AgRP神经元，以及 它在人类和小鼠中的表达水平显示出很大的性别二型性。损失 MC3R对雌性动物有着特别深远的影响。首先，我们演示 MC3R在禁食诱导的女性HPG轴抑制中是必不可少的。第二，我们 在缺乏MC3R的情况下，在进食行为中发现了迷人的性别二态。为 例如，在新奇抑制进食(NSF)试验中，禁食动物必须进入 开阔场地取食，MC3RKO雄鼠食量相当于WT小鼠，而雌鼠 MC3RKO无法探索，完全停止进食。相比之下，雄鼠而不是雌鼠 对束缚压力的反应表现出更强的厌食症。AgRP神经元，其中大部分 快递MC3R，将有关营养状态的信息直接发送给生殖和 代谢控制中心，如PVH和AVPV，以及行为控制中心，如 腹侧被盖区(VTA)、丘脑室旁核(PVT)和外侧核 臂旁核(PBL)，间接投射到岛叶皮质，参与感觉 对食物暗示的解释，并与神经性厌食症的病理生理学有关。这 Proposal将对MC3R神经元进行第一次系统的测绘和表征 参与能量平衡、繁殖和摄食行为的协调， 确定MC3R对禁食诱导需求的机制(S) 抑制HPG轴，并确定MC3R神经元和环路调节性 二态摄食行为。