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.

调节进食行为和繁殖的神经系统双向交流， 门生殖事件和调节能量储存的生殖状态的变化， 怀孕。黑皮质素-3受体（MC 3R）在多个细胞核中表达， 生殖和能量稳态，如弓状核的AgRP神经元，以及 在人类和小鼠中的表达水平上表现出很大的性二态性。损失 MC 3R对雌性动物具有特别深远的影响。首先，我们展示 MC 3R对禁食诱导的女性HPG轴抑制至关重要。二是 已经确定了在MC 3R缺失的情况下摄食行为中迷人的性二态性。为 例如，在新奇抑制摄食（NSF）试验中，禁食动物必须进入 开放领域检索食物，MC 3RKO雄性吃等量的WT小鼠，而雌性 MC 3RKO无法探索，并完全停止进食。相比之下，雄性而非雌性小鼠 表现出强烈的厌食症。AgRP神经元，其中大多数 表达MC 3R，将有关营养状况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（PVN） 臂旁核（PB 1），并间接投射到岛叶皮质，参与感觉神经元的活动。 食物线索的解释和神经性厌食症的病理生理学的牵连。这 该提案将首次对MC 3R神经元进行系统的映射和表征 参与协调能量平衡、生殖和进食行为， 确定MC 3R对禁食诱导的 抑制HPG轴，并确定MC 3R神经元和电路介导的性 二型摄食行为