Control of Gonadotropin Secretion during Lactation

哺乳期促性腺激素分泌的控制

• 批准号: 7931157
• 负责人: M. SUSAN SMITH
• 金额: $ 17.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931157
• 关键词: Ablation; Adult; Agonist; Amenorrhea; Anorexia Nervosa; Antisense Oligonucleotides; Chronic; Eating; Electrophysiology (science); Exercise; Fasting; Fiber; Food Intake Regulation; Goals; Gonadotropins; Hyperphagia; Hypothalamic structure; Insulin; Lactation; Lead; Leptin; Link; Malnutrition; Measures; Messenger RNA; Milk; Modeling; Neurokinin B; Neuromedin K Receptor; Neurons; Neuropeptides; Neurosecretory Systems; Obesity; Peripheral; Physiological; Play; Production; Rattus; Regulation; Research Personnel; Role; Signal Transduction; Stimulus; Structure of dorsomedial hypothalamic nucleus; Structure of nucleus infundibularis hypothalami; Study models; System; Techniques; Transgenic Organisms; Woman; density; energy balance; feeding; hypocretin; insight; interdisciplinary approach; loss of function; melanin-concentrating hormone; neuronal cell body; programs; receptor; relating to nervous system; reproductive; reproductive function; research study; restoration

DESCRIPTION (provided by applicant): The central hypothesis of this proposal is that suppression of GnRH/LH secretion during lactation is due to suckling- induced alterations in hypothalamic neural systems that regulate food intake and energy balance. Lactation is characterized by an excessive hyperphagia and negative energy balance due to milk production. Our studies have established that several hypothalamic neuropeptide orexigenic systems involved in regulating food intake/energy balance (NPY, orexin, melanin concentrating hormone [MCH], neurokinin B [NKB}) make direct connections with GnRH neurons, thus providing a neuroanatomical framework by which signals denoting changes in food intake/energy balance can be directly transmitted to GnRH neurons. The proposed studies will use a multidisciplinary approach to explore the following basic questions: 1) Do orexigenic and anorexigenic neuropeptides directly modulate GnRH neuronal activity and exert an increased inhibitory tone during lactation? Studies will use hypothalamic explants and electrophysiology to determine if agonists and antagonists to NPY, orexin, MCH or NKB receptors have direct effects on GnRH neurons. 2) Is the lactation-specific induction of NPY in the dorsomedial hypothalamic nucleus involved in the suppression of GnRH activity? Studies will examine the functional role of the suckling-specific induction of NPY in the suppression of GnRH/LH. 3) Are the profound suppression of leptin and the hypoinsulinemia associated with lactation important permissive signals that allow arcuate nucleus neurons to drive the suppression of GnRH neuronal activity and hyperphagia? Studies will restore leptin and insulin to postlactation levels and determine effects on hypothalamic neuropeptide feeding systems and on restoration of GnRH/LH secretion. Subsequent experiments will use ablation techniques to determine the functional relevance of identified factors in the suppression of GnRH neuronal activity during lactation. The lactating rat provides a physiological model for studying a number of conditions in women (undernutrition, anorexia nervosa, bulimia, exercise-induced amenorrhea and lactation) that involve a suppression of reproductive function associated with negative energy balance. The lactating rat is also a model of chronic hyperphagia and provides the opportunity to study physiological mechanisms underlying conditions of greatly increased food intake and may provide insights into causes of obesity.

描述(申请人提供)：这项建议的中心假设是，哺乳期间GnRH/LH分泌的抑制是由于哺乳引起调节食物摄取和能量平衡的下丘脑神经系统的改变。哺乳期的特点是过度吞噬和由于产奶而导致的能量负平衡。我们的研究已经证实，参与调节食物摄入/能量平衡的几个下丘脑神经肽促食欲素系统(NPY、增食欲素、黑色素浓缩激素[MCH]、神经激肽B[NKB})与GnRH神经元直接联系，从而提供了一个神经解剖学框架，通过该框架，指示食物摄入/能量平衡变化的信号可以直接传递到GnRH神经元。建议的研究将使用多学科的方法来探索以下基本问题：1)厌食和厌食神经肽是否直接调节GnRH神经元的活动，并在哺乳期间施加增加的抑制性张力？研究将使用下丘脑的外植体和电生理学来确定NPY、食欲素、MCH或NKB受体的激动剂和拮抗剂是否对GnRH神经元有直接影响。2)下丘脑背内侧核内分泌NPY是否参与了GnRH活性的抑制？研究将考察哺乳特异性诱导NPY在抑制GnRH/LH中的功能作用。3)Leptin的显著抑制和与哺乳相关的低胰岛素血症是否是允许弓状核神经元驱动抑制GnRH神经元活动和吞噬功能的重要允许信号？研究将使瘦素和胰岛素恢复到哺乳期后的水平，并确定对下丘脑神经肽喂养系统和恢复GnRH/LH分泌的影响。随后的实验将使用消融技术来确定在哺乳期抑制GnRH神经元活动的已确定因素的功能相关性。哺乳期大鼠为研究女性的多种情况(营养不良、神经性厌食症、暴食症、运动性闭经和哺乳期)提供了一个生理模型，这些情况涉及与负能量平衡相关的生殖功能抑制。哺乳期大鼠也是慢性吞噬症的模型，为研究食物摄入量大幅增加的潜在生理机制提供了机会，并可能为肥胖的原因提供见解。