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（由申请人提供）：该提案的中心假设是，哺乳期间GnRH/LH分泌的抑制是由于哺乳引起的下丘脑神经系统的改变，这些下丘脑神经系统调节食物摄入和能量平衡。泌乳的特征是由于牛奶的产生而导致过度的透明和负能量平衡。我们的研究已经确定，几种参与调节食物摄入/能量平衡（NPY，Orexin，黑色素浓缩激素[MCH]，Neurokinin b [NKB}）的下丘脑神经肽侵蚀性系统（NPY，Orexin，黑色素浓度GnRH神经元。拟议的研究将使用多学科的方法来探索以下基本问题：1）进行甲状腺素和厌食性神经肽直接调节GNRH神经元活性，并在哺乳过程中发挥抑制性张力？研究将使用下丘脑外植体和电生理学来确定对NPY，Orexin，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）在抑制GnRH活性抑制的背侧下丘脑核中NPY的泌乳特异性诱导是否？研究将研究NPY特异性诱导在GNRH/LH抑制中的功能作用。 3）对瘦素的深刻抑制和与泌乳相关的低胰岛素血症是否具有重要的允许信号，允许弓形核神经元驱动GNRH神经元活性和心phagia的抑制作用？研究将使瘦素和胰岛素恢复到腔术水平，并确定对下丘脑神经肽喂养系统以及GNRH/LH分泌的恢复的影响。随后的实验将使用消融技术来确定鉴于泌乳过程中GNRH神经元活性的识别因子的功能相关性。泌乳大鼠提供了一种生理模型，用于研究女性的许多疾病（营养不良，神经性厌食症，贪食症，运动诱导的闭经和泌乳），涉及抑制与负能量平衡相关的生殖功能。泌乳大鼠也是一种慢性多晶状体的模型，并提供了研究大大增加食物摄入量的生理机制的机会，并可能提供对肥胖症原因的见解。