Functional changes in GnRH neurons with age

GnRH 神经元的功能随年龄的变化

• 批准号: 7048305
• 负责人: M. CATHLEEN KUEHL-KOVARIK
• 金额: $ 9.84万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048305
• 关键词: AMPA receptors; NMDA receptors; age difference; aging; cell age; electrophysiology; estradiol; evoked potentials; female; genetically modified animals; gonadotropin releasing factor; hormone therapy; laboratory mouse; neurons; receptor expression; reproductive system; voltage /patch clamp

DESCRIPTION (provided by applicant): The goal of this project is to examine functional changes in the GnRH neuron with aging that may contribute to reproductive senescence. Reproduction in mammals is critically dependent upon the appropriate neurosecretion of gonadotropin-releasing hormone (GnRH). The pulsatile release of GnRH, resulting in the pulsatile release of gonadotropic hormones from the anterior pituitary, is necessary for the maintenance of normal reproductive function in both males and females. Before and during menopause, a number of changes occur at the level of the hypothalamus, including changes in GnRH activity. The studies outlined in this proposal are designed to determine if changes are seen in intrinsic episodic activity and/or excitatory amino acid receptor expression in GnRH neurons with age and reproductive status. Until recently, functional studies of the GnRH system have been extremely difficult, due to the scattered distribution and homogeneous appearance of cells. However, the development of a transgenic mouse that expresses enhanced green fluorescent protein (EGFP) in GnRH neurons is providing a promising new model for the study of GnRH function. Whole cell voltage-clamp and current clamp electrophysiology will be performed on isolated GnRH-EGFP neurons from young adult, middle-aged, and old female transgenic mice. All animals will be ovariectomized; half will be estrogen replaced. Functional studies will examine changes in spontaneous and evoked activity, ion channels, and excitatory amino acid receptor expression in these groups. Changes at the level of the GnRH neuron during aging would significantly influence reproductive function. The transition to menopause has a significant physical and emotional impact on aging women. Thus, it has become increasingly important to understand factors that contribute to reproductive aging and the transition to reproductive senescence.

描述（由申请人提供）：该项目的目标是研究GnRH神经元随年龄增长而发生的可能导致生殖衰老的功能变化。哺乳动物的生殖严重依赖于适当的促性腺激素释放激素（GnRH）的神经分泌。GnRH的脉动性释放导致垂体前叶促性腺激素的脉动性释放，对于维持男性和女性的正常生殖功能都是必要的。在绝经前和绝经期间，下丘脑水平发生了许多变化，包括GnRH活性的变化。本提案中概述的研究旨在确定GnRH神经元的内在发作性活动和/或兴奋性氨基酸受体表达是否随年龄和生殖状态而变化。直到最近，由于细胞的分散分布和均匀外观，GnRH系统的功能研究一直非常困难。然而，在GnRH神经元中表达增强绿色荧光蛋白（EGFP）的转基因小鼠的发展为GnRH功能的研究提供了一个有希望的新模型。将对青壮年、中年和老年雌性转基因小鼠分离的GnRH-EGFP神经元进行全细胞电压钳和电流钳电生理实验。所有动物的卵巢都将被切除；其中一半将被雌激素替代。功能研究将检查这些组中自发和诱发活性、离子通道和兴奋性氨基酸受体表达的变化。衰老过程中GnRH神经元水平的变化会显著影响生殖功能。更年期的过渡对老年妇女的身体和情绪都有重大影响。因此，了解导致生殖衰老和向生殖衰老过渡的因素变得越来越重要。