Functional changes in GnRH neurons with age

描述(申请人提供)：本项目的目标是研究促性腺激素释放激素神经元随年龄增长的功能变化，这些变化可能有助于生殖衰老。哺乳动物的生殖在很大程度上取决于促性腺激素释放激素(GnRH)的适当神经分泌。GnRH的脉冲性释放，导致垂体前叶促性腺激素的脉冲性释放，对于维持男性和女性的正常生殖功能是必要的。在绝经前和绝经期间，下丘脑水平会发生一些变化，包括GnRH活性的变化。这项研究旨在确定GnRH神经元的内源性事件活动和/或兴奋性氨基酸受体表达是否随年龄和生殖状态的变化而变化。直到最近，由于细胞的分散分布和均匀的外观，GnRH系统的功能研究一直是极其困难的。然而，在GnRH神经元中表达增强型绿色荧光蛋白(EGFP)的转基因小鼠的发展为GnRH功能的研究提供了一个有前途的新模型。对幼年、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学研究。所有的动物都将被切除卵巢；一半的动物将被雌激素替代。功能研究将检测这些组的自发和诱发活动、离子通道和兴奋性氨基酸受体表达的变化。随着年龄的增长，促性腺激素释放激素神经元水平的变化将显著影响生殖功能。更年期的过渡对老年女性的身体和情感都有重大影响。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。

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.