AGE-RELATED LOSS OF CYCLICITY--LHRH NEURONAL DYSFUNCTION

年龄相关的循环性丧失——LHRH 神经元功能障碍

• 批准号: 2758792
• 负责人: BEVERLY S RUBIN
• 金额: $ 22.09万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2758792
• 关键词: GABA receptor; NMDA receptors; aging; antisense nucleic acid; bicuculline; excitatory aminoacid; gamma aminobutyrate; gene expression; genetic transcription; glutamates; gonadotropin releasing factor; high performance liquid chromatography; in situ hybridization; juvenile animal; laboratory rat; luteinizing hormone; mature animal; messenger RNA; neural transmission; neuroendocrine system; preoptic areas; secretion; sex cycle

Reproductive cycles cease relatively early in the life-span of female mammals. Whereas alterations at all levels of the hypothalamic- pituitary-ovarian axis occur with age, considerable evidence confirms the importance of altered hypothalamic function to reproductive decline in female rodents. In contrast menopause is correlated with the loss of follicular reserves in the ovary and not routinely associated with hypothalamic dysfunction: however, recent studies reveal altered gonadotropin levels prior to the perimenopausal period and accelerated follicular loss in the 10 years prior to menopause. The potential contribution of altered patterns of gonadotropin secretion to follicular loss remains to be determined. Because luteinizing hormone releasing hormone (LHRH) is the primary signal regulating pituitary gonadotropin secretion, understanding the cause of age-related alterations in LHRH neuronal function are pivotal to unraveling the mechanisms of reproductive aging. Our studies have consistently revealed deficits in LHRH neuronal activity in aging female rats in conjunction with the spontaneous or steroid-induced LH surge, times of increased demand for LHRH secretion and biosynthesis. Alterations in excitatory and inhibitory influences on LHRH secretion have been identified with age and may be sufficient to explain the deficits observed in LHRH neuronal function. However, whether LHRH neurons in aging animals remain capable of responding to the relevant signals with significantly increased levels of gene transcription, biosynthesis and secretion remains to be determined. The studies in the present proposal test the following hypotheses: 1) LHRH gene transcription is markedly reduced in middle-aged females on the day of an LH surge; 2) reduced LHRH gene expression contributes to attenuation of the LH surge, and 3) diminished excitatory influences and / or increased inhibitory influences contribute to the marked decline in LHRH neuronal function with age. The studies proposed will determine if modulation of excitatory and inhibitory neurotransmission can enhance the normally diminished levels of LHRH neuronal activity in middle-aged females.

在女性的生命中，生殖周期相对较早就停止了 哺乳动物。 而下丘脑的各个级别的改变 大量证据证实，垂体 - 伏安的轴随着年龄的增长而发生 下丘脑功能变化对生殖下降的重要性 在女啮齿动物中。 相反的更年期与损失相关 卵巢中的卵泡储量，而与 下丘脑功能障碍：但是，最近的研究表明 围产期之前的促性腺激素水平，并加速 绝经前10年的卵泡损失。 潜力 促性腺激素分泌模式改变对卵泡的贡献 损失仍有待确定。 因为黄体生成激素释放激素（LHRH）是主要的 信号调节垂体性促性腺激素分泌，了解 LHRH神经元功能中与年龄相关的改变原因是关键 阐明生殖衰老的机制。 我们的研究有 始终揭示了女性衰老的LHRH神经元活性的缺陷 大鼠与自发或类固醇引起的LH激增一起 对LHRH分泌和生物合成的需求增加。 兴奋性和抑制性影响LHRH分泌的改变 已经被确定了年龄，可能足以解释 LHRH神经元功能中观察到的缺陷。但是，是否LHRH 衰老动物的神经元仍然能够对相关的反应 基因转录水平显着增加的信号， 生物合成和分泌仍有待确定。 研究 目前的提案测试以下假设：1）LHRH基因 当天，中年女性的转录显着减少 LH激增； 2）降低LHRH基因表达有助于衰减 LH激增，3）减少兴奋性影响和 /或 抑制作用增加导致LHRH明显下降 与年龄的神经元功能。 提出的研究将确定是否 调节兴奋性和抑制性神经传递可以增强 中年的LHRH神经元活性的通常降低 女性。