AGE-RELATED LOSS OF CYCLICITY--LHRH NEURONAL DYSFUNCTION

生殖周期在雌性的生命周期中相对较早地停止 哺乳动物。而下丘脑所有级别的改变- 大量证据证实，垂体轴-卵巢轴随年龄增长而发生 下丘脑功能改变对生殖功能下降的重要性 在雌性啮齿动物身上。相比之下，更年期与体重的减少有关 卵巢中的卵泡储备，通常不会与 下丘脑功能障碍：然而，最近的研究显示 围绝经期前促性腺激素水平及加速 绝经前10年内卵泡丢失。潜力 促性腺激素分泌模式改变对卵泡的作用 损失仍有待确定。 因为促黄体生成素释放激素(LHRH)是 信号调节垂体促性腺激素的分泌，了解 年龄相关性LHRH神经元功能改变的原因是关键 来解开生殖衰老的机制。我们的研究已经 持续显示老年女性LHRH神经元活性缺陷 大鼠在自发或类固醇诱导的促黄体生成素激增的同时， 对LHRH分泌和生物合成的需求增加的次数。 LHRH分泌的兴奋性和抑制性影响的变化 都与年龄有关，并可能足以解释 观察到LHRH神经元功能缺陷。然而，LHRH是否 衰老动物的神经元仍然能够对相关的 基因转录水平显著提高的信号， 生物合成和分泌仍有待确定。《纽约时报》上的研究 目前的建议检验了以下假设：1)LHRH基因 中年女性的转录显著减少 促黄体生成素释放激素激增；2)促黄体生成素释放激素基因表达减弱 以及3)减少兴奋性影响和/或 抑制作用增强是导致LHRH显著下降的原因之一 神经元功能随年龄增长而变化。建议的研究将确定是否 兴奋性和抑制性神经传递的调节可以增强 中年人LHRH神经元活性正常降低 女性。

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.