AGE-RELATED LOSS OF CYCLICITY--LHRH NEURONAL DYSFUNCTION

生殖周期在女性的生命周期中相对较早地停止 哺乳动物 下丘脑的各个层面都发生了变化- 垂体-卵巢轴随年龄增长而发生，大量证据证实 下丘脑功能改变对生殖能力下降的重要性 在雌性啮齿动物中。 相反，更年期与丧失 卵巢中的卵泡储备，而不是常规与 下丘脑功能障碍：然而，最近的研究表明， 促性腺激素水平在围月经期之前， 绝经前10年卵泡减少。 的潜在 促性腺激素分泌模式改变对卵泡发育的影响 损失仍有待确定。 因为促黄体生成激素释放激素（LHRH）是主要的 信号调节垂体促性腺激素分泌，了解 年龄相关的LHRH神经元功能改变的原因是关键的 生殖衰老的机制 我们的研究 在老年女性中，LHRH神经元活性的缺陷 大鼠结合自发或类固醇诱导的LH峰， 对LHRH分泌和生物合成的需求增加了一倍。 对LHRH分泌的兴奋性和抑制性影响的改变 已被确定与年龄，并可能足以解释 在LHRH神经元功能中观察到缺陷。无论LHRH 衰老动物的神经元仍然能够对相关的 基因转录水平显著增加的信号， 生物合成和分泌仍有待确定。 中研究 本研究拟验证以下假设：1）LHRH基因 转录在中年女性中显著减少， LH峰; 2）LHRH基因表达减少有助于衰减 LH峰，和3）减少兴奋性影响和/或 抑制作用的增强导致LHRH的显著下降 神经元功能随着年龄的增长。 拟议的研究将确定， 兴奋性和抑制性神经传递的调节可以增强 中年人LHRH神经元活性水平正常下降， 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.