In female mammals, reproductive senescence is a complex process involving progressive ovarian dysfunction, associated with altered central control of the hypothalamic-pituitary-gonadal axis and desynchronization of the circadian system. The objective of this study was to investigate daily- and age-dependent changes in the regulation of Arg-Phe amide-related peptide-3 (RFRP-3), a hypothalamic peptide involved in reproduction, and correlate those changes to the luteinizing hormone (LH) secretion in female C57BL/6 J mice of different age groups (4-, 13-, and 19- months old). Plasma LH levels were similar in diestrus mice from 4 to 13 months, but were markedly increased in 19 month-old mice. We found an age-dependent decrease in the total number of RFRP-3 neurons and in the relative number of activated (c-Fos-positive) RFRP-3 neurons. In 19 month-old mice also the daily variation in RFRP-3 neuronal activation was abolished. We found no daily- or age-dependent changes in the arginine vasopressin (AVP)- and vasoactive intestinal peptide (VIP)-fiber density in the dorsomedial hypothalamus. However, we did record a daily variation in the number of RFRP-3 neurons receiving close AVP- and VIP-ergic fiber appositions in 4 and 13 month- old, but not 19 month-old mice. The present findings indicate that RFRP-3 neurons are downregulated during old age and that the daily changes in their innervation by the circadian peptides, AVP and VIP, are abolished. This age-associated reduced rhythmic activity of the inhibitory RFRP-3 system could be implicated in the elevated LH secretion observed during reproductive senescence.

在雌性哺乳动物中，生殖衰老是一个复杂的过程，涉及进行性卵巢功能障碍，与下丘脑-垂体-性腺轴的中枢控制改变和昼夜节律系统的不同步有关。本研究的目的是研究 Arg-Phe 酰胺相关肽-3 (RFRP-3)（一种参与生殖的下丘脑肽）调节的日常和年龄依赖性变化，并将这些变化与促黄体激素相关联。 LH) 不同年龄组（4、13 和 19 个月大）的雌性 C57BL/6 J 小鼠的分泌。血浆 LH 水平在 4 至 13 个月的发情小鼠中相似，但在 19 个月大的小鼠中显着增加。我们发现 RFRP-3 神经元总数和激活（c-Fos 阳性）RFRP-3 神经元的相对数量随年龄增加而减少。在 19 个月大的小鼠中，RFRP-3 神经元激活的每日变化也被消除了。我们发现下丘脑背内侧的精氨酸加压素 (AVP) 和血管活性肠肽 (VIP) 纤维密度没有每日或年龄依赖性变化。然而，我们确实记录了在 4 和 13 个月大的小鼠中接受紧密 AVP 和 VIP 能纤维并用的 RFRP-3 神经元数量的每日变化，但不是 19 个月大的小鼠。目前的研究结果表明，RFRP-3 神经元在老年期间被下调，并且昼夜节律肽 AVP 和 VIP 对其神经支配的日常变化被消除。这种与年龄相关的抑制性 RFRP-3 系统节律活性降低可能与生殖衰老期间观察到的 LH 分泌升高有关。