Hypothalamic Molecular Changes Underlying Natural Reproductive Senescence in the Female Rat
Hypothalamic Molecular Changes Underlying Natural Reproductive Senescence in the Female Rat
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DOI：
10.1210/en.2014-1017
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发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Gore, Andrea C.
中科院分区：
文献类型：
--
作者：
Kermath, Bailey A.;Riha, Penny D.;Gore, Andrea C.
下丘脑在女性生殖衰老中的作用尚不清楚。在这里，我们发现了新的分子神经内分泌变化，在中年雌性大鼠从有规律的生殖周期到无周期的自然过程中，与女性围绝经期的过程类似。对48个神经内分泌基因在下丘脑三个区域的表达进行了定量研究：前腹侧脑室周围核(GnRH神经元的正反馈部位)、弓状核(ARC)和正中隆起(ME)，弓状核(ARC)是负反馈和GnRH脉动性释放的部位；令人惊讶的是，大多数变化发生在ARC和ME，对前腹侧脑室周围核几乎没有影响。总体模式是中年大鼠的mRNA水平随着年龄的增长而升高，随着生殖周期的变化而下降。受影响的基因包括转录因子(Stat5b、Arnt、Ahr)、性激素受体(ESR1、Esr2、PGR、Ar)、类固醇生成酶(Sts、Hsd17b8)、生长因子(Igf1、Tgfa)和神经肽(Kiss1、Tac2、Gnrh1)。生物网络分析揭示了基因和荷尔蒙之间特定区域的相关性。ARC内Kispeptin和雌激素受体-α的免疫组织化学分析显示，Kispeptin细胞数量以及Kispeptin-雌激素受体-α双标记细胞的数量随年龄的增长而减少。综上所述，这些结果确定了ME和ARC在生殖下降过程中出人意料的强大作用，并强调了有规律周期的中年大鼠与所有其他组之间的根本差异。我们的数据提供了随着年龄的增长兴奋性刺激减少和激素反馈改变的证据，并提出了值得进一步研究的新的神经内分泌途径。此外，这些变化可能会影响其他神经内分泌系统，这些系统随着年龄的增长而出现功能衰退。
The role of the hypothalamus in female reproductive senescence is unclear. Here we identified novel molecular neuroendocrine changes during the natural progression from regular reproductive cycles to acyclicity in middle-aged female rats, comparable with the perimenopausal progression in women. Expression of 48 neuroendocrine genes was quantified within three hypothalamic regions: the anteroventral periventricular nucleus, the site of steroid positive feedback onto GnRH neurons; the arcuate nucleus (ARC), the site of negative feedback and pulsatile GnRH release; and the median eminence (ME), the site of GnRH secretion. Surprisingly, the majority of changes occurred in the ARC and ME, with few effects in anteroventral periventricular nucleus. The overall pattern was increased mRNA levels with chronological age and decreases with reproductive cycle status in middle-aged rats. Affected genes included transcription factors (Stat5b, Arnt, Ahr), sex steroid hormone receptors (Esr1, Esr2, Pgr, Ar), steroidogenic enzymes (Sts, Hsd17b8), growth factors (Igf1, Tgfa), and neuropeptides (Kiss1, Tac2, Gnrh1). Bionetwork analysis revealed region-specific correlations between genes and hormones. Immunohistochemical analyses of kisspeptin and estrogen receptor-alpha in the ARC demonstrated age-related decreases in kisspeptin cell numbers as well as kisspeptin-estrogen receptor-alpha dual-labeled cells. Taken together, these results identify unexpectedly strong roles for the ME and ARC during reproductive decline and highlight fundamental differences between middle-aged rats with regular cycles and all other groups. Our data provide evidence of decreased excitatory stimulation and altered hormone feedback with aging and suggest novel neuroendocrine pathways that warrant future study. Furthermore, these changes may impact other neuroendocrine systems that undergo functional declines with age.