Abstract
In females, estrogens have two main modes of action relating to gonadotropin secretion: positive feedback and negative feedback. Estrogen positive and negative feedback are controlled by different regions of the hypothalamus: the preoptic area/anterior portion (mainly the anteroventral periventricular nucleus, AVPV) of the hypothalamus is associated with estrogen positive feedback while the mediobasal hypothalamus (mainly the arcuate nucleus of the hypothalamus, ARH), is associated with estrogen negative feedback. In this study, we examined the temporal pattern of gene transcription in these two regions following estrogen treatment. Adult, ovariectomized, Long Evans rats received doses of estradiol benzoate (EB) or oil every 4 days for 3 cycles. On the last EB priming cycle, hypothalamic tissues were dissected into the AVPV+ and ARH+ at 0 hrs (baseline/oil control), 6 hrs, or 24 hrs after EB treatment. RNA was extracted and sequenced using bulk RNA sequencing. Differential gene analysis, gene ontology, and weighted correlation network analysis (WGCNA) was performed. Overall, we found that the AVPV+ and ARH+ respond differently to estradiol stimulation. In both regions, estradiol treatment resulted in more gene up-regulation than down-regulation. S100g was very strongly up-regulated by estradiol in both regions at 6 and 24 hrs after EB treatment. In the AVPV+ the highest number of differentially expressed genes occurred 24 hrs after EB. In the ARH+, the highest number of genes differentially expressed by EB occurred between 6 and 24 hrs after EB, while in the AVPV+, the fewest genes changed their expression between these time points, demonstrating a temporal difference in the way that EB regulates transcription these two areas. Several genes strongly implicated in gonadotropin release were differentially affected by estradiol including Esr1, encoding estrogen receptor-α and Kiss1, encoding kisspeptin. As an internal validation, Kiss1 was up-regulated in the AVPV+ and down-regulated in the ARH+. Gene network analysis revealed the vastly different clustering of genes modulated by estradiol in the AVPV+ compared with the ARH+. These results indicate that gene expression in these two hypothalamic regions have specific responses to estradiol in timing and direction.
Highlights
In females, estrogen signaling in the hypothalamus elicits two different feedback loops that regulate reproduction
Genes such as Pomc and Npvf were very strongly upregulated in the arcuate nucleus of the hypothalamus (ARH)+, whereas genes such as Gnrh1 and Chat were very strongly upregulated in the anteroventral periventricular nucleus (AVPV)+
At baseline 57% of genes were upregulated in the ARH+ compared with the 43% that were upregulated in the AVPV+ (826 genes higher in ARH+ vs. 632 genes higher in AVPV+)
Summary
Estrogen signaling in the hypothalamus elicits two different feedback loops that regulate reproduction. The primary mediator of both estrogen negative and positive feedback appears to be the kisspeptin neurons, Kisspeptin neurons in the arcuate nucleus of the hypothalamus (ARH) mediate estrogen negative feedback and the pulsatile release of GnRH [1,2,3,4], while kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediate positive feedback [5,6,7]. Sex differences in these kisspeptin populations correspond to functional sex differences in estrogen feedback. While there is no sex difference in number of ARH kisspeptin neurons [8], in the AVPV, females have a larger population of kisspeptin neurons, which control positive feedback, which is only present females [9]
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