RNA-sequencing of AVPV and ARH reveals vastly different temporal and transcriptomic responses to estradiol in the female rat hypothalamus.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Arcuate Nucleus of Hypothalamus/*metabolism ; Estradiol/*pharmacology ; Gene Expression Regulation/*drug effects ; Gonadotropin-Releasing Hormone/*metabolism ; Hypothalamus/*metabolism ; Hypothalamus, Anterior/*metabolism ; Sequence Analysis, RNA/*methods; Animals ; Arcuate Nucleus of Hypothalamus/drug effects ; Estrogen Receptor alpha/metabolism ; Estrogens/pharmacology ; Female ; Hypothalamus/drug effects ; Hypothalamus, Anterior/drug effects ; Kisspeptins/metabolism ; Models, Animal ; Ovariectomy/methods ; Rats ; Rats, Long-Evans

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.
Competing Interests: The authors have declared that no competing interests exist.

Brain Res. 2004 Nov 12;1026(2):307-12. (PMID: 15488494)
J Neurosci. 2008 Aug 27;28(35):8691-7. (PMID: 18753370)
Endocrinology. 2000 Nov;141(11):4218-25. (PMID: 11089556)
Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22693-8. (PMID: 21149719)
Endocrinology. 2018 Sep 1;159(9):3219-3234. (PMID: 30010844)
J Neurosci. 2010 Feb 24;30(8):3124-32. (PMID: 20181609)
J Neurosci Res. 1994 Jul 1;38(4):386-98. (PMID: 7932871)
Endocrinology. 2012 Jun;153(6):2800-12. (PMID: 22508514)
PLoS One. 2013 Nov 04;8(11):e79437. (PMID: 24223949)
Mol Endocrinol. 2014 Jan;28(1):99-115. (PMID: 24284824)
Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
J Neurosci. 2009 Sep 23;29(38):11859-66. (PMID: 19776272)
Neuron. 2006 Oct 19;52(2):271-80. (PMID: 17046690)
Brain Res Bull. 2019 Oct;152:225-235. (PMID: 31357009)
Curr Opin Endocr Metab Res. 2020 Oct;14:92-96. (PMID: 32832725)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Front Endocrinol (Lausanne). 2014 Jan 22;4:195. (PMID: 24478756)
Biol Reprod. 2004 Aug;71(2):669-75. (PMID: 15070829)
Mol Cell Endocrinol. 2002 Jun 14;191(2):177-86. (PMID: 12062901)
Front Endocrinol (Lausanne). 2019 Oct 09;10:676. (PMID: 31649619)
Genome Biol. 2010;11(2):R14. (PMID: 20132535)
Mol Cell Endocrinol. 1992 Jul;86(1-2):119-23. (PMID: 1511778)
Neuroendocrinology. 1994 Oct;60(4):337-45. (PMID: 7529897)
Nature. 1983 Jul 28-Aug 3;304(5924):345-7. (PMID: 6348552)
Endocrinology. 2018 Nov 1;159(11):3723-3736. (PMID: 30272161)
Neuroscience. 1992 Sep;50(2):283-98. (PMID: 1359459)
Neuroscience. 2015 Sep 10;303:312-22. (PMID: 26166732)
Endocrinology. 2010 Jan;151(1):301-11. (PMID: 19880810)
Endocrinology. 2005 Sep;146(9):3686-92. (PMID: 15919741)
Adv Exp Med Biol. 2013;784:385-410. (PMID: 23550016)
Endocrinology. 2017 Mar 1;158(3):612-626. (PMID: 28359086)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
Front Endocrinol (Lausanne). 2012 May 21;3:60. (PMID: 22661968)
BMC Bioinformatics. 2008 Dec 29;9:559. (PMID: 19114008)
Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):E10216-E10223. (PMID: 29109258)
J Mol Biol. 1994 Jan 28;235(4):1231-8. (PMID: 8308886)
Endocrinology. 2008 Dec;149(12):6113-24. (PMID: 18755790)
Brain Res. 2015 Mar 10;1600:42-58. (PMID: 25529630)
Endocrinology. 2007 Oct;148(10):4937-51. (PMID: 17595223)
Brain Res. 2005 Aug 30;1054(2):116-24. (PMID: 16084918)
Endocrinology. 2015 Feb;156(2):627-37. (PMID: 25422875)
Endocrinology. 2007 Dec;148(12):5752-60. (PMID: 17823266)

F32 HD097965 United States HD NICHD NIH HHS; R01 DA013185 United States DA NIDA NIH HHS; R01 HD042635 United States HD NICHD NIH HHS; R01 HD098284 United States HD NICHD NIH HHS

0 (Estrogen Receptor alpha)
0 (Estrogens)
0 (Kiss1 protein, rat)
0 (Kisspeptins)
33515-09-2 (Gonadotropin-Releasing Hormone)
4TI98Z838E (Estradiol)

Date Created: 20210818 Date Completed: 20211230 Latest Revision: 20240506

20240506

PMC8372949

10.1371/journal.pone.0256148

34407144