The choroid plexus harbors a circadian oscillator modulated by estrogens

ABSTRACT

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered the master circadian oscillator in mammals. However, extra-SCN structures in the brain also display daily rhythms. Recently, we have demonstrated that the choroid plexus (CP) expresses core clock genes that are subjected to circadian regulation in a sex-dependent manner. By using CP explants cultured from female knock-in mice carrying the Period-luciferase transgene, we show that CP exhibits endogenous circadian rhythms of PERIOD2::LUCIFERASE expression. Furthermore, we demonstrate that estrogen declines following ovariectomy modulates the daily rhythm expression of Bmal1, Per1 and Per2 in female rat CP, corroborating data obtained in experiments where rat CP epithelial cell (CPEC) cultures were incubated with 17β-estradiol (E2). The molecular mechanism underlying these effects was also investigated, and we provide evidence that the estrogen receptor (ER) mediates the response of clock genes to E2.

In conclusion, our study proves that the CP harbors a circadian oscillator that is modulated by estrogens and demonstrates that E2 regulation occurs through an estrogen-receptor-dependent mechanism.

KEYWORDS:

• choroid plexus
• circadian rhythms
• clock genes
• estrogens

Acknowledgments

We thank Professor Jorge Maia, Physics Department, University of Beira Interior, Covilhã, Portugal, for the Origin analysis.

Declaration of interest

The authors declare that there is no conflict of interest.

Funding

This work was supported by FEDER funds through the POCI – COMPETE 2020 – Operational Programme Competitiveness and Internationalization in Axis I – Strengthening research, technological development and innovation (Project POCI-01-0145-FEDER-007491) and National Funds by FCT – Foundation for Science and Technology (Project UID/Multi/00709/2013) and the Swedish Research Foundation, the Swedish Brain Foundation, Åke Wibergs stiftelse and Karolinska Institutet Research Funds. Telma Quintela is a recipient of an FCT fellowship (SFRH/BPD/70781/2010).

Additional information

Funding

This work was supported by FEDER funds through the POCI – COMPETE 2020 – Operational Programme Competitiveness and Internationalization in Axis I – Strengthening research, technological development and innovation (Project POCI-01-0145-FEDER-007491) and National Funds by FCT – Foundation for Science and Technology (Project UID/Multi/00709/2013) and the Swedish Research Foundation, the Swedish Brain Foundation, Åke Wibergs stiftelse and Karolinska Institutet Research Funds. Telma Quintela is a recipient of an FCT fellowship (SFRH/BPD/70781/2010).