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dc.contributor.authorSchouten, Marijn
dc.contributor.authorBielefeld, Pascal
dc.contributor.authorGarcía Corzo, L.
dc.contributor.authorPasschier, E. M. J.
dc.contributor.authorGradari, S.
dc.contributor.authorJungenitz, T.
dc.contributor.authorPons Espinal, M.
dc.contributor.authorGebara, E.
dc.contributor.authorMartín Suárez, Soraya
dc.contributor.authorLucassen, Paul J.
dc.contributor.authorDe Vries, H. E.
dc.contributor.authorTrejo Pérez, Jose Luis
dc.contributor.authorSchwarzacher, S. W.
dc.contributor.authorDe Pietri Tonelli, D.
dc.contributor.authorToni, N.
dc.contributor.authorMira, H.
dc.contributor.authorEncinas Pérez, Juan Manuel
dc.contributor.authorFitzsimons, Carlos P.
dc.identifier.citationMolecular Psychiatry 2019 : 1-24 (2019)es_ES
dc.description.abstractA decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.es_ES
dc.description.sponsorshipThe experimental work was financed by grants from the Innovational Research Incentives Scheme VIDI 864.09.016 from the Netherlands organization for Scientific Research (NWO); the International Foundation for Alzheimer’s Research (ISAO), and Alzheimer Nederland to CPF. HM and LG-C were supported by the Spanish Ministry of Economy and Competitiveness, grant SAF2015- 70433-R to HM and Juan de la Cierva Program to LG-C. EG and NT were financed by the Swiss National Science Foundation. PJL was supported by Alzheimer Nederland. SM-S was financed by the Jesus de Gangoiti Foundation. We acknowledge the assistance of Rafael Hortigüela and Tijana Radic during the paper preparation and Ronald Breedijk and Mark Hink at the Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam for providing technical assistance with the confocal microscopees_ES
dc.subjectglucocorticoid hormoneses_ES
dc.subjectneural stem/precursor cellses_ES
dc.subjectglucocorticoid receptores_ES
dc.subjectaging braines_ES
dc.titleCircadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging braines_ES
dc.rights.holderThis article is licensed under a Creative Commons Attribution 4.0 International License. (CC BY 4.0)es_ES
dc.rights.holderAtribución 3.0 España*

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