Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain

M. Schouten, P. Bielefeld, L. Garcia-Corzo, E. M. J. Passchier, S. Gradari, T. Jungenitz, M. Pons-Espinal, E. Gebara, S. Martín-Suárez, P. J. Lucassen, H. E. de Vries, J. L. Trejo, S. W. Schwarzacher, D. de Pietri Tonelli, N. Toni, H. Mira, J. M. Encinas, C. P. Fitzsimons

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

A 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.
Original languageEnglish
JournalMolecular Psychiatry
DOIs
Publication statusPublished - 2019

Cite this

Schouten, M. ; Bielefeld, P. ; Garcia-Corzo, L. ; Passchier, E. M. J. ; Gradari, S. ; Jungenitz, T. ; Pons-Espinal, M. ; Gebara, E. ; Martín-Suárez, S. ; Lucassen, P. J. ; de Vries, H. E. ; Trejo, J. L. ; Schwarzacher, S. W. ; de Pietri Tonelli, D. ; Toni, N. ; Mira, H. ; Encinas, J. M. ; Fitzsimons, C. P. / Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain. In: Molecular Psychiatry. 2019.
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title = "Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain",
abstract = "A 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.",
author = "M. Schouten and P. Bielefeld and L. Garcia-Corzo and Passchier, {E. M. J.} and S. Gradari and T. Jungenitz and M. Pons-Espinal and E. Gebara and S. Mart{\'i}n-Su{\'a}rez and Lucassen, {P. J.} and {de Vries}, {H. E.} and Trejo, {J. L.} and Schwarzacher, {S. W.} and {de Pietri Tonelli}, D. and N. Toni and H. Mira and Encinas, {J. M.} and Fitzsimons, {C. P.}",
year = "2019",
doi = "10.1038/s41380-019-0440-2",
language = "English",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

}

Schouten, M, Bielefeld, P, Garcia-Corzo, L, Passchier, EMJ, Gradari, S, Jungenitz, T, Pons-Espinal, M, Gebara, E, Martín-Suárez, S, Lucassen, PJ, de Vries, HE, Trejo, JL, Schwarzacher, SW, de Pietri Tonelli, D, Toni, N, Mira, H, Encinas, JM & Fitzsimons, CP 2019, 'Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain' Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0440-2

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain. / Schouten, M.; Bielefeld, P.; Garcia-Corzo, L.; Passchier, E. M. J.; Gradari, S.; Jungenitz, T.; Pons-Espinal, M.; Gebara, E.; Martín-Suárez, S.; Lucassen, P. J.; de Vries, H. E.; Trejo, J. L.; Schwarzacher, S. W.; de Pietri Tonelli, D.; Toni, N.; Mira, H.; Encinas, J. M.; Fitzsimons, C. P.

In: Molecular Psychiatry, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain

AU - Schouten, M.

AU - Bielefeld, P.

AU - Garcia-Corzo, L.

AU - Passchier, E. M. J.

AU - Gradari, S.

AU - Jungenitz, T.

AU - Pons-Espinal, M.

AU - Gebara, E.

AU - Martín-Suárez, S.

AU - Lucassen, P. J.

AU - de Vries, H. E.

AU - Trejo, J. L.

AU - Schwarzacher, S. W.

AU - de Pietri Tonelli, D.

AU - Toni, N.

AU - Mira, H.

AU - Encinas, J. M.

AU - Fitzsimons, C. P.

PY - 2019

Y1 - 2019

N2 - A 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.

AB - A 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31222184

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DO - 10.1038/s41380-019-0440-2

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JO - Molecular Psychiatry

JF - Molecular Psychiatry

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