The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis
Open accessAbstract
Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
David, F. N., & Tukey, J. W. (1977) · Biometrics · doi:10.2307/2529486 · Cited by 12,708
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321
The HPA axis in major depression: classical theories and new developments
Pariante, C. M., & Lightman, S. L. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.06.006 · Cited by 2,009
Self-citationDisruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety
Tronche, F., Kellendonk, C., Kretz, O., Gass, P., Anlag, K., Orban, P. C., Bock, R., Klein, R., & Schütz, G. (1999) · Nature Genetics · doi:10.1038/12703 · Cited by 1,838
Adult hippocampal neurogenesis buffers stress responses and depressive behaviour
Snyder, J. S., Soumier, A., Brewer, M., Pickel, J., & Cameron, H. A. (2011) · Nature · doi:10.1038/nature10287 · Cited by 1,473
Bulmer, M. (1978) · Sociology · doi:10.1177/003803857801200331 · Cited by 1,412
David, D. J., Samuels, B. A., Rainer, Q., Wang, J.-W., Marsteller, D., Mendez, I., Drew, M., Craig, D. A., Guiard, B. P., Guilloux, J.-P., et al. (2009) · Neuron · doi:10.1016/j.neuron.2009.04.017 · Cited by 1,267
Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment
Pariante, C. M., & Miller, A. H. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(00)01088-x · Cited by 1,147
Self-citationLemaire, V., Koehl, M., Le Moal, M., & Abrous, D. N. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.20.11032 · Cited by 1,044 · cited 2×
“We have then conducted whole genome expression analysis of the rat hippocampus in animals subjected to prenatal stress, a well established animal model of depression in which glucocorticoid levels are elevated and hippocampal neurogenesis is decreased (Lemaire et al , 2000; Fumagalli et al , 2007).”
MethodIn vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog
Ahn, S., & Joyner, A. L. (2005) · Nature · doi:10.1038/nature03994 · Cited by 699
Antidepressants increase neural progenitor cells in the human hippocampus
Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., John Mann, J., & Arango, V. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.75 · Cited by 686
Neural stem cell proliferation is decreased in schizophrenia, but not in depression
Reif, A., Fritzen, S., Finger, M., Strobel, A., Lauer, M., Schmitt, A., & Lesch, K.-P. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001791 · Cited by 630
The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?
Anacker, C., Zunszain, P. A., Carvalho, L. A., & Pariante, C. M. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.03.007 · Cited by 592
Self-citationSurget, A., Saxe, M., Leman, S., Ibarguen-Vargas, Y., Chalon, S., Griebel, G., Hen, R., & Belzung, C. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.02.022 · Cited by 556
Glucocorticoids, cytokines and brain abnormalities in depression
Zunszain, P. A., Anacker, C., Cattaneo, A., Carvalho, L. A., & Pariante, C. M. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.04.011 · Cited by 554
Self-citationLimits of Neurogenesis in Primates
Rakic, P. (1985) · Science · doi:10.1126/science.3975601 · Cited by 502
Antidepressants recruit new neurons to improve stress response regulation
Surget, A., Tanti, A., Leonardo, E. D., Laugeray, A., Rainer, Q., Touma, C., Palme, R., Griebel, G., Ibarguen-Vargas, Y., Hen, R., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.48 · Cited by 471
Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor
Anacker, C., Zunszain, P. A., Cattaneo, A., Carvalho, L. A., Garabedian, M. J., Thuret, S., Price, J., & Pariante, C. M. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.26 · Cited by 435
Self-citationInterleukin-1β: A New Regulator of the Kynurenine Pathway Affecting Human Hippocampal Neurogenesis
Zunszain, P. A., Anacker, C., Cattaneo, A., Choudhury, S., Musaelyan, K., Myint, A. M., Thuret, S., Price, J., & Pariante, C. M. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.277 · Cited by 388
Self-citationRidder, S., Chourbaji, S., Hellweg, R., Urani, A., Zacher, C., Schmid, W., Zink, M., Hörtnagl, H., Flor, H., Henn, F. A., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.0736-05.2005 · Cited by 382
Purmorphamine activates the Hedgehog pathway by targeting Smoothened
Sinha, S., & Chen, J. K. (2006) · Nature Chemical Biology · doi:10.1038/nchembio753 · Cited by 370
The Notch-Hes pathway in mammalian neural development
KAGEYAMA, R., & OHTSUKA, T. (1999) · Cell Research · doi:10.1038/sj.cr.7290016 · Cited by 343
Brown, R. W., Diaz, R., Robson, A. C., Kotelevtsev, Y. V., Mullins, J. J., Kaufman, M. H., & Seckl, J. R. (1996) · Endocrinology · doi:10.1210/en.137.2.794 · Cited by 307
Battista, D., Ferrari, C. C., Gage, F. H., & Pitossi, F. J. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04539.x · Cited by 306
Stress during development: Impact on neuroplasticity and relevance to psychopathology
Fumagalli, F., Molteni, R., Racagni, G., & Riva, M. A. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.01.002 · Cited by 220
Self-citationLucassen, P. J., Stumpel, M. W., Wang, Q., & Aronica, E. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.01.012 · Cited by 212
Karalay, Ö., Doberauer, K., Vadodaria, K. C., Knobloch, M., Berti, L., Miquelajauregui, A., Schwark, M., Jagasia, R., Taketo, M. M., Tarabykin, V., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013456108 · Cited by 201
Wong, E. Y. H., & Herbert, J. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2005.08.073 · Cited by 200
Gould, E., Woolley, C. S., Cameron, H. A., Daniels, D. C., & McEwen, B. S. (1991) · Journal of Comparative Neurology · doi:10.1002/cne.903130309 · Cited by 194
Mayer, J. L., Klumpers, L., Maslam, S., De Kloet, E. R., Joëls, M., & Lucassen, P. J. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01455.x · Cited by 181
Boyle, M. P., Kolber, B. J., Vogt, S. K., Wozniak, D. F., & Muglia, L. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2173-05.2006 · Cited by 171
Smith, J. C., Boone, B. E., Opalenik, S. R., Williams, S. M., & Russell, S. B. (2008) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701149 · Cited by 170
Differential effects of prenatal stress on the morphological maturation of hippocampal neurons
Fujioka, A., Fujioka, T., Ishida, Y., Maekawa, T., & Nakamura, S. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.04.046 · Cited by 165
Gass, P., Kretz, O., Wolfer, D. P., Berger, S., Tronche, F., Reichardt, H. M., Kellendonk, C., Lipp, H., Schmid, W., & Schütz, G. (2000) · EMBO reports · doi:10.1093/embo-reports/kvd088 · Cited by 158
Dexamethasone inhibits proliferation of adult hippocampal neurogenesis in vivo and in vitro
Kim, J. B., Ju, J. Y., Kim, J. H., Kim, T., Yang, B., Lee, Y., & Son, H. (2004) · Brain Research · doi:10.1016/j.brainres.2004.07.093 · Cited by 147
Graciarena, M., Depino, A. M., & Pitossi, F. J. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.06.005 · Cited by 131
Musil, R., Schwarz, M., Riedel, M. J., Dehning, S., Cerovecki, A., Spellmann, I., Arolt, V., & Müller, N. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.05.047 · Cited by 127
de Kloet, E. R., & DeRijk, R. H. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1314.003 · Cited by 115
Datson, N. A., Speksnijder, N., Mayer, J. L., Steenbergen, P. J., Korobko, O. B., Goeman, J. J., de Kloet, E. R., Joëls, M., & Lucassen, P. J. (2010) · Hippocampus · doi:10.1002/hipo.20905 · Cited by 101
ABC transporters, neural stem cells and neurogenesis – a different perspective
Lin, T., Islam, O., & Heese, K. (2006) · Cell Research · doi:10.1038/sj.cr.7310107 · Cited by 98
Pryce, C. R., Aubert, Y., Maier, C., Pearce, P. C., & Fuchs, E. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1989-2 · Cited by 94
Implication of corticosteroid receptors in the regulation of hippocampal structural plasticity
Montaron, M., Piazza, P. V., Aurousseau, C., Urani, A., Moal, M. L., & Abrous, D. N. (2003) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2003.03048.x · Cited by 85
Hedgehog Serves as a Mitogen and Survival Factor During Embryonic Stem Cell Neurogenesis
Cai, C., Thorne, J. T., & Grabel, L. B. (2008) · Stem Cells · doi:10.1634/stemcells.2007-0684 · Cited by 66
Induction of the Wnt Antagonist Dickkopf-1 Is Involved in Stress-Induced Hippocampal Damage
Matrisciano, F., Busceti, C. L., Bucci, D., Orlando, R., Caruso, A., Molinaro, G., Cappuccio, I., Riozzi, B., Gradini, R., Motolese, M., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016447 · Cited by 65
Reduced hippocampal neurogenesis in the GR+/− genetic mouse model of depression
Kronenberg, G., Kirste, I., Inta, D., Chourbaji, S., Heuser, I., Endres, M., & Gass, P. (2009) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-009-0036-y · Cited by 64
Salaria, S., Chana, G., Caldara, F., Feltrin, E., Altieri, M., Faggioni, F., Domenici, E., Merlo‐Pich, E., & Everall, I. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.05.003 · Cited by 63
Characterization of ABC transporter ABCB1 expressed in human neural stem/progenitor cells
Islam, M. O., Kanemura, Y., Tajria, J., Mori, H., Kobayashi, S., Shofuda, T., Miyake, J., Hara, M., Yamasaki, M., & Okano, H. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.05.019 · Cited by 58
Bujalska, I. J., Quinkler, M. O., Tomlinson, J., Montague, C. T., Smith, D. M., & Stewart, P. M. (2006) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.02048 · Cited by 56
Chang, Y.-T., Chen, Y., Wu, C.-W. J., Yu, L., Chen, H., Jen, C. J., & Kuo, Y. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.05.014 · Cited by 53
Glucocorticoid Regulation of Astrocytic Fate and Function
Yu, S., Yang, S., Holsboer, F., Sousa, N., & Almeida, O. F. X. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022419 · Cited by 52
Transforming Growth Factor type β and Smad family signaling in stem cell function
Seuntjens, E., Umans, L., Zwijsen, A., Sampaolesi, M., Verfaillie, C. M., & Huylebroeck, D. (2009) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.10.005 · Cited by 51
Guo, Y., Zhang, Z., Wang, S., Sui, Y., & Sun, Y. (2009) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2009.03.022 · Cited by 50
Meisler, N. T., Shull, S., Xie, R., Long, G. L., Absher, M. P., Connolly, J. P., & Cutroneo, K. R. (1995) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240590309 · Cited by 48
Fischer, A., von Rosenstiel, P., Fuchs, E., Goula, D., Almeida, O. F. X., & Czéh, B. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03042-1 · Cited by 47
Can adult neurogenesis buffer stress responses and depressive behaviour?
Anacker, C., & Pariante, C. M. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.133 · Cited by 45
Self-citationXi, G., Zhang, X., Zhang, L., Sui, Y., Hui, J., Liu, S., Wang, Y., Li, L., & Zhang, Z. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2077-3 · Cited by 43
Pariante, C. M., Alhaj, H. A., Arulnathan, V. E., Gallagher, P., Hanson, A., Massey, E., & McAllister-Williams, R. H. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.08.011 · Cited by 33
Self-citationShull, S., Meisler, N. T., Absher, M. P., Phan, S. H., & Cutroneo, K. R. (1995) · Lung · doi:10.1007/bf02981467 · Cited by 25
Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells
Sippel, M., Rajala, R., Korhonen, L., Bornhauser, B. C., Sokka, A.-L., Naito, M., & Lindholm, D. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.06.018 · Cited by 21
Cited by
Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood
Anacker, C., & Hen, R. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.45 · Cited by 1,014
Self-citationInflammation: Depression Fans the Flames and Feasts on the Heat
Kiecolt-Glaser, J. K., Derry, H. M., & Fagundes, C. P. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.15020152 · Cited by 844
Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects
Mahar, I., Bambico, F. R., Mechawar, N., & Nobrega, J. N. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.11.009 · Cited by 694
The effects of aging in the hippocampus and cognitive decline
Bettio, L. E. B., Rajendran, L., & Gil-Mohapel, J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.04.030 · Cited by 649
Tyler, C. R., & Allan, A. M. (2014) · Current Environmental Health Reports · doi:10.1007/s40572-014-0012-1 · Cited by 537
Metadata
- Authors
- Anacker, C., Cattaneo, A., Luoni, A., Musaelyan, K., Zunszain, P. A., Milanesi, E., Rybka, J., Berry, A., Cirulli, F., Thuret, S., Price, J., Riva, M. A., Gennarelli, M., & Pariante, C. M.
- Venue
- Neuropsychopharmacology
- Published
- 2012-12-06
- Volume
- 38
- Issue
- 5
- Pages
- 872-883
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2096160341
- Cited by
- 317
- References
- 60
- FWCI
- 5.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
