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.
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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
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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
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Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment
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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).”
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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
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- 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. (2013). Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis. Neuropsychopharmacology. https://doi.org/10.1038/npp.2012.253
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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