Key Points
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There is reciprocal regulation between adult neurogenesis and stress: adult neurogenesis can affect the stress response, and stress can modulate levels of adult neurogenesis.
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One potential mechanism by which adult neurogenesis could regulate the stress response is through the neurogenesis-dependent modulation of perception of novel events, which would then influence whether events are perceived as stressful.
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Many pathways that affect adult neurogenesis are also modulated by stress, including the cytokine, neurotrophic factor and morphogen signalling pathways. However, glucocorticoid hormones are undoubtedly the most important group of molecules in this context.
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The glucocorticoid receptor signalling pathway can be modulated through several mechanisms, both upstream and downstream of the glucocorticoid receptor; all of these mechanisms can potentially modulate the effects of stress on neurogenesis.
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Glucocorticoid receptor signalling pathways may be modified during stress through crosstalk with other stress-regulated pathways, indicating that the dynamics of the regulation of adult neurogenesis by stress are highly complex.
Abstract
Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress.
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References
Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013). The authors take advantage of known fluctuations in atmospheric 14C to quantify the rate of adult hippocampal neurogenesis in humans.
Welberg, L. A bombshell of a finding. Nature Rev. Neurosci. 14, 522 (2013).
Kempermann, G. New neurons for 'survival of the fittest'. Nature Rev. Neurosci. 13, 727–736 (2012).
Cameron, H. A. & Gould, E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209 (1994). The first paper to investigate the possible link between stress and neurogenesis.
Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).
Gould, E., Tanapat, P., McEwen, B. S., Flügge, G. & Fuchs, E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl Acad. Sci. USA 95, 3168–3171 (1998).
Schoenfeld, T. J. & Gould, E. Stress, stress hormones, and adult neurogenesis. Exp. Neurol. 233, 12–21 (2012).
Tanapat, P., Hastings, N. B., Rydel, T. A., Galea, L. A. M. & Gould, E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J. Comp. Neurol. 437, 496–504 (2001).
Czéh, B. et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc. Natl Acad. Sci. USA 98, 12796–12801 (2001).
Czéh, B. & Lucassen, P. J. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur. Arch. Psychiatry Clin. Neurosci. 257, 250–260 (2007).
Ferragud, A. et al. Enhanced habit-based learning and decreased neurogenesis in the adult hippocampus in a murine model of chronic social stress. Behav. Brain Res. 210, 134–139 (2010).
Pham, K., Nacher, J., Hof, P. R. & McEwen, B. S. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17, 879–886 (2003).
Wong, E. Y. H. & Herbert, J. The corticoid environment: a determining factor for neural progenitors' survival in the adult hippocampus. Eur. J. Neurosci. 20, 2491–2498 (2004).
Mirescu, C. & Gould, E. Stress and adult neurogenesis. Hippocampus 16, 233–238 (2006).
Mineur, Y. S., Belzung, C. & Crusio, W. E. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience 150, 251–259 (2007).
Petrik, D., Lagace, D. C. & Eisch, A. J. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62, 21–34 (2011). A critical but balanced review of the correlations between neurogenesis, stress and depression; it summarizes the major findings up to the time of publication.
Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H. A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011). A pivotal paper on the role of adult neurogenesis in the regulation of the stress response.
Surget, A. et al. Antidepressants recruit new neurons to improve stress response regulation. Mol. Psychiatry 16, 1177–1188 (2011).
Sahay, A., Wilson, D. A. & Hen, R. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588 (2011).
Aimone, J. B., Deng, W. & Gage, F. H. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596 (2011).
Kheirbek, M. A., Klemenhagen, K. C., Sahay, A. & Hen, R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nature Neurosci. 15, 1613–1620 (2012). A review on the role of neurogenesis in hippocampal function, particularly on the role of pattern separation in certain behavioural functions such as overgeneralization.
Christian, K. M., Song, H. & Ming, G.-L. Functions and dysfunctions of adult hippocampal neurogenesis. Annu. Rev. Neurosci. 37, 243–262 (2014).
Temprana, S. G. et al. Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells. Neuron 85, 116–130 (2015). This paper investigates novel properties of newborn neurons and demonstrates how these properties may enable specific functions related to information processing.
Kirby, E. D. et al. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2. eLife 2, e00362 (2013).
Kronenberg, G. et al. Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol. Aging 27, 1505–1513 (2006).
Leuner, B., Glasper, E. R. & Gould, E. Sexual experience promotes adult neurogenesis in the hippocampus despite an initial elevation in stress hormones. PLoS ONE 5, e11597 (2010).
De Kloet, E. R., Joëls, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463–475 (2005).
Cameron, H. A., Woolley, C. S. & Gould, E. Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus. Brain Res. 611, 342–346 (1993).
Garcia, A., Steiner, B., Kronenberg, G., Bick-Sander, A. & Kempermann, G. Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus. Aging Cell 3, 363–371 (2004).
Wong, E. Y. H. & Herbert, J. Raised circulating corticosterone inhibits neuronal differentiation of progenitor cells in the adult hippocampus. Neuroscience 137, 83–92 (2006).
Hellsten, J. et al. Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment. Eur. J. Neurosci. 16, 283–290 (2002).
Murray, F., Smith, D. W. & Hutson, P. H. Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Eur. J. Pharmacol. 583, 115–127 (2008).
Anacker, C. et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol. Psychiatry 16, 738–750 (2011).
Mayer, J. L. et al. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosterone-induced reduction of adult hippocampal neurogenesis. J. Neuroendocrinol. 18, 629–631 (2006).
Oomen, C. A., Mayer, J. L., de Kloet, E. R., Joëls, M. & Lucassen, P. J. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress. Eur. J. Neurosci. 26, 3395–3401 (2007).
Wong, E. Y. H. & Herbert, J. Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus. Eur. J. Neurosci. 22, 785–792 (2005).
Hu, P. et al. A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation. PLoS ONE 7, e46224 (2012).
Anacker, C. et al. Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacology 38, 872–883 (2013).
Fitzsimons, C. P. et al. Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Mol. Psychiatry 18, 993–1005 (2013).
Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009).
Wu, Y. et al. CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway. J. Neurochem. 109, 1157–1167 (2009).
Graciarena, M., Depino, A. M. & Pitossi, F. J. Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFβ1 downregulation. Brain. Behav. Immun. 24, 1301–1309 (2010).
Ahn, S. & Joyner, A. L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897 (2005).
He, Y. et al. ALK5-dependent TGF-β signaling is a major determinant of late-stage adult neurogenesis. Nature Neurosci. 17, 943–952 (2014).
Anacker, C. et al. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 110, 8708–8713 (2013). This paper (by our group) describes a series of cellular, animal and clinical studies showing that SGK1 is one of the mechanisms by which glucocorticoids affect neurogenesis, with actions both upstream and downstream of the glucocorticoid receptor.
Datson, N. A. et al. The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus. Hippocampus 22, 359–371 (2012).
Frotscher, M., Haas, C. A. & Förster, E. Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold. Cereb. Cortex 13, 634–640 (2003).
Beffert, U. et al. Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J. Neurosci. 26, 2041–2052 (2006).
Li, Z. et al. Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J. Neurosci. 28, 6557–6568 (2008).
Koo, J. W. & Duman, R. S. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl Acad. Sci. USA 105, 751–756 (2008). The first paper to examine the role of inflammation in stress-induced inhibition of neurogenesis.
Tozuka, Y., Fukuda, S., Namba, T., Seki, T. & Hisatsune, T. GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47, 803–815 (2005).
Lightman, S. L. et al. Hypothalamic–pituitary–adrenal function. Arch. Physiol. Biochem. 110, 90–93 (2002).
Stavreva, D. A. et al. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nature Cell Biol. 11, 1093–1102 (2009).
Sarabdjitsingh, R. A., Joëls, M. & de Kloet, E. R. Glucocorticoid pulsatility and rapid corticosteroid actions in the central stress response. Physiol. Behav. 106, 73–80 (2012).
Huang, G.-J. & Herbert, J. Stimulation of neurogenesis in the hippocampus of the adult rat by fluoxetine requires rhythmic change in corticosterone. Biol. Psychiatry 59, 619–624 (2006).
Sarabdjitsingh, R. A. et al. Recovery from disrupted ultradian glucocorticoid rhythmicity reveals a dissociation between hormonal and behavioural stress responsiveness. J. Neuroendocrinol. 22, 862–871 (2010).
Scheff, J. D., Calvano, S. E., Lowry, S. F. & Androulakis, I. P. Transcriptional implications of ultradian glucocorticoid secretion in homeostasis and in the acute stress response. Physiol. Genomics 44, 121–129 (2012).
Rankin, J., Walker, J. J., Windle, R., Lightman, S. L. & Terry, J. R. Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve. PLoS ONE 7, e30978 (2012).
Noguchi, T. et al. Regulation of glucocorticoid receptor transcription and nuclear translocation during single and repeated immobilization stress. Endocrinology 151, 4344–4355 (2010).
Guidotti, G. et al. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology 38, 616–627 (2013).
Cheng, L.-C., Pastrana, E., Tavazoie, M. & Doetsch, F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature Neurosci. 12, 399–408 (2009).
Vreugdenhil, E. et al. MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Endocrinology 150, 2220–2228 (2009).
Uchida, S. et al. Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. Eur. J. Neurosci. 27, 2250–2261 (2008).
Wallace, A. D. & Cidlowski, J. A. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J. Biol. Chem. 276, 42714–42721 (2001).
Conway-Campbell, B. L. et al. Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone. Endocrinology 148, 5470–5477 (2007).
Mardirossian, S., Rampon, C., Salvert, D., Fort, P. & Sarda, N. Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome. Exp. Neurol. 220, 341–348 (2009).
Godavarthi, S. K., Dey, P., Maheshwari, M. & Jana, N. R. Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome. Hum. Mol. Genet. 21, 1824–1834 (2012).
Ito, K. et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression. J. Exp. Med. 203, 7–13 (2006).
Koo, J. W., Russo, S. J., Ferguson, D., Nestler, E. J. & Duman, R. S. Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc. Natl Acad. Sci. USA 107, 2669–2674 (2010).
Tian, S., Poukka, H., Palvimo, J. J. & Jänne, O. A. Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor. Biochem. J. 367, 907–911 (2002).
Lin, D.-Y. et al. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol. Cell 24, 341–354 (2006).
Holmstrom, S. R., Chupreta, S., So, A. Y.-L. & Iñiguez-Lluhí, J. A. SUMO-mediated inhibition of glucocorticoid receptor synergistic activity depends on stable assembly at the promoter but not on DAXX. Mol. Endocrinol. 22, 2061–2075 (2008).
Jewell, C. M. Mouse glucocorticoid receptor phosphorylation status influences multiple functions of the receptor protein. J. Biol. Chem. 272, 9287–9293 (1997).
Wang, Z., Frederick, J. & Garabedian, M. J. Deciphering the phosphorylation 'code' of the glucocorticoid receptor in vivo. J. Biol. Chem. 277, 26573–26580 (2002).
Yang, J., Liu, J. & DeFranco, D. B. Subnuclear trafficking of glucocorticoid receptors in vitro: chromatin recycling and nuclear export. J. Cell Biol. 137, 523–538 (1997).
Blind, R. D. & Garabedian, M. J. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes. J. Steroid Biochem. Mol. Biol. 109, 150–157 (2008).
Ismaili, N. & Garabedian, M. J. Modulation of glucocorticoid receptor function via phosphorylation. Ann. NY Acad. Sci. 1024, 86–101 (2004).
Rogatsky, I., Waase, C. L. M. & Garabedian, M. J. Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activation by glycogen synthase kinase-3 (GSK-3). Species-specific differences between human and rat glucocorticoid receptor signaling as revealed through GSK-3 phosphorylation. J. Biol. Chem. 273, 14315–14321 (1998).
Adzic, M. et al. Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain. J. Endocrinol. 202, 87–97 (2009).
Bledsoe, R. K. et al. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110, 93–105 (2002).
Freeman, B. C. & Yamamoto, K. R. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296, 2232–2235 (2002).
Conway-Campbell, B. L. et al. The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its coregulatory molecules CBP/p300 during ultradian ligand treatment. Mol. Endocrinol. 25, 944–954 (2011).
Han, S. J., Lonard, D. M. & O'Malley, B. W. Multi-modulation of nuclear receptor coactivators through posttranslational modifications. Trends Endocrinol. Metab. 20, 8–15 (2009).
Zalachoras, I., Houtman, R. & Meijer, O. C. Understanding stress-effects in the brain via transcriptional signal transduction pathways. Neuroscience 242, 97–109 (2013).
Bierhaus, A. et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc. Natl Acad. Sci. USA 100, 1920–1925 (2003).
Haroon, E., Raison, C. L. & Miller, A. H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37, 137–162 (2012). This is an extensive and very useful review on the role of inflammation in depression.
Johnson, J. D. et al. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295–1307 (2005).
Horowitz, M., Zunszain, P. A., Anacker, C., Musaelyan, K. & Pariante, C. M. in Inflammation in Psychiatry (eds Halaris, A & Leonard, B. E.) 127–143 (Karger, 2013).
Miller, G. E. et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272 (2008).
Grippo, A. J., Francis, J., Beltz, T. G., Felder, R. B. & Johnson, A. K. Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia. Physiol. Behav. 84, 697–706 (2005).
Goshen, I. et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol. Psychiatry 13, 717–728 (2008).
Zunszain, P. A. et al. Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology 37, 939–949 (2011).
Green, H. F. & Nolan, Y. M. Unlocking mechanisms in interleukin-1β-induced changes in hippocampal neurogenesis — a role for GSK-3β and TLX. Transl. Psychiatry 2, e194 (2012).
Seguin, J. A., Brennan, J., Mangano, E. & Hayley, S. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration. Neuropsychiatr. Dis. Treat. 5, 5–14 (2009).
Mahar, I., Bambico, F. R., Mechawar, N. & Nobrega, J. N. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci. Biobehav. Rev. 38, 173–192 (2013).
Gray, J. D., Milner, T. A. & McEwen, B. S. Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors. Neuroscience 239, 214–227 (2013).
Donovan, M. H., Yamaguchi, M. & Eisch, A. J. Dynamic expression of TrkB receptor protein on proliferating and maturing cells in the adult mouse dentate gyrus. Hippocampus 18, 435–439 (2008).
Schmidt, H. D. & Duman, R. S. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav. Pharmacol. 18, 391–418 (2007).
Waterhouse, E. G. et al. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J. Neurosci. 32, 14318–14330 (2012).
Nowacka, M. & Obuchowicz, E. BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies. Pharmacol. Rep. 65, 535–546 (2013).
Jin, K. et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl Acad. Sci. USA 99, 11946–11950 (2002).
Schänzer, A. et al. Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol. 14, 237–248 (2004).
Segi-Nishida, E., Warner-Schmidt, J. L. & Duman, R. S. Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc. Natl Acad. Sci. USA 105, 11352–11357 (2008).
Fournier, N. M., Lee, B., Banasr, M., Elsayed, M. & Duman, R. S. Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology 63, 642–652 (2012).
Taylor, S. B. et al. Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. Physiol. Behav. 104, 205–214 (2011).
Mahar, I. et al. Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects. PLoS ONE 6, e26610 (2011).
Faigle, R. & Song, H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim. Biophys. Acta 1830, 2435–2448 (2013).
Han, Y.-G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nature Neurosci. 11, 277–284 (2008).
Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).
Petrova, R., Garcia, A. D. R. & Joyner, A. L. Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions. J. Neurosci. 33, 17490–17505 (2013).
Lie, D.-C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).
Matrisciano, F. et al. Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage. PLoS ONE 6, e16447 (2011).
Wang, X. et al. Interleukin-1β mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway. Mol. Cell. Neurosci. 36, 343–354 (2007).
Hayley, S., Poulter, M. O., Merali, Z. & Anisman, H. The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135, 659–678 (2005).
McKay, L. I. & Cidlowski, J. A. CBP (CREB binding protein) integrates NF-κB (nuclear factor-κB) and glucocorticoid receptor physical interactions and antagonism. Mol. Endocrinol. 14, 1222–1234 (2000).
Galliher-Beckley, A. J., Williams, J. G., Collins, J. B. & Cidlowski, J. A. Glycogen synthase kinase 3β-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. Mol. Cell. Biol. 28, 7309–7322 (2008).
Suri, D. & Vaidya, V. A. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity. Neuroscience 239, 196–213 (2013).
Kumamaru, E. et al. Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol. Endocrinol. 22, 546–558 (2008).
Jeanneteau, F., Garabedian, M. J. & Chao, M. V. Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc. Natl Acad. Sci. USA 105, 4862–4867 (2008). This paper examines the potential crosstalk between neurotrophin signalling pathways and the glucocorticoid receptor, with potential implications for adult neurogenesis.
Chen, M. J. & Russo-Neustadt, A. A. Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 19, 962–972 (2009).
Lambert, W. M. et al. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation. Mol. Cell. Biol. 33, 3700–3714 (2013).
Miller, B. R. & Hen, R. The current state of the neurogenic theory of depression and anxiety. Curr. Opin. Neurobiol. 30, 51–58 (2015).
Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).
Boldrini, M. et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 2376–2389 (2009).
Windle, R. J., Wood, S. A., Shanks, N., Lightman, S. L. & Ingram, C. D. Ultradian rhythm of basal corticosterone release in the female rat: dynamic interaction with the response to acute stress. Endocrinology 139, 443–450 (1998).
Acknowledgements
C.M.P. and P.A.Z. are supported by the National Institute of Health Research Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London, and by the Medical Research Council UK (MR/J002739/1 and MR/L014815/1). M.E. is supported by a Marie Curie Fellowship from the European Commission and a grant from the Lundbeck Foundation. The authors thank S. Thuret and T. Murphy for discussions on this Review.
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Patricia A. Zunszain and Carmine M. Pariante have received research funding from pharmaceutical companies interested in depression such as Johnson & Johnson, but this Review is unrelated to this funding.
Glossary
- Subgranular zone
-
(SGZ). A small region on the inner boundaries of the granular layer in the dentate gyrus of rodents. Cell proliferation of precursors to adult neurogenesis of granular neurons occurs in the SGZ.
- Cell proliferation
-
Among the adult neurogenesis stages, this is an often-quantified stage of the process and is a measure of the number of new cells being formed in the subgranular zone that have the potential to become new neurons or glia.
- Unpredictable mild stress
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A rodent model of depression in which animals are exposed to repeated stressors that are deemed as mild in an order that cannot be predicted to avoid the development of habituation resilience.
- Pattern separation
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The process of reducing interference among similar inputs using non-overlapping representations.
- Overgeneralization
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In behaviour, this is the use of a few and/or non-representative experiences to make an inference of a current experience that is incorrect.
- Contextual emotional processing
-
The process of putting a novel experience into an emotional context using the emotional valence of similar previous experiences.
- Dorsal dentate gyrus
-
A region that is thought to be associated with spatial memory processing.
- Cell differentiation
-
A quantifiable stage of adult neurogenesis in which the number of cells fated to become neurons can be measured.
- Circadian rhythms
-
In terms of hormone secretion, these rhythms vary throughout the day and comprise a period in which there is generally a high level of hormone secretion and a period in which a generally lower level of hormone is secreted.
- Ultradian rhythms
-
In terms of hormone secretion, these rhythms vary within circadian rhythms and are composed of roughly hourly pulses of hormone release that result in peaks in hormone levels followed by troughs in which the hormone is broken down.
- Subventricular zone
-
(SVZ). A thin strip composed of several layers on the inner walls of the lateral ventricles of the rodent forebrain. Cell proliferation of precursors to adult neurogenesis of mainly olfactory bulb neurons occurs in the SVZ.
- Ventral dentate gyrus
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A region that is thought to be associated with emotional memory processing.
- Morphogens
-
A group of signalling molecules that govern tissue development. They classically control morphogenesis through cell proliferation and differentiation.
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Egeland, M., Zunszain, P. & Pariante, C. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci 16, 189–200 (2015). https://doi.org/10.1038/nrn3855
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DOI: https://doi.org/10.1038/nrn3855
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Molecular Psychiatry (2022)
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Prenatal glucocorticoid exposure selectively impairs neuroligin 1-dependent neurogenesis by suppressing astrocytic FGF2–neuronal FGFR1 axis
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