Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The neuro-symphony of stress

Abstract

The impact of stress on brain function is increasingly recognized. Various substances are released in response to stress and can influence distinct neuronal circuits, but the functional advantages of having such a diversity of stress mediators remain unclear. Individual neurotransmitter, neuropeptide and steroid stress mediators have specific spatial and temporal niches, but these niches also overlap. In addition, the effects of individual mediators on neuronal function and plasticity are integrated, and emerging evidence suggests that there is crosstalk between them. Together, this results in the stress instruments producing an orchestrated 'symphony' that enables fine-tuned responses to diverse challenges.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Different stressors require different responses.
Figure 2: 'Hot spots' of receptors for key stress mediators.
Figure 3: Subcellular localization of stress-mediator receptors.
Figure 4: Direct interaction between different stress mediators.

References

  1. Ulrich-Lai, Y. M. & Herman, J. P. et al. Neural regulation of endocrine and autonomic stress responses. Nature Rev. Neurosci. (in the press).

  2. De Kloet, E. R., Joëls, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463–475 (2005).

    Article  CAS  Google Scholar 

  3. Fenoglio, K. A., Brunson, K. L. & Baram, T. Z. Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. Front. Neuroendocrinol. 27, 180–192 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).

    Article  PubMed  Google Scholar 

  5. McGaugh, J. L. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu. Rev. Neurosci. 27, 1–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Joëls, M., Karst, H., Krugers, H. J. & Lucassen, P. J. Chronic stress: implications for neuronal morphology, function and neurogenesis. Front. Neuroendocrinol. 28, 72–96 (2007).

    Article  PubMed  Google Scholar 

  7. Lupien, S. J. et al. Stress hormones and human memory function across the lifespan. Psychoneuroendocrinology 30, 225–242 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Shors, T. J. Stressful experience and learning across the lifespan. Annu. Rev. Psychol. 57, 55–85 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Baram, T. Z. & Hatalski, C. G. Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci. 21, 471–476 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rice, C. J., Sandman, C. A., Lenjavi, M. R. & Baram, T. Z. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology 149, 4892–4900 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, Y., Fenoglio, K. A., Dube, C. M., Grigoriadis, D. E. & Baram, T. Z. Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent. Mol. Psychiatry 11, 992–1002 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brunson, K. L. et al. Mechanisms of late-onset cognitive decline after early-life stress. J. Neurosci. 25, 9328–9338 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Maier, S. F. & Watkins, L. R. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci. Biobehav. Rev. 29, 829–841 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Morilak, D. A. et al. Role of brain norepinephrine in the behavioral response to stress. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 1214–1224 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Goto, Y., Otani, S. & Grace, A. A. The yin and yang of dopamine release: a new perspective. Neuropharmacology 53, 583–587 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Linthorst, A. C. & Reul, J. M. Stress and the brain: solving the puzzle using microdialysis. Pharmacol. Biochem. Behav. 90, 163–173 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Mitsushima, D., Yamada, K., Takase, K., Funabashi, T. & Kimura, F. Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats. Eur. J. Neurosci. 24, 3245–3254 (2006).

    Article  PubMed  Google Scholar 

  18. Piazza, P. V. et al. Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission. Proc. Natl Acad. Sci. USA 93, 8716–8720 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Amat, J. et al. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neurosci. 8, 365–371 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Jackson, M. E. & Moghaddam, B. Stimulus-specific plasticity of prefrontal cortex dopamine neurotransmission. J. Neurochem. 88, 1327–1334 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Adamec, R., Holmes, A. & Blundell, J. Vulnerability to lasting anxiogenic effects of brief exposure to predator stimuli: sex, serotonin and other factors-relevance to PTSD. Neurosci. Biobehav. Rev. 32, 1287–1292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mathew, S. J., Price, R. B. & Charney, D. S. Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics. Am. J. Med. Genet. C Semin. Med. Genet. 148, 89–98 (2008).

    Article  CAS  Google Scholar 

  24. Swanson, L. W., Sawchenko, P. E., Rivier, J. & Vale, W. W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36, 165–186 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Landgraf, R. & Neumann, I. D. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front. Neuroendocrinol. 25, 150–176 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Koob, G. F. A role for brain stress systems in addiction. Neuron 59, 11–34 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen, Y., Bender, R. A., Frotscher, M. & Baram, T. Z. Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J. Neurosci. 21, 7171–7181 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Valentino, R. J. & Van Bockstaele, E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur. J. Pharmacol. 583, 194–203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Aldenhoff, J. B., Gruol, D. L., Rivier, J., Vale, W. & Siggins, G. R. Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. Science 221, 875–877 (1983).

    Article  CAS  PubMed  Google Scholar 

  30. Gallagher, J. P., Orozco-Cabal, L. F., Liu, J. & Shinnick-Gallagher, P. Synaptic physiology of central CRH system. Eur. J. Pharmacol. 583, 215–225 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Coste, S. C. et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nature Genet. 24, 403–409 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Bale, T. L. et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nature Genet. 24, 410–414 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Muller, M. B. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nature Neurosci. 6, 1100–1107 (2003).

    Article  PubMed  CAS  Google Scholar 

  34. Roozendaal, B., Brunson, K. L., Holloway, B. L., McGaugh, J. L. & Baram, T. Z. Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc. Natl Acad. Sci. USA 99, 13908–13913 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Merali, Z., Khan, S., Michaud, D. S., Shippy, S. A. & Anisman, H. Does amygdaloid corticotropin-releasing hormone (CRH) mediate anxiety-like behaviors? Dissociation of anxiogenic effects and CRH release. Eur. J. Neurosci. 20, 229–239 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Blank, T., Nijholt, I., Eckart, K. & Spiess, J. Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J. Neurosci. 22, 3788–3794 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, H. L., Wayner, M. J., Chai, C. Y. & Lee, E. H. Corticotrophin-releasing factor produces a long-lasting enhancement of synaptic efficacy in the hippocampus. Eur. J. Neurosci. 10, 3428–3437 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Chen, Y. et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus. Proc. Natl Acad. Sci. USA 101, 15782–15787 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen, Y., Dube, C. M., Rice, C. J. & Baram, T. Z. Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J. Neurosci. 28, 2903–2911 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ehlers, C. L. et al. Corticotropin releasing factor produces increases in brain excitability and convulsive seizures in rats. Brain Res. 278, 332–336 (1983).

    Article  CAS  PubMed  Google Scholar 

  41. Kozicz, T. On the role of urocortin 1 in the non-preganglionic Edinger-Westphal nucleus in stress adaptation. Gen. Comp. Endocrinol. 153, 235–240 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Harbuz, M. S. et al. Paradoxical responses of hypothalamic corticotropin-releasing factor (CRF) messenger ribonucleic acid (mRNA) and CRF-41 peptide and adenohypophysial proopiomelanocortin mRNA during chronic inflammatory stress. Endocrinology 130, 1394–1400 (1992).

    CAS  PubMed  Google Scholar 

  43. Raggenbass, M. Overview of cellular electrophysiological actions of vasopressin. Eur. J. Pharmacol. 583, 243–254 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Young, E. A., Abelson, J. & Lightman, S. L. Cortisol pulsatility and its role in stress regulation and health. Front. Neuroendocrinol. 25, 69–76 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Karssen, A. M. et al. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 142, 2686–2694 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Mason, B. L., Pariante, C. M. & Thomas, S. A. A revised role for p-glycoprotein in the brain distribution of dexamethasone, cortisol, and corticosterone in wild type and ABCB1A/B-deficient mice. Endocrinology 149, 5244–5253 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Droste, S. K. et al. Corticosterone levels in the brain show a distinct ultradian rhythm but a delayed response to forced swim stress. Endocrinology 149, 3244–3253 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Chen, Y., Brunson, K. L., Muller, M. B., Cariaga, W. & Baram, T. Z. Immunocytochemical distribution of corticotropin-releasing hormone receptor type-1 (CRF1)-like immunoreactivity in the mouse brain: light microscopy analysis using an antibody directed against the C-terminus. J. Comp. Neurol. 420, 305–323 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lu, N. Z. et al. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol. Rev. 58, 782–797 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Kim, J. J. & Diamond, D. M. The stressed hippocampus, synaptic plasticity and lost memories. Nature Rev. Neurosci. 3, 453–462 (2002).

    Article  CAS  Google Scholar 

  51. Champagne, D. L. et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J. Neurosci. 28, 6037–6045 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Duvarci, S. & Paré, D. Glucocorticoids enhance the excitability of principal basolateral amygdala neurons. J. Neurosci. 27, 4482–4491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bloom, F. E. The functional significance of neurotransmitter diversity. Am. J. Physiol. 246, C184–C194 (1984).

    Article  CAS  PubMed  Google Scholar 

  54. Nishi, M., Ogawa, H., Ito, T., Matsuda, K. I. & Kawata, M. Dynamic changes in subcellular localization of mineralocorticoid receptor in living cells: in comparison with glucocorticoid receptor using dual-color labeling with green fluorescent protein spectral variants. Mol. Endocrinol. 15, 1077–1092 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Olijslagers, J. E. et al. Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors. Eur. J. Neurosci. 27, 2542–2550 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Chen, Y. et al. Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress. Neuroscience 126, 533–540 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Swanson, L. W., Kohler, C. & Björklund, A. in Handbook of Chemical Neuroanatomy vol. 5 (eds Björklund, A., Hökfelt, T. & Swanson, L. W.) 125–227 (Elsevier, Amsterdam, 1987).

    Google Scholar 

  58. Oleskevich, S., Descarries, L. & Lacaille, J. C. Quantified distribution of the noradrenaline innervation in the hippocampus of adult rat. J. Neurosci. 9, 3803–3815 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Johnson, L. R., Farb, C., Morrison, J. H., McEwen, B. S. & LeDoux, J. E. Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala. Neuroscience 136, 289–299 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Reyes, B. A., Valentino, R. J. & Van Bockstaele, E. J. Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons. Endocrinology 149, 122–130 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Joëls, M., Pu, Z., Wiegert, O. & Krugers, H. J. Learning under stress: how does it work? Trends Cogn. Sci. 10, 152–158 (2006).

    Article  PubMed  Google Scholar 

  62. McIntyre, C. K. et al. Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus. Proc. Natl Acad. Sci. USA 102, 10718–10723 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sabban, E. L. & Kvetnansky, R. Stress-triggered activation of gene expression in catecholaminergic systems: dynamics of transcriptional events. Trends Neurosci. 24, 91–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Tasker, J. G., Di, S. & Malcher-Lopes, R. Minireview: rapid glucocorticoid signaling via membrane-associated receptors. Endocrinology 147, 5549–5556 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Karst, H. et al. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc. Natl Acad. Sci. USA 102, 19204–19207 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Groc, L., Choquet, D. & Chaouloff, F. The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. Nature Neurosci. 11, 868–870 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Joëls, M., Karst, H., DeRijk, R. & de Kloet, E. R. The coming out of the brain mineralocorticoid receptor. Trends Neurosci. 31, 1–7 (2008).

    Article  PubMed  CAS  Google Scholar 

  68. Kreibich, A. et al. Presynaptic inhibition of diverse afferents to the locus ceruleus by κ-opiate receptors: a novel mechanism for regulating the central norepinephrine system. J. Neurosci. 28, 6516–6525 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Curtis, A. L., Bello, N. T. & Valentino, R. J. Evidence for functional release of endogenous opioids in the locus ceruleus during stress termination. J. Neurosci. 21, RC152 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pu, Z., Krugers, H. J. & Joëls, M. Corticosterone time-dependently modulates beta-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus. Learn. Mem. 14, 359–367 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Akirav, I. & Richter-Levin, G. Mechanisms of amygdala modulation of hippocampal plasticity. J. Neurosci. 22, 9912–9921 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Roozendaal, B., Okuda, S., de Quervain, D. J. & McGaugh, J. L. Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions. Neuroscience 138, 901–910 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Orozco-Cabal, L. et al. Dopamine and corticotropin-releasing factor synergistically alter basolateral amygdala-to-medial prefrontal cortex synaptic transmission: functional switch after chronic cocaine administration. J. Neurosci. 28, 529–542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chalmers, D. T., Lovenberg, T. W. & De Souza, E. B. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 15, 6340–6350 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rainbow, T. C., Parsons, B. & Wolfe, B. B. Quantitative autoradiography of b1- and b2-adrenergic receptors in rat brain. Proc. Natl Acad. Sci. USA 81, 1585–1589 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Reul, J. M. H. M. & de Kloet, E. R. Anatomical resolution of two types of corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis. J. Steroid Biochem. 24, 269–272 (1986).

    Article  CAS  PubMed  Google Scholar 

  77. Härfstrand, A. et al. Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain. Proc. Natl Acad. Sci. USA 83, 9779–9783 (1986).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Van Pett, K. et al. Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J. Comp. Neurol. 428, 191–212 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Pu, Z., Krugers, H. J. & Joëls, M. Beta-adrenergic facilitation of synaptic plasticity in the rat basolateral amygdala in vitro is gradually reversed by corticosterone. Learn. Mem. 16, 155–160 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Avishai-Eliner, S., Brunson, K. L., Sandman, C. A. & Baram, T. Z. Stressed-out, or in (utero)? Trends Neurosci. 25, 518–524 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lim, M. M. et al. CRF receptors in the nucleus accumbens modulate partner preference in prairie voles. Horm. Behav. 51, 508–515 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chavkin, C. Dynorphins are endogenous opioid peptides released from granule cells to act neurohumorally and inhibit excitatory neurotransmission in the hippocampus. Prog. Brain Res. 125, 363–367 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank E. R. de Kloet and A. Korosi for critical reading of the text and help with the figures. Supported by NWO grant #91204042 (M.J.) and grants NS29012 and MH 73136 from the National Institute of Health (T.Z.B.).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Joëls, M., Baram, T. The neuro-symphony of stress. Nat Rev Neurosci 10, 459–466 (2009). https://doi.org/10.1038/nrn2632

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2632

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing