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.

  • Letter
  • Published:

Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive

Nature volume 490, pages 402–406 (2012)Cite this article

Subjects

This article has been updated

Abstract

Stressors motivate an array of adaptive responses ranging from ‘fight or flight’ to an internal urgency signal facilitating long-term goals1. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments2. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal3. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry4. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors5 and other arousing environmental stimuli6, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF’s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cellular localization of CRF peptide, CRFR1 and CRFR2 in the nucleus accumbens.
Figure 2: CRF increases dopamine release in the nucleus accumbens through coactivation of CRFR1 and CRFR2.
Figure 3: CRF in the nucleus accumbens promotes appetitive behaviour.
Figure 4: Stress exposure abolishes the CRF-mediated increase in evoked dopamine release and subsequent appetitive behaviours.

Similar content being viewed by others

Change history

  • 17 October 2012

    The spelling of an author name (J.R.S.) was corrected.

References

  1. Korte, S. M., Koolhaas, J. M., Wingfield, J. C. & McEwen, B. S. The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci. Biobehav. Rev. 29, 3–38 (2005)

    Article  Google Scholar 

  2. Beck, A. T. The evolution of the cognitive model of depression and its neurobiological correlates. Am. J. Psychiatry 165, 969–977 (2008)

    Article  Google Scholar 

  3. Clark, D. A. & Beck, A. T. Cognitive theory and therapy of anxiety and depression: convergence with neurobiological findings. Trends Cogn. Sci. 14, 418–424 (2010)

    Article  Google Scholar 

  4. Nestler, E. J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002)

    Article  CAS  Google Scholar 

  5. Wang, B. et al. Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J. Neurosci. 25, 5389–5396 (2005)

    Article  CAS  Google Scholar 

  6. Merali, Z., McIntosh, J. & Anisman, H. Anticipatory cues differentially provoke in vivo peptidergic and monoaminergic release at the medial prefrontal cortex. Neuropsychopharmacology 29, 1409–1418 (2004)

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

  8. Steckler, T. & Holsboer, F. Corticotropin-releasing hormone receptor subtypes and emotion. Biol. Psychiatry 46, 1480–1508 (1999)

    Article  CAS  Google Scholar 

  9. Peciña, S., Schulkin, J. & Berridge, K. C. Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress? BMC Biol. 4, 8 (2006)

    Article  Google Scholar 

  10. 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  Google Scholar 

  11. Aragona, B. J. et al. Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nature Neurosci. 9, 133–139 (2006)

    Article  CAS  Google Scholar 

  12. Lex, A. & Hauber, W. Dopamine D1 and D2 receptors in the nucleus accumbens core and shell mediate Pavlovian-instrumental transfer. Learn. Mem. 15, 483–491 (2008)

    Article  Google Scholar 

  13. Waselus, M., Nazzaro, C., Valentino, R. J. & Van Bockstaele, E. J. Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biol. Psychiatry 66, 76–83 (2009)

    Article  CAS  Google Scholar 

  14. Timpl, P. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nature Genet. 19, 162–166 (1998)

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. Cador, M., Ahmed, S. H., Koob, G. F., Le Moal, M. & Stinus, L. Corticotropin-releasing factor induces a place aversion independent of its neuroendocrine role. Brain Res. 597, 304–309 (1992)

    Article  CAS  Google Scholar 

  17. Oldfield, E. H. et al. Active clearance of corticotropin-releasing factor from the cerebrospinal fluid. Neuroendocrinology 40, 84–87 (1985)

    Article  CAS  Google Scholar 

  18. Fink, J. S. & Smith, G. P. Mesolimbic and mesocortical dopaminergic neurons are necessary for normal exploratory behavior in rats. Neurosci. Lett. 17, 61–65 (1980)

    Article  CAS  Google Scholar 

  19. Bale, T. L. Stress sensitivity and the development of affective disorders. Horm. Behav. 50, 529–533 (2006)

    Article  CAS  Google Scholar 

  20. Bruchas, M. R. et al. Stress-induced p38 mitogen-activated protein kinase activation mediates κ-opioid-dependent dysphoria. J. Neurosci. 27, 11614–11623 (2007)

    Article  CAS  Google Scholar 

  21. Coryell, W. et al. The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression–Clinical Studies. Arch. Gen. Psychiatry 51, 405–410 (1994)

    Article  CAS  Google Scholar 

  22. Torres, G., Horowitz, J. M., Laflamme, N. & Rivest, S. Fluoxetine induces the transcription of genes encoding c-fos, corticotropin-releasing factor and its type 1 receptor in rat brain. Neuroscience 87, 463–477 (1998)

    Article  CAS  Google Scholar 

  23. Bruchas, M. R. & Chavkin, C. Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology (Berl.) 210, 137–147 (2010)

    Article  CAS  Google Scholar 

  24. Iredale, P. A. & Duman, R. S. Glucocorticoid regulation of corticotropin-releasing factor1 receptor expression in pituitary-derived AtT-20 cells. Mol. Pharmacol. 51, 794–799 (1997)

    Article  CAS  Google Scholar 

  25. Cryan, J. F. & Mombereau, C. In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol. Psychiatry 9, 326–357 (2004)

    Article  CAS  Google Scholar 

  26. Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005); erratum. 62, 768 (2005)

  27. Gelenberg, A. J. Depression symptomatology and neurobiology. J. Clin. Psychiatry 71, e02 (2010)

    Google Scholar 

  28. Refojo, D. et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333, 1903–1907 (2011)

    Article  CAS  ADS  Google Scholar 

  29. Chaki, S. et al. Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450. Eur. J. Pharmacol. 485, 145–158 (2004)

    Article  CAS  Google Scholar 

  30. 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  Google Scholar 

  31. van Bockstaele, E. J., Sesack, S. R. & Pickel, V. M. Dynorphin-immunoreactive terminals in the rat nucleus accumbens: cellular sites for modulation of target neurons and interactions with catecholamine afferents. J. Comp. Neurol. 341, 1–15 (1994)

    Article  CAS  Google Scholar 

  32. Reyes, B. A., Fox, K., Valentino, R. J. & Van Bockstaele, E. J. Agonist-induced internalization of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Eur. J. Neurosci. 23, 2991–2998 (2006)

    Article  Google Scholar 

  33. Peters, A., Palay, S. L. & Webster, H. D. The Fine Structure of the Nervous System (Oxford Univ. Press, 1991)

    Google Scholar 

  34. Peters, A. & Palay, S. L. The morphology of synapses. J. Neurocytol. 25, 687–700 (1996)

    Article  CAS  Google Scholar 

  35. Bruchas, M. R., Land, B. B., Lemos, J. C. & Chavkin, C. CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS ONE 4, e8528 (2009)

    Article  ADS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants F31-MH086269 (J.C.L.), F32-DA026273 (M.J.W.), R01-DA009082 (E.J.V.B.), R01-DA030074 (C.C.), R01-MH079292 and R01-DA016782 (P.E.M.P.), the National Science Foundation (N.G.H.) and NARSAD (P.E.M.P.). We thank C. Zietz, M. Miyatake and P. Groblewski for assisting with histological verification of cannula placement, H. Gill for help with data analysis, D. Messinger for breeding and genotyping mice and N. Stella for use of a microscope. We thank M. Darvas and R. Palmiter for providing Thfs/fs;DbhTh/+ mice. We thank R. Sapolsky, J. Day, S. Sesack, M. Soden, C. Walker and E. Horne for useful suggestions and insights.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 98195, USA

    Julia C. Lemos, Matthew J. Wanat, Nick G. Hollon & Paul E. M. Phillips

  2. Department of Pharmacology, University of Washington, Seattle, 98195, Washington, USA

    Julia C. Lemos, Matthew J. Wanat, Jeffrey S. Smith, Nick G. Hollon, Charles Chavkin & Paul E. M. Phillips

  3. Program in Neurobiology and Behavior, University of Washington, Seattle, 98195, Washington, USA

    Julia C. Lemos, Nick G. Hollon, Charles Chavkin & Paul E. M. Phillips

  4. Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA

    Beverly A. S. Reyes & Elisabeth J. Van Bockstaele

Authors
  1. Julia C. Lemos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew J. Wanat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey S. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beverly A. S. Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nick G. Hollon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabeth J. Van Bockstaele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles Chavkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul E. M. Phillips
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author Contributions J.C.L. performed immunohistochemistry. J.C.L. and N.G.H. carried out fast-scan cyclic-voltammetry experiments. J.C.L., M.J.W. and J.S.S. performed the behavioural experiments. B.A.S.R. and E.J.V.B. provided transmission electron microscopy data. J.C.L., M.J.W., C.C. and P.E.M.P. developed the conceptual and experimental framework, and J.C.L. and P.E.M.P. wrote the paper.

Corresponding author

Correspondence to Paul E. M. Phillips.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-15, Supplementary Table 1, a Supplementary Discussion and additional references. (PDF 1880 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lemos, J., Wanat, M., Smith, J. et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490, 402–406 (2012). https://doi.org/10.1038/nature11436

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11436

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced 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