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.

  • Review Article
  • Published:

Region-specific roles of the corticotropin-releasing factor–urocortin system in stress

Nature Reviews Neuroscience volume 17, pages 636–651 (2016)Cite this article

Subjects

Key Points

  • Depending on the brain region involved, local activation of corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 by their ligands can induce acute anxiolytic or anxiogenic effects.

  • The region-specific modulation of anxiety-like behaviour by CRFR activation depends on the specific cell type in which it is expressed and the neuronal circuit in which it plays a part.

  • The downstream intracellular pathways triggered by CRFR activation are also brain-region specific and depend on the exact ligand–receptor interaction by which they are induced.

  • Local differences in the regulation of CRFR signalling exist, with processes of desensitization being dependent on local expression of its regulators (including G protein-coupled receptor kinases (GRKs) and β-arrestins) and of the binding ligand.

  • Many effects of CRFR activation that are observed at the cellular and behavioural level depend on the individual's current stress level and history of exposure to stress. These dose-dependent effects may be caused by loss of receptor specificity at higher concentrations of available ligand, whereas previous experience modulates receptor sensitivity by regulating receptor internalization or recruitment.

  • Long-lasting activation of CRFRs, for example, through chronic or repeated exposure to stress, can induce effects that are very distinct from their acute effects and seem to involve remodelling of structural plasticity.

Abstract

Dysregulation of the corticotropin-releasing factor (CRF)–urocortin (UCN) system has been implicated in stress-related psychopathologies such as depression and anxiety. It has been proposed that CRF–CRF receptor type 1 (CRFR1) signalling promotes the stress response and anxiety-like behaviour, whereas UCNs and CRFR2 activation mediate stress recovery and the restoration of homeostasis. Recent findings, however, provide clear evidence that this view is overly simplistic. Instead, a more complex picture has emerged that suggests that there are brain region- and cell type-specific effects of CRFR signalling that are influenced by the individual's prior experience and that shape molecular, cellular and ultimately behavioural responses to stressful challenges.

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: mRNA expression of components of the CRF–UCN system.
Figure 2: Region-specific effects of CRFRs on anxiety-like behaviour.

Similar content being viewed by others

References

  1. Vale, W., Spiess, J., Rivier, C. & Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213, 1394–1397 (1981). This is the first study to describe the discovery and characterization of CRF, which has initiated decades of research on the CRF–UCN system.

    CAS  PubMed  Google Scholar 

  2. Dunn, A. J. & Berridge, C. W. Is corticotropin-releasing factor a mediator of stress responses? Ann. NY Acad. Sci. 579, 183–191 (1990).

    CAS  PubMed  Google Scholar 

  3. Bale, T. L. & Vale, W. W. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu. Rev. Pharmacol. Toxicol. 44, 525–557 (2004).

    CAS  PubMed  Google Scholar 

  4. Valentino, R. J., Foote, S. L. & Page, M. E. The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann. NY Acad. Sci. 697, 173–188 (1993).

    CAS  PubMed  Google Scholar 

  5. Brown, M. R. et al. Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism. Endocrinology 111, 928–931 (1982).

    CAS  PubMed  Google Scholar 

  6. Reul, J. M. & Holsboer, F. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr. Opin. Pharmacol. 2, 23–33 (2002).

    CAS  PubMed  Google Scholar 

  7. Heinrichs, S. C., Lapsansky, J., Lovenberg, T. W., De Souza, E. B. & Chalmers, D. T. Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior. Regul. Pept. 71, 15–21 (1997).

    CAS  PubMed  Google Scholar 

  8. van Gaalen, M. M., Stenzel-Poore, M. P., Holsboer, F. & Steckler, T. Effects of transgenic overproduction of CRH on anxiety-like behaviour. Eur. J. Neurosci. 15, 2007–2015 (2002).

    PubMed  Google Scholar 

  9. Skutella, T. et al. Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide induces anxiolytic effects in rat. Neuroreport 5, 2181–2185 (1994).

    CAS  PubMed  Google Scholar 

  10. Skutella, T. et al. Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats. Cell. Mol. Neurobiol. 14, 579–588 (1994).

    CAS  PubMed  Google Scholar 

  11. Nemeroff, C. B. et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226, 1342–1344 (1984). This study provides the first evidence that disturbances in CRF signalling may have a role in depression.

    CAS  PubMed  Google Scholar 

  12. Bremner, J. D. et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am. J. Psychiatry 154, 624–629 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. De Bellis, M. D. et al. Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am. J. Psychiatry 150, 656–657 (1993).

    CAS  PubMed  Google Scholar 

  14. Heuser, I. et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress. Anxiety 8, 71–79 (1998).

    CAS  PubMed  Google Scholar 

  15. Zorrilla, E. P., Valdez, G. R., Nozulak, J., Koob, G. F. & Markou, A. Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat. Brain Res. 952, 188–199 (2002).

    CAS  PubMed  Google Scholar 

  16. Smith, G. W. et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Muller, M. B. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat. Neurosci. 6, 1100–1107 (2003). This paper describes the first conditional knockout mice related to the CRF–UCN system. Moreover, it demonstrates that CRFR1 modulates anxiety-related behaviour independently of its role in controlling the HPA axis.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Kishimoto, T. et al. Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat. Genet. 24, 415–419 (2000).

    CAS  PubMed  Google Scholar 

  22. Issler, O. et al. Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas. Biol. Mood Anxiety Disord. 4, 1 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Neufeld-Cohen, A. et al. A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery. Proc. Natl Acad. Sci. USA 107, 19020–19025 (2010).

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  Google Scholar 

  25. Valentino, R. J. & Commons, K. G. Peptides that fine-tune the serotonin system. Neuropeptides 39, 1–8 (2005).

    CAS  PubMed  Google Scholar 

  26. Bale, T. L. & Vale, W. W. Increased depression-like behaviors in corticotropin-releasing factor receptor-2-deficient mice: sexually dichotomous responses. J. Neurosci. 23, 5295–5301 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Janssen, D. & Kozicz, T. Is it really a matter of simple dualism? Corticotropin-releasing factor receptors in body and mental health. Front. Endocrinol. (Lausanne) 4, 28 (2013).

    Google Scholar 

  28. Radulovic, J., Ruhmann, A., Liepold, T. & Spiess, J. Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J. Neurosci. 19, 5016–5025 (1999).

    CAS  PubMed  Google Scholar 

  29. Zorrilla, E. P., Roberts, A. J., Rivier, J. E. & Koob, G. F. Anxiolytic-like effects of antisauvagine-30 in mice are not mediated by CRF2 receptors. PLoS ONE 8, e63942 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Justice, N. J., Yuan, Z. F., Sawchenko, P. E. & Vale, W. Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J. Comp. Neurol. 511, 479–496 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuhne, C. et al. Visualizing corticotropin-releasing hormone receptor type 1 expression and neuronal connectivities in the mouse using a novel multifunctional allele. J. Comp. Neurol. 520, 3150–3180 (2012).

    PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. Reyes, B. A., Bangasser, D. A., Valentino, R. J. & Van Bockstaele, E. J. Using high resolution imaging to determine trafficking of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Life Sci. 112, 2–9 (2014). This review summarizes electron microscopy-based neuroanatomical studies indicating that the distribution of CRFRs is a highly dynamic process that, in addition to being sexually dimorphic, involves complex regulation of receptor trafficking within extrasynaptic sites and has important consequences for adaptations to stress.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Davis, M., Walker, D. L., Miles, L. & Grillon, C. Phasic versus sustained fear in rats and humans: role of the extended amygdala in fear versus anxiety. Neuropsychopharmacology 35, 105–135 (2010).

    PubMed  Google Scholar 

  37. Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423–433 (2009).

    CAS  PubMed  Google Scholar 

  38. Rostkowski, A. B., Leitermann, R. J. & Urban, J. H. Differential activation of neuronal cell types in the basolateral amygdala by corticotropin releasing factor. Neuropeptides 47, 273–280 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Rainnie, D. G., Fernhout, B. J. & Shinnick-Gallagher, P. Differential actions of corticotropin releasing factor on basolateral and central amygdaloid neurones, in vitro. J. Pharmacol. Exp. Ther. 263, 846–858 (1992).

    CAS  PubMed  Google Scholar 

  40. Refojo, D. et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333, 1903–1907 (2011). In this study, the authors investigate electrophysiological and behavioural outcome measures of conditional Crfr1 inactivation in glutamatergic, GABAergic, dopaminergic and serotonergic neuronal populations to show that the effects of CRFR1-mediated signalling are cell-type specific.

    CAS  PubMed  Google Scholar 

  41. Gehlert, D. R. et al. Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor. Eur. J. Pharmacol. 509, 145–153 (2005).

    CAS  PubMed  Google Scholar 

  42. Sajdyk, T. J., Schober, D. A., Gehlert, D. R. & Shekhar, A. Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses. Behav. Brain Res. 100, 207–215 (1999).

    CAS  PubMed  Google Scholar 

  43. Spiga, F., Lightman, S. L., Shekhar, A. & Lowry, C. A. Injections of urocortin 1 into the basolateral amygdala induce anxiety-like behavior and c-Fos expression in brainstem serotonergic neurons. Neuroscience 138, 1265–1276 (2006).

    CAS  PubMed  Google Scholar 

  44. Bijlsma, E. Y., van Leeuwen, M. L., Westphal, K. G., Olivier, B. & Groenink, L. Local repeated corticotropin-releasing factor infusion exacerbates anxiety- and fear-related behavior: differential involvement of the basolateral amygdala and medial prefrontal cortex. Neuroscience 173, 82–92 (2011).

    CAS  PubMed  Google Scholar 

  45. Abiri, D. et al. Fear extinction learning can be impaired or enhanced by modulation of the CRF system in the basolateral nucleus of the amygdala. Behav. Brain Res. 271, 234–239 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. Roozendaal, B., Schelling, G. & McGaugh, J. L. Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the β-adrenoceptor–cAMP pathway: dependence on glucocorticoid receptor activation. J. Neurosci. 28, 6642–6651 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hubbard, D. T., Nakashima, B. R., Lee, I. & Takahashi, L. K. Activation of basolateral amygdala corticotropin-releasing factor 1 receptors modulates the consolidation of contextual fear. Neuroscience 150, 818–828 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sztainberg, Y., Kuperman, Y., Tsoory, M., Lebow, M. & Chen, A. The anxiolytic effect of environmental enrichment is mediated via amygdalar CRF receptor type 1. Mol. Psychiatry 15, 905–917 (2010).

    CAS  PubMed  Google Scholar 

  50. Gray, J. M. et al. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J. Neurosci. 35, 3879–3892 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Veening, J. G., Swanson, L. W. & Sawchenko, P. E. The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res. 303, 337–357 (1984).

    CAS  PubMed  Google Scholar 

  52. LeDoux, J. E., Iwata, J., Cicchetti, P. & Reis, D. J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988).

    CAS  PubMed  Google Scholar 

  53. Silberman, Y. & Winder, D. G. Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: an update and future directions. Alcohol 49, 179–184 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu, B. & Shinnick-Gallagher, P. Corticotropin-releasing factor increases dihydropyridine- and neurotoxin-resistant calcium currents in neurons of the central amygdala. J. Pharmacol. Exp. Ther. 284, 170–179 (1998).

    CAS  PubMed  Google Scholar 

  55. Silberman, Y. & Winder, D. G. Corticotropin releasing factor and catecholamines enhance glutamatergic neurotransmission in the lateral subdivision of the central amygdala. Neuropharmacology 70, 316–323 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ji, G. & Neugebauer, V. Pro- and anti-nociceptive effects of corticotropin-releasing factor (CRF) in central amygdala neurons are mediated through different receptors. J. Neurophysiol. 99, 1201–1212 (2008).

    CAS  PubMed  Google Scholar 

  57. Fu, Y. & Neugebauer, V. Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. J. Neurosci. 28, 3861–3876 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu, J. et al. Corticotropin-releasing factor and urocortin I modulate excitatory glutamatergic synaptic transmission. J. Neurosci. 24, 4020–4029 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Nie, Z. et al. Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303, 1512–1514 (2004).

    CAS  PubMed  Google Scholar 

  60. Nie, Z. et al. Presynaptic CRF1 receptors mediate the ethanol enhancement of GABAergic transmission in the mouse central amygdala. ScientificWorldJournal 9, 68–85 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Gilpin, N. W., Herman, M. A. & Roberto, M. The central amygdala as an integrative hub for anxiety and alcohol use disorders. Biol. Psychiatry 77, 859–869 (2015).

    PubMed  Google Scholar 

  62. Herman, M. A. et al. Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: alcohol and CRF effects. Neuropharmacology 102, 21–31 (2016).

    CAS  PubMed  Google Scholar 

  63. Henry, B., Vale, W. & Markou, A. The effect of lateral septum corticotropin-releasing factor receptor 2 activation on anxiety is modulated by stress. J. Neurosci. 26, 9142–9152 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Liebsch, G. et al. Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats. Regul. Pept. 59, 229–239 (1995).

    CAS  PubMed  Google Scholar 

  65. Ji, G., Fu, Y., Adwanikar, H. & Neugebauer, V. Non-pain-related CRF1 activation in the amygdala facilitates synaptic transmission and pain responses. Mol. Pain 9, 2 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ji, G., Fu, Y., Ruppert, K. A. & Neugebauer, V. Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala. Mol. Pain 3, 13 (2007).

    PubMed  PubMed Central  Google Scholar 

  67. Haramati, S. et al. MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34. J. Neurosci. 31, 14191–14203 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Matys, T. et al. Tissue plasminogen activator promotes the effects of corticotropin-releasing factor on the amygdala and anxiety-like behavior. Proc. Natl Acad. Sci. USA 101, 16345–16350 (2004).

    CAS  PubMed  Google Scholar 

  69. Pawlak, R., Magarinos, A. M., Melchor, J., McEwen, B. & Strickland, S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat. Neurosci. 6, 168–174 (2003).

    CAS  PubMed  Google Scholar 

  70. Davis, M. Are different parts of the extended amygdala involved in fear versus anxiety? Biol. Psychiatry 44, 1239–1247 (1998).

    CAS  PubMed  Google Scholar 

  71. Kash, T. L., Nobis, W. P., Matthews, R. T. & Winder, D. G. Dopamine enhances fast excitatory synaptic transmission in the extended amygdala by a CRF-R1-dependent process. J. Neurosci. 28, 13856–13865 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Silberman, Y., Matthews, R. T. & Winder, D. G. A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. J. Neurosci. 33, 950–960 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sahuque, L. L. et al. Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacol. (Berl.) 186, 122–132 (2006).

    CAS  Google Scholar 

  74. Nobis, W. P., Kash, T. L., Silberman, Y. & Winder, D. G. β-Adrenergic receptors enhance excitatory transmission in the bed nucleus of the stria terminalis through a corticotrophin-releasing factor receptor-dependent and cocaine-regulated mechanism. Biol. Psychiatry 69, 1083–1090 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Tran, L., Schulkin, J. & Greenwood-Van Meerveld, B. Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain. Neuropsychopharmacology 39, 2633–2645 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Huang, M. M. et al. Corticotropin-releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization. J. Pharmacol. Exp. Ther. 332, 298–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Maras, P. M. & Baram, T. Z. Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci. 35, 315–324 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen, Y., Andres, A. L., Frotscher, M. & Baram, T. Z. Tuning synaptic transmission in the hippocampus by stress: the CRH system. Front. Cell. Neurosci. 6, 13 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. 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).

    CAS  PubMed  Google Scholar 

  81. Hung, H. C., Chou, C. K., Chiu, T. H. & Lee, E. H. CRF increases protein phosphorylation and enhances retention performance in rats. Neuroreport 3, 181–184 (1992).

    CAS  PubMed  Google Scholar 

  82. Ma, Y. L., Chen, K. Y., Wei, C. L. & Lee, E. H. Corticotropin-releasing factor enhances brain-derived neurotrophic factor gene expression to facilitate memory retention in rats. Chin. J. Physiol. 42, 73–81 (1999).

    CAS  PubMed  Google Scholar 

  83. Pentkowski, N. S. et al. Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats. Horm. Behav. 56, 35–43 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Contarino, A. et al. Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res. 835, 1–9 (1999).

    CAS  PubMed  Google Scholar 

  85. Croiset, G., Nijsen, M. J. & Kamphuis, P. J. Role of corticotropin-releasing factor, vasopressin and the autonomic nervous system in learning and memory. Eur. J. Pharmacol. 405, 225–234 (2000).

    CAS  PubMed  Google Scholar 

  86. Stern, C. M., Meitzen, J. & Mermelstein, P. G. Corticotropin-releasing factor and urocortin I activate CREB through functionally selective Gβγ signaling in hippocampal pyramidal neurons. Eur. J. Neurosci. 34, 671–681 (2011). This study shows that the downstream effects of CRFR1 activation in the hippocampus are dependent on the ligand that is bound to it, and that UCN2, but not CRF, induces CREB phosphorylation via a MEK–MAPK-dependent pathway.

    PubMed  PubMed Central  Google Scholar 

  87. Sheng, H. et al. Corticotropin-releasing hormone stimulates SGK-1 kinase expression in cultured hippocampal neurons via CRH-R1. Am. J. Physiol. Endocrinol. Metab. 295, E938–E946 (2008).

    CAS  PubMed  Google Scholar 

  88. Bonci, A. & Borgland, S. Role of orexin/hypocretin and CRF in the formation of drug-dependent synaptic plasticity in the mesolimbic system. Neuropharmacology 56, 107–111 (2009).

    CAS  PubMed  Google Scholar 

  89. Wise, R. A. & Morales, M. A ventral tegmental CRF–glutamate–dopamine interaction in addiction. Brain Res. 1314, 38–43 (2010).

    CAS  PubMed  Google Scholar 

  90. Zorrilla, E. P., Logrip, M. L. & Koob, G. F. Corticotropin releasing factor: a key role in the neurobiology of addiction. Front. Neuroendocrinol. 35, 234–244 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Korotkova, T. M., Brown, R. E., Sergeeva, O. A., Ponomarenko, A. A. & Haas, H. L. Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat. Eur. J. Neurosci. 23, 2677–2685 (2006).

    CAS  PubMed  Google Scholar 

  92. Williams, C. L., Buchta, W. C. & Riegel, A. C. CRF-R2 and the heterosynaptic regulation of VTA glutamate during reinstatement of cocaine seeking. J. Neurosci. 34, 10402–10414 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Wanat, M. J., Hopf, F. W., Stuber, G. D., Phillips, P. E. & Bonci, A. Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. J. Physiol. 586, 2157–2170 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kalivas, P. W., Duffy, P. & Latimer, L. G. Neurochemical and behavioral effects of corticotropin-releasing factor in the ventral tegmental area of the rat. J. Pharmacol. Exp. Ther. 242, 757–763 (1987).

    CAS  PubMed  Google Scholar 

  95. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Sparta, D. R. et al. Binge ethanol-drinking potentiates corticotropin releasing factor R1 receptor activity in the ventral tegmental area. Alcohol Clin. Exp. Res. 37, 1680–1687 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Hahn, J., Hopf, F. W. & Bonci, A. Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons. J. Neurosci. 29, 6535–6544 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang, B., You, Z. B., Rice, K. C. & Wise, R. A. Stress-induced relapse to cocaine seeking: roles for the CRF2 receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacol. (Berl.) 193, 283–294 (2007).

    CAS  Google Scholar 

  99. Blacktop, J. M. et al. Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J. Neurosci. 31, 11396–11403 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Grieder, T. E. et al. VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat. Neurosci. 17, 1751–1758 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Boyson, C. O. et al. Social stress and CRF-dopamine interactions in the VTA: role in long-term escalation of cocaine self-administration. J. Neurosci. 34, 6659–6667 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hwa, L. S., Debold, J. F. & Miczek, K. A. Alcohol in excess: CRF1 receptors in the rat and mouse VTA and DRN. Psychopharmacol. (Berl.) 225, 313–327 (2013).

    CAS  Google Scholar 

  103. Chen, N. A. et al. Knockdown of CRF1 receptors in the ventral tegmental area attenuates cue- and acute food deprivation stress-induced cocaine seeking in mice. J. Neurosci. 34, 11560–11570 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Wanat, M. J., Bonci, A. & Phillips, P. E. CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors. Nat. Neurosci. 16, 383–385 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kim, Y., Park, M. K. & Chung, S. Regulation of somatodendritic dopamine release by corticotropin-releasing factor via the inhibition of voltage-operated Ca2+ channels. Neurosci. Lett. 465, 31–35 (2009).

    CAS  PubMed  Google Scholar 

  106. Foote, S. L., Bloom, F. E. & Aston-Jones, G. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol. Rev. 63, 844–914 (1983).

    CAS  PubMed  Google Scholar 

  107. Zitnik, G. A. Control of arousal through neuropeptide afferents of the locus coeruleus. Brain Res. 1641, 338–350 (2015).

    PubMed  Google Scholar 

  108. Aston-Jones, G. & Bloom, F. E. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876–886 (1981).

    CAS  PubMed  Google Scholar 

  109. Aston-Jones, G. & Bloom, F. E. Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J. Neurosci. 1, 887–900 (1981).

    CAS  PubMed  Google Scholar 

  110. Rassnick, S., Hoffman, G. E., Rabin, B. S. & Sved, A. F. Injection of corticotropin-releasing hormone into the locus coeruleus or foot shock increases neuronal Fos expression. Neuroscience 85, 259–268 (1998).

    CAS  PubMed  Google Scholar 

  111. Curtis, A. L., Lechner, S. M., Pavcovich, L. A. & Valentino, R. J. Activation of the locus coeruleus noradrenergic system by intracoerulear microinfusion of corticotropin-releasing factor: effects on discharge rate, cortical norepinephrine levels and cortical electroencephalographic activity. J. Pharmacol. Exp. Ther. 281, 163–172 (1997).

    CAS  PubMed  Google Scholar 

  112. 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).

    CAS  PubMed  Google Scholar 

  113. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Devilbiss, D. M., Waterhouse, B. D., Berridge, C. W. & Valentino, R. Corticotropin-releasing factor acting at the locus coeruleus disrupts thalamic and cortical sensory-evoked responses. Neuropsychopharmacology 37, 2020–2030 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Snyder, K., Wang, W. W., Han, R., McFadden, K. & Valentino, R. J. Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility. Neuropsychopharmacology 37, 520–530 (2012).

    CAS  PubMed  Google Scholar 

  116. 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).

    PubMed  Google Scholar 

  117. Jedema, H. P. & Grace, A. A. Corticotropin-releasing hormone directly activates noradrenergic neurons of the locus ceruleus recorded in vitro. J. Neurosci. 24, 9703–9713 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Lejeune, F. & Millan, M. J. The CRF1 receptor antagonist, DMP695, abolishes activation of locus coeruleus noradrenergic neurones by CRF in anesthetized rats. Eur. J. Pharmacol. 464, 127–133 (2003).

    CAS  PubMed  Google Scholar 

  119. McCall, J. G. et al. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87, 605–620 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Chaijale, N. N. et al. Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence. Neuropsychopharmacology 38, 1833–1843 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Taneja, M. et al. Differential effects of inescapable stress on locus coeruleus GRK3, alpha2-adrenoceptor and CRF1 receptor levels in learned helpless and non-helpless rats: a potential link to stress resilience. Behav. Brain Res. 221, 25–33 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Curtis, A. L., Pavcovich, L. A., Grigoriadis, D. E. & Valentino, R. J. Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus. Neuroscience 65, 541–550 (1995).

    CAS  PubMed  Google Scholar 

  123. Curtis, A. L., Pavcovich, L. A. & Valentino, R. J. Long-term regulation of locus ceruleus sensitivity to corticotropin-releasing factor by swim stress. J. Pharmacol. Exp. Ther. 289, 1211–1219 (1999).

    CAS  PubMed  Google Scholar 

  124. Bangasser, D. A. et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol. Psychiatry 877, 896–904 (2010).

    Google Scholar 

  125. Retson, T. A., Reyes, B. A. & Van Bockstaele, E. J. Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors. Prog. Neuropsychopharmacol. Biol. Psychiatry 56, 66–74 (2015).

    CAS  PubMed  Google Scholar 

  126. Roche, M., Commons, K. G., Peoples, A. & Valentino, R. J. Circuitry underlying regulation of the serotonergic system by swim stress. J. Neurosci. 23, 970–977 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kirby, L. G., Rice, K. C. & Valentino, R. J. Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology 22, 148–162 (2000).

    CAS  PubMed  Google Scholar 

  129. Lukkes, J. L., Forster, G. L., Renner, K. J. & Summers, C. H. Corticotropin-releasing factor 1 and 2 receptors in the dorsal raphe differentially affect serotonin release in the nucleus accumbens. Eur. J. Pharmacol. 578, 185–193 (2008).

    CAS  PubMed  Google Scholar 

  130. Price, M. L., Curtis, A. L., Kirby, L. G., Valentino, R. J. & Lucki, I. Effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology 18, 492–502 (1998).

    CAS  PubMed  Google Scholar 

  131. Price, M. L. & Lucki, I. Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. J. Neurosci. 21, 2833–2841 (2001).

    CAS  PubMed  Google Scholar 

  132. de Paula, D. C., Torricelli, A. S., Lopreato, M. R., Nascimento, J. O. & Viana, M. B. 5-HT2A receptor activation in the dorsolateral septum facilitates inhibitory avoidance in the elevated T-maze. Behav. Brain Res. 226, 50–55 (2012).

    CAS  PubMed  Google Scholar 

  133. Fox, J. H. & Lowry, C. A. Corticotropin-releasing factor-related peptides, serotonergic systems, and emotional behavior. Front. Neurosci. 7, 169 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Bowers, L. K., Swisher, C. B. & Behbehani, M. M. Membrane and synaptic effects of corticotropin-releasing factor on periaqueductal gray neurons of the rat. Brain Res. 981, 52–57 (2003).

    CAS  PubMed  Google Scholar 

  135. Martins, A. P., Marras, R. A. & Guimaraes, F. S. Anxiolytic effect of a CRH receptor antagonist in the dorsal periaqueductal gray. Depress. Anxiety 12, 99–101 (2000).

    CAS  PubMed  Google Scholar 

  136. Sergio Tde, O., Spiacci, A. Jr & Zangrossi, H. Jr. Effects of dorsal periaqueductal gray CRF1- and CRF2-receptor stimulation in animal models of panic. Psychoneuroendocrinology 49, 321–330 (2014).

    PubMed  Google Scholar 

  137. Litvin, Y., Pentkowski, N. S., Blanchard, D. C. & Blanchard, R. J. CRF type 1 receptors in the dorsal periaqueductal gray modulate anxiety-induced defensive behaviors. Horm. Behav. 52, 244–251 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Miguel, T. T. & Nunes-de-Souza, R. L. Anxiogenic and antinociceptive effects induced by corticotropin-releasing factor (CRF) injections into the periaqueductal gray are modulated by CRF1 receptor in mice. Horm. Behav. 60, 292–300 (2011).

    CAS  PubMed  Google Scholar 

  139. Ji, G. & Neugebauer, V. Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. J. Neurophysiol. 97, 3893–3904 (2007).

    CAS  PubMed  Google Scholar 

  140. Elharrar, E. et al. Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear. Biol. Psychiatry 74, 827–836 (2013).

    CAS  PubMed  Google Scholar 

  141. Lebow, M. et al. Susceptibility to PTSD-like behavior is mediated by corticotropin-releasing factor receptor type 2 levels in the bed nucleus of the stria terminalis. J. Neurosci. 32, 6906–6916 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Hammack, S. E., Mania, I. & Rainnie, D. G. Differential expression of intrinsic membrane currents in defined cell types of the anterolateral bed nucleus of the stria terminalis. J. Neurophysiol. 98, 638–656 (2007).

    CAS  PubMed  Google Scholar 

  143. Lebow, M. A. & Chen, A. Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol. Psychiatry 21, 450–463 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Myers, B., Mark Dolgas, C., Kasckow, J., Cullinan, W. E. & Herman, J. P. Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct. Funct. 219, 1287–1303 (2014).

    CAS  PubMed  Google Scholar 

  145. Anthony, T. E. et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014). In this study, the authors optogenetically target CRFR2-expressing cells in the LS, including GABAergic projection neurons, that (persistently) enhance stress-induced behavioural measures of anxiety and increase circulating corticosteroid levels, in part through projections to the medial hypothalamus.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Liu, J. et al. Chronic cocaine administration switches corticotropin-releasing factor2 receptor-mediated depression to facilitation of glutamatergic transmission in the lateral septum. J. Neurosci. 25, 577–583 (2005). This study shows that exposure to drugs of abuse alters the sensitivity and function of local UCN signalling in the LS; the CRFR2-mediated depression of LS neuronal activity induced by UCN1 is switched by chronic cocaine to facilitation (with a comparable UCN1 potency), and this switch is linked to a change from a PKA-dominant pathway to a PKC-dominant pathway downstream of CRFR2.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bakshi, V. P., Smith-Roe, S., Newman, S. M., Grigoriadis, D. E. & Kalin, N. H. Reduction of stress-induced behavior by antagonism of corticotropin-releasing hormone 2 (CRH2) receptors in lateral septum or CRH1 receptors in amygdala. J. Neurosci. 22, 2926–2935 (2002).

    CAS  PubMed  Google Scholar 

  149. Ho, S. P. et al. Attenuation of fear conditioning by antisense inhibition of brain corticotropin releasing factor-2 receptor. Brain Res. Mol. Brain Res. 89, 29–40 (2001).

    CAS  PubMed  Google Scholar 

  150. Todorovic, C. et al. Differential activation of CRF receptor subtypes removes stress-induced memory deficit and anxiety. Eur. J. Neurosci. 25, 3385–3397 (2007).

    PubMed  Google Scholar 

  151. Ungless, M. A. et al. Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron 39, 401–407 (2003).

    CAS  PubMed  Google Scholar 

  152. Day, H. E. et al. Differential expression of 5HT-1A, α1b adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, γ-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J. Comp. Neurol. 474, 364–378 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Pernar, L., Curtis, A. L., Vale, W. W., Rivier, J. E. & Valentino, R. J. Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions. J. Neurosci. 24, 1305–1311 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lowry, C. A., Rodda, J. E., Lightman, S. L. & Ingram, C. D. Corticotropin-releasing factor increases in vitro firing rates of serotonergic neurons in the rat dorsal raphe nucleus: evidence for activation of a topographically organized mesolimbocortical serotonergic system. J. Neurosci. 20, 7728–7736 (2000).

    CAS  PubMed  Google Scholar 

  155. Greenwood, B. N. et al. 5-HT2C receptors in the basolateral amygdala and dorsal striatum are a novel target for the anxiolytic and antidepressant effects of exercise. PLoS ONE 7, e46118 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Campbell, B. M. & Merchant, K. M. Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment. Brain Res. 993, 1–9 (2003).

    CAS  PubMed  Google Scholar 

  157. Forster, G. L. et al. Corticotropin-releasing factor in the dorsal raphe nucleus increases medial prefrontal cortical serotonin via type 2 receptors and median raphe nucleus activity. Eur. J. Neurosci. 28, 299–310 (2008).

    PubMed  Google Scholar 

  158. Hammack, S. E. et al. The role of corticotropin-releasing hormone in the dorsal raphe nucleus in mediating the behavioral consequences of uncontrollable stress. J. Neurosci. 22, 1020–1026 (2002).

    CAS  PubMed  Google Scholar 

  159. Hammack, S. E. et al. Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress. J. Neurosci. 23, 1019–1025 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Orozco-Cabal, L., Pollandt, S., Liu, J., Shinnick-Gallagher, P. & Gallagher, J. P. Regulation of synaptic transmission by CRF receptors. Rev. Neurosci. 17, 279–307 (2006).

    CAS  PubMed  Google Scholar 

  161. Dabrowska, J., Hazra, R., Guo, J. D., Dewitt, S. & Rainnie, D. G. Central CRF neurons are not created equal: phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Front. Neurosci. 7, 156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Pomrenze, M. B. et al. A transgenic rat for investigating the anatomy and function of corticotrophin releasing factor circuits. Front. Neurosci. 9, 487 (2015).

    PubMed  PubMed Central  Google Scholar 

  163. Partridge, J. G. et al. Stress increases GABAergic neurotransmission in CRF neurons of the central amygdala and bed nucleus stria terminalis. Neuropharmacology 107, 239–250 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Crawley, J. N., Olschowka, J. A., Diz, D. I. & Jacobowitz, D. M. Behavioral investigation of the coexistence of substance P, corticotropin releasing factor, and acetylcholinesterase in lateral dorsal tegmental neurons projecting to the medial frontal cortex of the rat. Peptides 6, 891–901 (1985).

    CAS  PubMed  Google Scholar 

  166. Zhao-Shea, R. et al. Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nat. Commun. 6, 6770 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Magalhaes, A. C. et al. CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling. Nat. Neurosci. 13, 622–629 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Holsboer, F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 (1999).

    CAS  PubMed  Google Scholar 

  169. Chen, P., Vaughan, J., Donaldson, C., Vale, W. & Li, C. Injection of urocortin 3 into the ventromedial hypothalamus modulates feeding, blood glucose levels, and hypothalamic POMC gene expression but not the HPA axis. Am. J. Physiol. Endocrinol. Metab. 298, E337–E345 (2010).

    CAS  PubMed  Google Scholar 

  170. Deussing, J. M. et al. Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2. J. Neurosci. 30, 9103–9116 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Lewis, K. et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc. Natl Acad. Sci. USA 98, 7570–7575 (2001).

    CAS  PubMed  Google Scholar 

  172. Merchenthaler, I., Vigh, S., Petrusz, P. & Schally, A. V. Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat brain. Am. J. Anat. 165, 385–396 (1982).

    CAS  PubMed  Google Scholar 

  173. Reyes, T. M. et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc. Natl Acad. Sci. USA 98, 2843–2848 (2001).

    CAS  PubMed  Google Scholar 

  174. Grammatopoulos, D. K., Randeva, H. S., Levine, M. A., Kanellopoulou, K. A. & Hillhouse, E. W. Rat cerebral cortex corticotropin-releasing hormone receptors: evidence for receptor coupling to multiple G-proteins. J. Neurochem. 76, 509–519 (2001).

    CAS  PubMed  Google Scholar 

  175. Grammatopoulos, D. K. & Chrousos, G. P. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol. Metab. 13, 436–444 (2002).

    CAS  PubMed  Google Scholar 

  176. Brar, B. K., Chen, A., Perrin, M. H. & Vale, W. Specificity and regulation of extracellularly regulated kinase1/2 phosphorylation through corticotropin-releasing factor (CRF) receptors 1 and 2β by the CRF/urocortin family of peptides. Endocrinology 145, 1718–1729 (2004). By showing in CHO cells expressing CRFR2 that this receptor selectively activates the ERK–MAPK signalling cascade when bound by UCN2 or UCN3, but not by CRF, this study shows that the preferred G protein-signalling pathway that is initiated by CRFR activation depends on the exact ligand by which it is activated.

    CAS  PubMed  Google Scholar 

  177. Gutknecht, E., Hauger, R. L., Van der Linden, I., Vauquelin, G. & Dautzenberg, F. M. Expression, binding, and signaling properties of CRF2(a) receptors endogenously expressed in human retinoblastoma Y79 cells: passage-dependent regulation of functional receptors. J. Neurochem. 104, 926–936 (2008). This paper indicates that desensitization and internalization processes following CRFR activation depend on the specific ligand that is bound; desensitization of CRFR2–cAMP signalling was shown to occur more rapidly and to a greater extent in response to UCN2 than to UCN3, whereas CRF is a relatively weak desensitizing agonist.

    CAS  PubMed  Google Scholar 

  178. Markovic, D., Punn, A., Lehnert, H. & Grammatopoulos, D. K. Intracellular mechanisms regulating corticotropin-releasing hormone receptor-2β endocytosis and interaction with extracellularly regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling cascades. Mol. Endocrinol. 22, 689–706 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Erdtmann-Vourliotis, M., Mayer, P., Ammon, S., Riechert, U. & Hollt, V. Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5 and 6 mRNA in the rat brain. Brain Res. Mol. Brain Res. 95, 129–137 (2001).

    CAS  PubMed  Google Scholar 

  180. Gurevich, E. V., Benovic, J. L. & Gurevich, V. V. Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development. Neuroscience 109, 421–436 (2002).

    CAS  PubMed  Google Scholar 

  181. Lemos, J. C. et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490, 402–406 (2012). This study demonstrates the state dependency of CRFR1 signalling on anxiety-like behaviour: activation of CRFR1 in the NAc induces a positive affective state in naive mice that is abolished by a history of severe stress exposure and switches to an aversive behavioural response.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Joels, M. & Baram, T. Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459–466 (2009). This seminal review tackles both the spatial and temporal complexity of stress mediators — including neurotransmitters, neuropeptides and steroids — that are released in response to stress, and describes their effects on neural function.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Dautzenberg, F. M. & Hauger, R. L. The CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol. Sci. 23, 71–77 (2002).

    CAS  PubMed  Google Scholar 

  184. Perrin, M. H. & Vale, W. W. Corticotropin releasing factor receptors and their ligand family. Ann. NY Acad. Sci. 885, 312–328 (1999).

    CAS  PubMed  Google Scholar 

  185. Lovenberg, T. W. et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc. Natl Acad. Sci. USA 92, 836–840 (1995).

    CAS  PubMed  Google Scholar 

  186. Perrin, M. et al. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc. Natl Acad. Sci. USA 92, 2969–2973 (1995).

    CAS  PubMed  Google Scholar 

  187. Stenzel, P. et al. Identification of a novel murine receptor for corticotropin-releasing hormone expressed in the heart. Mol. Endocrinol. 9, 637–645 (1995).

    CAS  PubMed  Google Scholar 

  188. Vaughan, J. et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378, 287–292 (1995).

    CAS  PubMed  Google Scholar 

  189. Behan, D. P. et al. Corticotropin releasing factor (CRF) binding protein: a novel regulator of CRF and related peptides. Front. Neuroendocrinol. 16, 362–382 (1995).

    CAS  PubMed  Google Scholar 

  190. Seasholtz, A. F., Valverde, R. A. & Denver, R. J. Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals. J. Endocrinol. 175, 89–97 (2002).

    CAS  PubMed  Google Scholar 

  191. Slater, P. G., Cerda, C. A., Pereira, L. A., Andres, M. E. & Gysling, K. CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface. Proc. Natl Acad. Sci. USA 113, 4075–4080 (2016).

    CAS  PubMed  Google Scholar 

  192. Hauger, R. L., Risbrough, V., Brauns, O. & Dautzenberg, F. M. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol. Disord. Drug Targets 5, 453–479 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Gutknecht, E. et al. Molecular mechanisms of corticotropin-releasing factor receptor-induced calcium signaling. Mol. Pharmacol. 75, 648–657 (2009).

    CAS  PubMed  Google Scholar 

  194. Kelly, E., Bailey, C. P. & Henderson, G. Agonist-selective mechanisms of GPCR desensitization. Br. J. Pharmacol. 153, S379–S388 (2008).

    CAS  PubMed  Google Scholar 

  195. Kohout, T. A. & Lefkowitz, R. J. Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol. Pharmacol. 63, 9–18 (2003).

    CAS  PubMed  Google Scholar 

  196. Moore, C. A., Milano, S. K. & Benovic, J. L. Regulation of receptor trafficking by GRKs and arrestins. Annu. Rev. Physiol. 69, 451–482 (2007).

    CAS  PubMed  Google Scholar 

  197. Krasel, C., Bunemann, M., Lorenz, K. & Lohse, M. J. β-Arrestin binding to the β2-adrenergic receptor requires both receptor phosphorylation and receptor activation. J. Biol. Chem. 280, 9528–9535 (2005).

    CAS  PubMed  Google Scholar 

  198. Bender, J. et al. Corticotropin-releasing hormone receptor type 1 (CRHR1) clustering with MAGUKs is mediated via its C-terminal PDZ binding motif. PLoS ONE 10, e0136768 (2015).

    PubMed  PubMed Central  Google Scholar 

  199. Walther, C., Caetano, F. A., Dunn, H. A. & Ferguson, S. S. PDZK1/NHERF3 differentially regulates corticotropin-releasing factor receptor 1 and serotonin 2A receptor signaling and endocytosis. Cell. Signal. 27, 519–531 (2015).

    CAS  PubMed  Google Scholar 

  200. Magalhaes, A. C., Dunn, H. & Ferguson, S. S. Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. Br. J. Pharmacol. 165, 1717–1736 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Dunn, H. A. et al. PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment. Cell. Signal. 28, 531–540 (2016).

    CAS  PubMed  Google Scholar 

  202. Griebel, G. & Holsboer, F. Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning? Nat. Rev. Drug Discov. 11, 462–478 (2012).

    CAS  PubMed  Google Scholar 

  203. Young, E. A., Abelson, J. L. & Cameron, O. G. Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression. Biol. Psychiatry 56, 113–120 (2004).

    CAS  PubMed  Google Scholar 

  204. Ising, M. et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology 32, 1941–1949 (2007).

    CAS  PubMed  Google Scholar 

  205. Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 (2000).

    CAS  PubMed  Google Scholar 

  206. Held, K. et al. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J. Psychiatr. Res. 38, 129–136 (2004).

    CAS  PubMed  Google Scholar 

  207. Binneman, B. et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 165, 617–620 (2008).

    PubMed  Google Scholar 

  208. Kimura, M. et al. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. Mol. Psychiatry 15, 154–165 (2010).

    CAS  PubMed  Google Scholar 

  209. Holsboer, F. & Ising, M. Stress hormone regulation: biological role and translation into therapy. Annu. Rev. Psychol. 61, 81–109 (2010).

    PubMed  Google Scholar 

  210. Valentino, R. J., Van Bockstaele, E. & Bangasser, D. Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharmacol. Sci. 34, 437–444 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Holmes, K. D., Babwah, A. V., Dale, L. B., Poulter, M. O. & Ferguson, S. S. Differential regulation of corticotropin releasing factor 1α receptor endocytosis and trafficking by β-arrestins and Rab GTPases. J. Neurochem. 96, 934–949 (2006).

    CAS  PubMed  Google Scholar 

  212. Oakley, R. H. et al. Carboxyl-terminal and intracellular loop sites for CRF1 receptor phosphorylation and β-arrestin-2 recruitment: a mechanism regulating stress and anxiety responses. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R209–R222 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Keen-Rhinehart, E. et al. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol. Psychiatry 14, 37–50 (2009).

    CAS  PubMed  Google Scholar 

  214. Regev, L. et al. Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation. Mol. Psychiatry 16, 714–728 (2011).

    CAS  PubMed  Google Scholar 

  215. Chen, Y. et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol. Psychiatry 18, 485–496 (2013).

    CAS  PubMed  Google Scholar 

  216. Andres, A. L. et al. NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH. J. Neurosci. 33, 16945–16960 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Wang, X. D. et al. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiol. Dis. 42, 300–310 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Ivy, A. S. et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J. Neurosci. 30, 13005–13015 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Brewin, C. R., Kleiner, J. S., Vasterling, J. J. & Field, A. P. Memory for emotionally neutral information in posttraumatic stress disorder: a meta-analytic investigation. J. Abnorm Psychol. 116, 448–463 (2007).

    PubMed  Google Scholar 

  220. Philbert, J., Belzung, C. & Griebel, G. The CRF1 receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: comparison with paroxetine and d-cycloserine. Psychopharmacol. (Berl.) 228, 97–107 (2013).

    CAS  Google Scholar 

  221. Koenig, J. I., Walker, C. D., Romeo, R. D. & Lupien, S. J. Effects of stress across the lifespan. Stress 14, 475–480 (2011).

    PubMed  Google Scholar 

  222. Sauvage, M. & Steckler, T. Detection of corticotropin-releasing hormone receptor 1 immunoreactivity in cholinergic, dopaminergic and noradrenergic neurons of the murine basal forebrain and brainstem nuclei – potential implication for arousal and attention. Neuroscience 104, 643–652 (2001).

    CAS  PubMed  Google Scholar 

  223. Pollandt, S. et al. Cocaine withdrawal enhances long-term potentiation induced by corticotropin-releasing factor at central amygdala glutamatergic synapses via CRF, NMDA receptors and PKA. Eur. J. Neurosci. 24, 1733–1743 (2006).

    PubMed  Google Scholar 

  224. Kash, T. L. & Winder, D. G. Neuropeptide Y and corticotropin-releasing factor bi-directionally modulate inhibitory synaptic transmission in the bed nucleus of the stria terminalis. Neuropharmacology 51, 1013–1022 (2006).

    CAS  PubMed  Google Scholar 

  225. Lodge, D. J. & Grace, A. A. Acute and chronic corticotropin-releasing factor 1 receptor blockade inhibits cocaine-induced dopamine release: correlation with dopamine neuron activity. J. Pharmacol. Exp. Ther. 314, 201–206 (2005).

    CAS  PubMed  Google Scholar 

  226. 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).

    CAS  PubMed  Google Scholar 

  227. Wang, X. D. et al. Forebrain CRF1 modulates early-life stress-programmed cognitive deficits. J. Neurosci. 31, 13625–13634 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Zieba, B. et al. The behavioural and electrophysiological effects of CRF in rat frontal cortex. Neuropeptides 42, 513–523 (2008).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank P. E. Sawchenko (Salk Institute, USA) for valuable information regarding the CRF family anatomical distribution. A.C. is Head of the Max Planck Society–Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. His work is supported by an FP7 grant from the European Research Council (260463); a research grant from the Israel Science Foundation (1565/15); research support from Roberto and Renata Ruhman; the Nella and Leon Benoziyo Center for Neurological Diseases; the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, founded by Louis L. and Anita M. Perlman; the Adelis Foundation and the Irving I. Moskowitz Foundation; the I-CORE Program of the Planning and Budgeting Committee; and the Israel Science Foundation (grant No 1916/12). M.H. is the recipient of the Niels Stensen Fellowship and a dean of Faculty Postdoctoral Fellowship of the Feinberg Graduate School of the Weizmann Institute of Science. J.D.'s work is supported by the German Federal Ministry of Education and Research within the framework of the e:Med research and funding concept (IntegraMent: Integrated Understanding of Causes and Mechanisms in Mental Disorders; FKZ 01ZX1314H); the programme for medical genome research within the framework of NGFN-Plus (FKZ: 01GS08151 and FKZ: 01GS08155); the Max Planck Institute for Psychiatry and the Helmholtz Zentrum München with their Clinical Cooperation Group (CCG); and the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215).

Author information

Authors and Affiliations

  1. Department of Neurobiology, Weizmann Institute of Science, Rehovot, 7610001, Israel

    Marloes J. A. G. Henckens & Alon Chen

  2. Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany

    Marloes J. A. G. Henckens, Jan M. Deussing & Alon Chen

  3. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, 6500, HB, The Netherlands

    Marloes J. A. G. Henckens

Authors
  1. Marloes J. A. G. Henckens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan M. Deussing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alon Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alon Chen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Region-specific functions of CRFRs in the brain (PDF 903 kb)

Supplementary information S2 (table)

Effects of regional manipulation of CRFR1-mediated signalling on behavioural anxiety and stress-coping behaviour (PDF 903 kb)

Supplementary information S3 (table)

Effects of regional manipulation of CRFR2-induced signalling on behavioural anxiety and stress-coping behaviour (PDF 903 kb)

PowerPoint slides

Glossary

Controllable stress

A stress paradigm in which exposure to a stressor (usually footshock or tailshock) can either be avoided or escaped.

Learned helplessness

A paradigm in which exposure to a severe inescapable stressor induces 'helpless' behaviour when it becomes possible to escape the stressor.

Uncontrollable stress

A paradigm in which exposure to a stressor (usually footshock or tailshock) is unavoidable and inescapable.

Prepulse inhibition

The neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the response to a subsequent, strong startling stimulus (pulse). Prepulse inhibition is thought to represent sensorimotor gating.

Fatty acid amide hydrolase

A serine hydrolase that is the principal catabolic enzyme for the fatty acid amides (including the endocannabinoid anandamide).

Immobilization stress

A stress paradigm in which the animal is (sometimes repeatedly) restrained in a confined space for a certain amount of time, during which it is unable to move.

Social defeat

A phenomenon that typically manifests in a 'resident–intruder' paradigm: the animal (the intruder) is repeatedly placed in the cage of a dominant animal (the resident) in a manner that allows a non-lethal conflict.

Afterhyperpolarization

The hyperpolarizing phase of an action potential during which the cell membrane potential temporarily falls below the normal resting potential by an excessive potassium efflux.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Henckens, M., Deussing, J. & Chen, A. Region-specific roles of the corticotropin-releasing factor–urocortin system in stress. Nat Rev Neurosci 17, 636–651 (2016). https://doi.org/10.1038/nrn.2016.94

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2016.94

This article is cited by

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