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Cell and Tissue Research

, Volume 375, Issue 1, pp 133–142 | Cite as

Urocortins and their unfolding role in mammalian social behavior

  • Shlomo WagnerEmail author
Review

Abstract

The corticotropin-releasing factor (CRF) system is well known for its major role in coordinating the endocrine, autonomic and behavioral responses to stress. These functions have been shown to be mediated mainly by the binding of the CRF neuropeptide to its specific receptor CRFR1. Yet, the CRF system comprises several more neuropeptides, including the three urocortins, UCN1, UCN2 and UCN3, of which the latter two bind specifically to a distinct receptor—CRFR2. Unlike the brain-wide abundant expression of CRF and CRFR1, the brain expression of the urocortins and CRFR2 is rather restricted and seems to be focused in limbic areas associated with social behavior. Here, we will review accumulating evidence from recent studies that unfold the role of UCN2 and UCN3 in regulating mammalian social behavior, via activation of CRFR2.

Keywords

Urocortins Social behavior CRF system CRFR2 Medial amygdala 

Notes

Acknowledgments

I wish to thank Dr. Shai Netser for his help.

Funding information

This research was supported by The Human Frontier Science Program (HFSP grant RGP0019/2015), the Israel Science Foundation (ISF grant #1361/17) and by the Ministry of Science, Technology and Space of Israel (Grant #3-12068).

References

  1. Adolphs R (2009) The social brain: neural basis of social knowledge. Annu Rev Psychol 60:693–716CrossRefGoogle Scholar
  2. Ahern TH, Young LJ 2009 The impact of early life family structure on adult social attachment, alloparental behavior, and the neuropeptide systems regulating affiliative behaviors in the monogamous prairie vole (Microtus ochrogaster). Front Behav Neurosci 3Google Scholar
  3. Bagosi Z, Czebely-Lenart A, Karasz G, Csabafi K, Jaszberenyi M, Telegdy G (2017a) The effects of CRF and urocortins on the preference for social novelty of mice. Behav Brain Res 324:146–154CrossRefGoogle Scholar
  4. Bagosi Z, Karasz G, Czebely-Lenart A, Csabafi K, Jaszberenyi M, Telegdy G (2017b) The effects of CRF and urocortins on the sociability of mice. Brain Res 1663:114–122CrossRefGoogle Scholar
  5. Bittencourt JC, Vaughan J, Arias C, Rissman RA, Vale WW, Sawchenko PE (1999) Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J Comp Neurol 415:285–312CrossRefGoogle Scholar
  6. Bledsoe AC, Oliver KM, Scholl JL, Forster GL (2011) Anxiety states induced by post-weaning social isolation are mediated by CRF receptors in the dorsal raphe nucleus. Brain Res Bull 85:117–122CrossRefGoogle Scholar
  7. Bosch OJ, Dabrowska J, Modi ME, Johnson ZV, Keebaugh AC, Barrett CE, Ahern TH, Guo J, Grinevich V, Rainnie DG, Neumann ID, Young LJ (2016) Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles. Psychoneuroendocrinology 64:66–78CrossRefGoogle Scholar
  8. Breu J, Touma C, Holter SM, Knapman A, Wurst W, Deussing JM (2012) Urocortin 2 modulates aspects of social behaviour in mice. Behav Brain Res 233:331–336CrossRefGoogle Scholar
  9. Brown MR, Fisher LA, Spiess J, Rivier C, Rivier J, Vale W (1982) Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism. Endocrinology 111:928–931CrossRefGoogle Scholar
  10. Chalmers DT, Lovenberg TW, Desouza EB (1995) Localization of novel corticotropin-releasing factor-receptor (Crf(2)) messenger-Rna expression to specific subcortical nuclei in rat-brain - comparison with Crf(1) receptor messenger-Rna expression. J Neurosci 15:6340–6350CrossRefGoogle Scholar
  11. Chen AM, Perrin MH, Digruccio MR, Vaughan JM, Brar BK, Arias CM, Lewis KA, Rivier JE, Sawchenko PE, Vale WW (2005) A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity. Proc Natl Acad Sci U S A 102:2620–2625CrossRefGoogle Scholar
  12. Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5:374–381CrossRefGoogle Scholar
  13. Cooper MA, Huhman KL (2005) Corticotropin-releasing factor type II (CRF-sub-2) receptors in the bed nucleus of the stria terminalis modulate conditioned defeat in Syrian hamsters (Mesocricetus auratus). Behav Neurosci 119:1042–1051CrossRefGoogle Scholar
  14. Cooper MA, Huhman KL (2007) Corticotropin-releasing factor receptors in the dorsal raphe nucleus modulate social behavior in Syrian hamsters. Psychopharmacology 194:297–307CrossRefGoogle Scholar
  15. Cooper MA, Huhman KL (2010) Blocking corticotropin-releasing factor-2 receptors, but not corticotropin-releasing factor-1 receptors or glucocorticoid feedback, disrupts the development of conditioned defeat. Physiol Behav 101:527–532CrossRefGoogle Scholar
  16. Coste SC, Heard AD, Phillips TJ, Stenzel-Poore MP (2006) Corticotropin-releasing factor receptor type 2-deficient mice display impaired coping behaviors during stress. Genes Brain Behav 5:131–138CrossRefGoogle Scholar
  17. D'Anna KL, Gammie SC (2009) Activation of corticotropin-releasing factor receptor 2 in lateral septum negatively regulates maternal defense. Behav Neurosci 123:356–368CrossRefGoogle Scholar
  18. D'Anna KL, Stevenson SA, Gammie SC (2005) Urocortin 1 and 3 impair maternal defense behavior in mice. Behav Neurosci 119:1061–1071CrossRefGoogle Scholar
  19. da Silva AV, Torres KR, Haemmerle CA, Cespedes IC, Bittencourt JC (2013) The Edinger-Westphal nucleus II: hypothalamic afferents in the rat. J Chem Neuroanat 54:5–19CrossRefGoogle Scholar
  20. Dabrowska J, Hazra R, Ahern TH, Guo JD, McDonald AJ, Mascagni F, Muller JF, Young LJ, Rainnie DG (2011) Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: implications for balancing stress and affect. Psychoneuroendocrinology 36:1312–1326CrossRefGoogle Scholar
  21. Dautzenberg FM, Hauger RL (2002) The CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci 23:71–77CrossRefGoogle Scholar
  22. Dedic N, Chen A, Deussing JM (2018) The CRF family of neuropeptides and their receptors - mediators of the central stress response. Curr Mol Pharmacol 11:4–31CrossRefGoogle Scholar
  23. Denver RJ (2009) Structural and functional evolution of vertebrate neuroendocrine stress systems. Ann N Y Acad Sci 1163:1–16CrossRefGoogle Scholar
  24. Deussing J, Breu J, Binder EB, Ohl F, Holsboer F, Wurst W (2003) Addressing in vivo functions of urocortin III, a novel member of the CRH family of neuropeptides. Pharmacopsychiatry 36:221–221Google Scholar
  25. Deussing JM, Breu J, Kuhne C, Kallnik M, Bunck M, Glasl L, Yen YC, Schmidt MV, Zurmuhlen R, Vogl AM, Gailus-Durner V, Fuchs H, Holter SM, Wotjak CT, Landgraf R, de Angelis MH, Holsboer F, Wurst W (2010) Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2. J Neurosci 30:9103–9116CrossRefGoogle Scholar
  26. Dos Santos Junior ED, Da Silva AV, Da Silva KR, Haemmerle CA, Batagello DS, Da Silva JM, Lima LB, Da Silva RJ, Diniz GB, Sita LV, Elias CF, Bittencourt JC (2015) The centrally projecting Edinger-Westphal nucleus--I: efferents in the rat brain. J Chem Neuroanat 68:22–38CrossRefGoogle Scholar
  27. Dunn AJ, File SE (1987) Corticotropin-releasing factor has an anxiogenic action in the social interaction test. Horm Behav 21:193–202CrossRefGoogle Scholar
  28. Engelmann M, Wotjak CT, Landgraf R (1995) Social discrimination procedure: an alternative method to investigate juvenile recognition abilities in rats. Physiol Behav 58:315–321CrossRefGoogle Scholar
  29. Fekete EM, Zhao Y, Li C, Sabino V, Vale WW, Zorrilla EP (2009) Social defeat stress activates medial amygdala cells that express type 2 corticotropin-releasing factor receptor mRNA. Neuroscience 162:5–13CrossRefGoogle Scholar
  30. Fekete EM, Zorrilla EP (2007) Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol 28:1–27CrossRefGoogle Scholar
  31. Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21:8278–8285CrossRefGoogle Scholar
  32. Fone KC, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32:1087–1102CrossRefGoogle Scholar
  33. Frankiensztajn LM, Gur-Pollack R, Wagner S (2018) A combinatorial modulation of synaptic plasticity in the rat medial amygdala by oxytocin, urocortin3 and estrogen. Psychoneuroendocrinology 92:95–102CrossRefGoogle Scholar
  34. Gammie SC, Hasen NS, Stevenson SA, Bale TL, D'Anna KL (2005) Elevated stress sensitivity in corticotropin-releasing factor receptor 2 deficient mice decreases maternal, but not intermale aggression. Behav Brain Res 160:169–177CrossRefGoogle Scholar
  35. Gehlert DR, Shekhar A, Morin SM, Hipskind PA, Zink C, Gackenheimer SL, Shaw J, Fitz SD, Sajdyk TJ (2005) Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor. Eur J Pharmacol 509:145–153CrossRefGoogle Scholar
  36. Goodson JL, Kabelik D (2009) Dynamic limbic networks and social diversity in vertebrates: from neural context to neuromodulatory patterning. Front Neuroendocrinol 30:429–441CrossRefGoogle Scholar
  37. Grammatopoulos DK, Randeva HS, Levine MA, Kanellopoulou KA, Hillhouse EW (2001) Rat cerebral cortex corticotropin-releasing hormone receptors: evidence for receptor coupling to multiple G-proteins. J Neurochem 76:509–519CrossRefGoogle Scholar
  38. Gur R, Tendler A, Wagner S (2014) Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala. Biol Psychiatry 76:377–386CrossRefGoogle Scholar
  39. Hale MW, Stamper CE, Staub DR, Lowry CA (2010) Urocortin 2 increases c-Fos expression in serotonergic neurons projecting to the ventricular/periventricular system. Exp Neurol 224:271–281CrossRefGoogle Scholar
  40. Hauger RL, Risbrough V, Brauns O, Dautzenberg FM (2006) Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets 5:453–479CrossRefGoogle Scholar
  41. Henckens MJ, Deussing JM, Chen A (2016) Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci 17:636–651CrossRefGoogle Scholar
  42. Hostetler CM, Ryabinin AE, 2013. The CRF system and social behavior: a review. Front Neurosci-Switz 7Google Scholar
  43. Hsu SY, Hsueh AJ (2001) Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 7:605–611CrossRefGoogle Scholar
  44. Joels M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10:459–466CrossRefGoogle Scholar
  45. Ketchesin KD, Stinnett GS, Seasholtz AF (2017) Corticotropin-releasing hormone-binding protein and stress: from invertebrates to humans. Stress 20:449–464CrossRefGoogle Scholar
  46. Klampfl SM, Brunton PJ, Bayerl DS, Bosch OJ (2014) Hypoactivation of CRF receptors, predominantly type 2, in the medial-posterior BNST is vital for adequate maternal behavior in lactating rats. J Neurosci 34:9665–9676CrossRefGoogle Scholar
  47. Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flugge G, Korte SM, Meerlo P, Murison R, Olivier B, Palanza P, Richter-Levin G, Sgoifo A, Steimer T, Stiedl O, van Dijk G, Wohr M, Fuchs E (2011) Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev 35:1291–1301CrossRefGoogle Scholar
  48. Kuperman Y, Chen A (2008) Urocortins: emerging metabolic and energy homeostasis perspectives. Trends Endocrinol Metab 19:122–129CrossRefGoogle Scholar
  49. Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW (2001) 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 U S A 98:7570–7575CrossRefGoogle Scholar
  50. Li X, Chen W, Pan K, Li H, Pang P, Guo Y, Shu S, Cai Y, Pei L, Liu D, Afewerky HK, Tian Q, Zhu LQ, Lu Y (2018) Serotonin receptor 2c-expressing cells in the ventral CA1 control attention via innervation of the Edinger-Westphal nucleus. Nat Neurosci 21:1239–1250CrossRefGoogle Scholar
  51. Lovejoy DA (2009) Structural evolution of urotensin-I: reflections of life before corticotropin releasing factor. Gen Comp Endocrinol 164:15–19CrossRefGoogle Scholar
  52. Lovejoy DA, Chang BS, Lovejoy NR, del Castillo J (2014) Molecular evolution of GPCRs: CRH/CRH receptors. J Mol Endocrinol 52:T43–T60CrossRefGoogle Scholar
  53. Lovenberg TW, Chalmers DT, Liu C, De Souza EB (1995a) CRF2 alpha and CRF2 beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 136:4139–4142CrossRefGoogle Scholar
  54. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, Desouza EB, Oltersdorf T (1995b) Cloning and characterization of a functionally distinct corticotropin-releasing factor-receptor subtype from rat-brain (Vol 92, Pg 836, 1995). Proc Natl Acad Sci U S A 92:5759CrossRefGoogle Scholar
  55. Lovett-Barron M, Andalman AS, Allen WE, Vesuna S, Kauvar I, Burns VM, Deisseroth K (2017) Ancestral circuits for the coordinated modulation of brain state. Cell 171(1411–1423):e1417Google Scholar
  56. Lukkes J, Vuong S, Scholl J, Oliver H, Forster G (2009a) Corticotropin-releasing factor receptor antagonism within the dorsal raphe nucleus reduces social anxiety-like behavior after early-life social isolation. J Neurosci 29:9955–9960CrossRefGoogle Scholar
  57. Lukkes JL, Summers CH, Scholl JL, Renner KJ, Forster GL (2009b) Early life social isolation alters corticotropin-releasing factor responses in adult rats. Neuroscience 158:845–855CrossRefGoogle Scholar
  58. Maroun M, Wagner S (2016) Oxytocin and memory of emotional stimuli: some dance to remember, some dance to forget. Biol Psychiatry 79:203–212CrossRefGoogle Scholar
  59. Marsden CA, King MV, Fone KC (2011) Influence of social isolation in the rat on serotonergic function and memory--relevance to models of schizophrenia and the role of 5-HT(6) receptors. Neuropharmacology 61:400–407CrossRefGoogle Scholar
  60. Martinon D, Dabrowska J (2018) Corticotropin-releasing factor receptors modulate oxytocin release in the dorsolateral bed nucleus of the stria terminalis (BNST) in male rats. Front Neurosci 12:183CrossRefGoogle Scholar
  61. Merchenthaler I, Vigh S, Petrusz P, Schally AV (1982) Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat brain. Am J Anat 165:385–396CrossRefGoogle Scholar
  62. Miczek KA (1979) A new test for aggression in rats without aversive stimulation: differential effects of d-amphetamine and cocaine. Psychopharmacology 60:253–259CrossRefGoogle Scholar
  63. Muchimapura S, Mason R, Marsden CA (2003) Effect of isolation rearing on pre- and post-synaptic serotonergic function in the rat dorsal hippocampus. Synapse 47:209–217CrossRefGoogle Scholar
  64. Perrin M, Donaldson C, Chen R, Blount A, Berggren T, Bilezikjian L, Sawchenko P, Vale W (1995) Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc Natl Acad Sci U S A 92:2969–2973CrossRefGoogle Scholar
  65. Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW (1993) Cloning and functional expression of a rat-brain corticotropin-releasing factor (Crf) receptor. Endocrinology 133:3058–3061CrossRefGoogle Scholar
  66. Pournajafi-Nazarloo H, Partoo L, Sanzenbacher L, Paredes J, Hashimoto K, Azizi F, Sue Carter C (2009) Stress differentially modulates mRNA expression for corticotrophin-releasing hormone receptors in hypothalamus, hippocampus and pituitary of prairie voles. Neuropeptides 43:113–123CrossRefGoogle Scholar
  67. Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE (2001) 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 U S A 98:2843–2848CrossRefGoogle Scholar
  68. Richard D, Lin Q, Timofeeva E (2002) The corticotropin-releasing factor family of peptides and CRF receptors: their roles in the regulation of energy balance. Eur J Pharmacol 440:189–197CrossRefGoogle Scholar
  69. Sajdyk TJ, Schober DA, Gehlert DR, Shekhar A (1999) Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses. Behav Brain Res 100:207–215CrossRefGoogle Scholar
  70. Sawchenko PE, Swanson LW (1985) Localization, colocalization, and plasticity of corticotropin-releasing factor immunoreactivity in rat-brain. Fed Proc 44:221–227Google Scholar
  71. Shair HN (2007) Acquisition and expression of a socially mediated separation response. Behav Brain Res 182:180–192CrossRefGoogle Scholar
  72. Shemesh Y, Forkosh O, Mahn M, Anpilov S, Sztainberg Y, Manashirov S, Shlapobersky T, Elliott E, Tabouy L, Ezra G, Adler ES, Ben-Efraim YJ, Gil S, Kuperman Y, Haramati S, Dine J, Eder M, Deussing JM, Schneidman E, Yizhar O, Chen A (2016) Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics. Nat Neurosci 19:1489–1496CrossRefGoogle Scholar
  73. Slater PG, Cerda CA, Pereira LA, Andres ME, Gysling K (2016) CRF binding protein facilitates the presence of CRF type 2 alpha receptor on the cell surface. Proc Natl Acad Sci U S A 113:4075–4080CrossRefGoogle Scholar
  74. Soga T, Teo CH, Cham KL, Idris MM, Parhar IS (2015) Early-life social isolation impairs the gonadotropin-inhibitory hormone neuronal activity and serotonergic system in male rats. Front Endocrinol (Lausanne) 6:172CrossRefGoogle Scholar
  75. Staub DR, Spiga F, Lowry CA (2005) Urocortin 2 increases c-Fos expression in topographically organized subpopulations of serotonergic neurons in the rat dorsal raphe nucleus. Brain Res 1044:176–189CrossRefGoogle Scholar
  76. Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6:269–324CrossRefGoogle Scholar
  77. Thor DH, Holloway wR (1982) Social memory of the male laboratory rat. J Comp Physiol Psychol 96:1000–1006CrossRefGoogle Scholar
  78. Turnbull AV, Rivier C (1997) Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides. Proc Soc Exp Biol Med 215:1–10CrossRefGoogle Scholar
  79. Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245–270Google Scholar
  80. Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE (2000) Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428:191–212CrossRefGoogle Scholar
  81. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C, Rivier J, Sawchenko PE, Vale W (1995) Urocortin, a mammalian neuropeptide related to fish urotensin-I and to corticotropin-releasing factor. Nature 378:287–292CrossRefGoogle Scholar
  82. Wood SK, McFadden KV, Grigoriadis D, Bhatnagar S, Valentino RJ (2012) Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor. Psychopharmacology 222:325–336CrossRefGoogle Scholar
  83. Xu L, Scheenen WJ, Roubos EW, Kozicz T (2012) Peptidergic Edinger-Westphal neurons and the energy-dependent stress response. Gen Comp Endocrinol 177:296–304CrossRefGoogle Scholar
  84. Young LJ (2002) The neurobiology of social recognition, approach, and avoidance. Biol Psychiatry 51:18–26CrossRefGoogle Scholar
  85. Zhao Y, Valdez GR, Fekete EM, Rivier JE, Vale WW, Rice KC, Weiss F, Zorrilla EP (2007) Subtype-selective corticotropin-releasing factor receptor agonists exert contrasting, but not opposite, effects on anxiety-related behavior in rats. J Pharmacol Exp Ther 323:846–854CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Sagol Department of Neurobiology, the Integrated Brain and Behavior Research Center (IBBR), Faculty of Natural SciencesUniversity of HaifaHaifaIsrael

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