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A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing

Molecular Psychiatry volume 15, pages 1067–1074 (2010)Cite this article

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A Corrigendum to this article was published on 26 March 2012

Abstract

Neuropeptide S (NPS) is a recently discovered G protein-coupled receptor ligand that modulates fear-like behaviors in rodents. A frequent A>T single-nucleotide polymorphism in the human NPS receptor gene NPSR1 confers a 10-fold higher efficacy of NPS signaling in vitro and has been linked with panic disorder (PD). We here report data from a classical fear-conditioning paradigm in healthy normal volunteers, in which carriers of the NPSR1 T allele evaluated their fear reactions to conditioned stimuli (CSs) as more pronounced than AA homozygous participants, although they did not show elevated peripheral-physiological conditioned responses (skin conductance responses—SCRs). T carriers also exhibited stronger CS-evoked brain activity in the rostral dorsomedial prefrontal cortex (dmPFC), an area that supports the explicit, conscious appraisal of threat stimuli. By contrast, more caudally situated mid-dmPFC, which has previously been associated with the generation of SCRs, showed no elevated response. Moreover, rostral dmPFC activation was correlated with participants’ fear evaluations, further strengthening the link of this activation to increased individual fear appraisal. Our data suggest a genetic and neuroanatomical substrate for catastrophizing overinterpretations of fear reactions and provide a mechanistic explanation for the association between the NPSR1 T allele and PD.

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References

  1. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH et al. Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 2004; 43: 487–497.

    Article  CAS  Google Scholar 

  2. Reinscheid RK, Xu YL, Okamura N, Zeng J, Chung S, Pai R et al. Pharmacological characterization of human and murine neuropeptide s receptor variants. J Pharmacol Exp Ther 2005; 315: 1338–1345.

    Article  CAS  Google Scholar 

  3. Jungling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD et al. Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron 2008; 59: 298–310.

    Article  Google Scholar 

  4. Meis S, Bergado-Acosta JR, Yanagawa Y, Obata K, Stork O, Munsch TS . Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus. PLoS ONE 2008; 3: e2695.

    Article  Google Scholar 

  5. Vitale G, Filaferro M, Ruggieri V, Pennella S, Frigeri C, Rizzi A et al. Anxiolytic-like effect of neuropeptide S in the rat defensive burying. Peptides 2008; 29: 2286–2291.

    Article  CAS  Google Scholar 

  6. Duangdao DM, Clark SD, Okamura N, Reinscheid RK . Behavioral phenotyping of neuropeptide S receptor knockout mice. Behav Brain Res 2009; 205: 1–9.

    Article  CAS  Google Scholar 

  7. Paneda C, Huitron-Resendiz S, Frago LM, Chowen JA, Picetti R, de Lecea L et al. Neuropeptide S reinstates cocaine-seeking behavior, increases locomotor activity through corticotropin-releasing factor receptor 1 in mice. J Neurosci 2009; 29: 4155–4161.

    Article  CAS  Google Scholar 

  8. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA et al. Results of a genome-wide genetic screen for panic disorder. Am J Med Genet 1998; 81: 139–147.

    Article  CAS  Google Scholar 

  9. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes Jr R . Genomewide survey of panic disorder. Am J Med Genet 2001; 105: 105–109.

    Article  CAS  Google Scholar 

  10. Logue MW, Vieland VJ, Goedken RJ, Crowe RR . Bayesian analysis of a previously published genome screen for panic disorder reveals new, compelling evidence for linkage to chromosome 7. Am J Med Genet B Neuropsychiatr Genet 2003; 121B: 95–99.

    Article  Google Scholar 

  11. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P et al. Characterization of a common susceptibility locus for asthma-related traits. Science 2004; 304: 300–304.

    Article  CAS  Google Scholar 

  12. Okamura N, Hashimoto K, Iyo M, Shimizu E, Dempfle A, Friedel S et al. Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1444–1448.

    Article  CAS  Google Scholar 

  13. Wolpe J, Rowan VC . Panic disorder: a product of classical conditioning. Behav Res Ther 1988; 26: 441–450.

    Article  CAS  Google Scholar 

  14. Bouton ME, Mineka S, Barlow DH . A modern learning theory perspective on the etiology of panic disorder. Psychol Rev 2001; 108: 4–32.

    Article  CAS  Google Scholar 

  15. Grillon C, Lissek S, McDowell D, Levenson J, Pine DS . Reduction of trace but not delay eyeblink conditioning in panic disorder. Am J Psychiatry 2007; 164: 283–289.

    Article  Google Scholar 

  16. Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS et al. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatry 2010; 167: 47–55.

    Article  Google Scholar 

  17. Beck AT, Emery G, Greenberg RL . Anxiety Disorders, Phobias. Basic Books: New York, 1985.

    Google Scholar 

  18. Reiss S, McNally RJ . The expectancy model of fear. In: Reiss S & Bootzin RR (eds). Theoretical Issues in Behavior Therapy. Academic Press: New York, 1985. pp 107–122.

    Google Scholar 

  19. Clark DM . A cognitive approach to panic. Behav Res Ther 1986; 24: 461–470.

    Article  CAS  Google Scholar 

  20. Hettema JM, Neale MC, Kendler KS . A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 2001; 158: 1568–1578.

    Article  CAS  Google Scholar 

  21. Weinberger DA, Singer JL . The construct validity of repressive coping style. In: Singer JL (ed). Repression and Dissociation: Implications for Personality Theory, Psychopathology, and Health. University of Chicago Press: Chicago, 1990. pp 337–386.

    Google Scholar 

  22. Mechias ML, Etkin A, Kalisch R . A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. Neuroimage 2010; 49: 1760–1768.

    Article  Google Scholar 

  23. Knight DC, Nguyen HT, Bandettini PA . The role of the human amygdala in the production of conditioned fear responses. Neuroimage 2005; 26: 1193–2000.

    Article  Google Scholar 

  24. Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL . A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry 2007; 62: 1191–1194.

    Article  Google Scholar 

  25. Gentil AF, Eskandar EN, Marci CD, Evans KC, Dougherty DD . Physiological responses to brain stimulation during limbic surgery: further evidence of anterior cingulate modulation of autonomic arousal. Biol Psychiatry 2009; 66: 695–701.

    Article  Google Scholar 

  26. Kalisch R, Wiech K, Critchley HD, Dolan RJ . Levels of appraisal: a medial prefrontal role in high-level appraisal of emotional material. Neuroimage 2006; 30: 1458–1466.

    Article  Google Scholar 

  27. Lee KH, Siegle GJ . Common and distinct brain networks underlying explicit emotional evaluation: a meta-analytic study. Soc Cogn Affect Neurosci 2009. e-pub ahead of print, 6 March 2009; doi: 10.1093/scan/nsp001.

    Article  Google Scholar 

  28. Klucken T, Tabbert K, Schweckendiek J, Merz CJ, Kagerer S, Vaitl D et al. Contingency learning in human fear conditioning involves the ventral striatum. Hum Brain Mapp 2009; 30: 3636–3644.

    Article  Google Scholar 

  29. Hajcak G, Castille C, Olvet DM, Dunning JP, Roohi J, Hatchwell E . Genetic variation in brain-derived neurotrophic factor and human fear conditioning. Genes Brain Behav 2009; 8: 80–85.

    Article  CAS  Google Scholar 

  30. Lonsdorf TB, Weike AI, Nikamo P, Schalling M, Hamm AO, Ohman A . Genetic gating of human fear learning and extinction: possible implications for gene-environment interaction in anxiety disorder. Psychol Sci 2009; 20: 198–206.

    Article  Google Scholar 

  31. Kalisch R, Holt B, Petrovic P, De Martino B, Klöppel S, Büchel C et al. The NMDA agonist D-cycloserine facilitates fear memory consolidation in humans. Cereb Cortex 2009; 19: 187–196.

    Article  Google Scholar 

  32. Boshuisen ML, Ter Horst GJ, Paans AM, Reinders AA, Den Boer JA . rCBF differences between panic disorder patients and control subjects during anticipatory anxiety and rest. Biol Psychiatry 2002; 52: 126–135.

    Article  Google Scholar 

  33. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC et al. Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch Gen Psychiatry 2005; 62: 922–933.

    Article  Google Scholar 

  34. Asami T, Hayano F, Nakamura M, Yamasue H, Uehara K, Otsuka T et al. Anterior cingulate cortex volume reduction in patients with panic disorder. Psychiatry Clin Neurosci 2008; 62: 322–330.

    Article  Google Scholar 

  35. Uchida RR, Del-Ben CM, Busatto GF, Duran FL, Guimarães FS, Crippa JA et al. Regional gray matter abnormalities in panic disorder: a voxel-based morphometry study. Psychiatry Res 2008; 163: 21–29.

    Article  Google Scholar 

  36. Kalisch R, Wiech K, Critchley HD, Seymour B, O’Doherty JP, Oakley DA et al. Anxiety reduction through detachment: subjective, physiological, and neural effects. J Cogn Neurosci 2005; 17: 874–883.

    Article  Google Scholar 

  37. Xu YL, Gall CM, Jackson VR, Civelli O, Reinscheid RK . Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. J Comp Neurol 2007; 500: 84–102.

    Article  CAS  Google Scholar 

  38. Han C, O’Tuathaigh CM, van Trigt L, Quinn JJ, Fanselow MS, Mongeau R et al. Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc Natl Acad Sci USA 2003; 100: 13087–13092.

    Article  CAS  Google Scholar 

  39. Scherer KR . Appraisal considered as a process of multilevel sequential checking. In: Scherer KR, Schorr A and Johnstone T (eds). Appraisal Processes in Emotion: Theory, Methods, Research. Oxford University Press: NY, 2001. pp 92–120.

    Google Scholar 

  40. Gross JJ . Emotion regulation: affective, cognitive, and social consequences. Psychophysiology 2002; 39: 281–291.

    Article  Google Scholar 

  41. Houston BK, Holmes DS . Effect of avoidant thinking and reappraisal for coping with threat involving temporal uncertainty. J Pers Soc Psychol 1974; 30: 382–388.

    Article  CAS  Google Scholar 

  42. Wiech K, Kalisch R, Weiskopf N, Pleger B, Stephan KE, Dolan RJ . Anterolateral prefrontal cortex mediates the analgesic effects of expected and perceived control over pain. J Neurosci 2006; 26: 11501–11509.

    Article  CAS  Google Scholar 

  43. Kalisch R . The functional neuroanatomy of reappraisal: time matters. Neurosci Biobehav Rev 2009; 33: 1215–1226.

    Article  Google Scholar 

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Acknowledgements

We thank F Fassbinder, GW Alpers, H-C Pape, M Pessiglione and T Dresler for technical help and comments. This work was funded by the Deutsche Forschungsgemeinschaft (DFG Emmy Noether Grant KA1623/3–1 (KR, NG, MLM, RK); DFG Transregional Collaborative Research Centre grant SFB TRR 58, subproject Z2 (AR, JD)) and the UKE's complementary funding program (RK).

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Authors and Affiliations

  1. Institute for Systems Neuroscience, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany

    K A Raczka, N Gartmann, M-L Mechias, C Büchel & R Kalisch

  2. Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    A Reif & J Deckert

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  1. K A Raczka
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Correspondence to R Kalisch.

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Raczka, K., Gartmann, N., Mechias, ML. et al. A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. Mol Psychiatry 15, 1067–1074 (2010). https://doi.org/10.1038/mp.2010.79

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