CRC-TRR58 „Fear, Anxiety, Anxiety Disorders“

succeeded and finished after more than 12 years of funding by the German Research Foundation

  • Summary

    Fear (the feeling of a discrete threat exerted for instance by a person or an object) and anxiety (the diffuse sensation of being scared, for instance in a situation that is considered unsafe) are important adaptive components of the behaviour, which are generated in anticipation of or in response to potentially harmful stimuli. Anxiety or anxiety-like states are considered as part of a universal survival strategy, where inter-individual variability reflects an evolutionary principle for survival of the population. However, extreme alterations or a distortion of these behavioral mechanisms may trigger disproportional and prolonged states of anxiety that are difficult to cope with and to control by the ones affected: such states are experienced, for instance, as excessive anxiety with respect to the triggering stimulus, persistence of anxiety following withdrawal of the stimulus or omnipresent generalized anxiety. This sort of maladaptive anxiety likely reflects an underlying pathology, an anxiety disorder, requiring treatment. In fact, anxiety disorders are ranked among the most frequent psychiatric disorders (life time prevalence 14-29% in the EU), and among those with earliest disease onset. Such a disease has a dramatic impact on life quality, learning and other intellectual capabilities, ability to work and to socially interact. (cf Neuroforum 3.13, September 2013. Springer-Spektrum. D 13882 F ISSN 0947-0875).

    Any attempt of systematic, scientific analyses of these emotions and their pathological alterations requires an interdisciplinary strategy, aiming at the identification of detailed mechanisms and, and the same time, allowing translational approaches, thereby paving the way for novel avenues in diagnosis, therapy and identification of individual risk profiles for the disease. These are the strategic lines, along which the Transregional Collaborative Research Center „Fear, Anxiety, Anxiety Disorders (CRC-TRR58)“ has been designed, established and funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) in July 2008. It has been finished after twelve years of funding in December 2020. The center joined scientists from the Universities of Münster, Hamburg, and Würzburg, and a connected group at Mainz University, contributing expertise in molecular biology, genetics, neurophysiology, behavioral biology, psychology, psychiatry and imaging.

    This concentration of expertise and interdisciplinary collaborations has been truly unique in this field of research. Together, this scientific concept and the transregional collaborative structure enabled a conceptual overlap between animal experimental and human studies, providing a rational basis for dedicated interdisciplinary and translational approaches. Results of mechanistic principles were imported into clinically oriented studies, and data from patient studies were incorporated into the design of basic research. Making use of this strategy, traditional mostly static views on fear and anxiety have been extended into a dynamic concept, where acute or accumulated environmental influences, nested into genetic dispositions, drive the individual anxiety profile. Strategic aims, which had been defined around the stating period, were largely reached after a decade of collaborative effort: (i) scientifically, understanding of synaptic mechanisms linking gene-environment interactions in distinct pathways of the brain has been complemented by identification of predictive neurobiological markers, paving the way for individualized preventive and therapeutic intervention strategies; (ii) structurally, the research program has attracted excellent scientists in the field and beyond, the young researchers program has sustainably improved the conditions for scientists at an early career step and directed a „new“ generation of scientists towards research on emotion, and through all of this neuroscience has become a significant profiling element of the participating universities; (iii) nationally and internationally, impulses and integrative influences of CRC-TRR58 have strengthened research on fear, anxiety and anxiety disorders, and has provided a promising base for future collaborative concepts on the study of stress- and anxiety-related behaviour.


  • 40 besten Publikationen

    1. Andreatta M, Neueder D, Herzog K, Genheimer H, Schiele MA, Deckert J, Domschke K, Reif A, Wieser MJ, Pauli P (2020) Generalization of Conditioned Contextual Anxiety and the Modulatory Effects of Anxiety Sensitivity. Neurotherapeutics: doi:10.1007/s13311-020-00831-8.
    2. Bartsch JC, Jamil S, Remmes J, Verma D, Pape HC (2020) Functional deletion of neuropeptide Y receptors type 2 in local synaptic networks of anteroventral BNST facilitates recall and increases return of fear. Mol Psychiatry,
    3. Biedermann SV, Biedermann DG, Wenzlaff F, Kurjak T, Nouri S, Auer MK, Wiedemann K, Briken P, Haaker J, Lonsdorf TB, Fuss J (2017) An elevated plus-maze in mixed reality for studying human anxiety-related behavior. BMC Biol 15:125.
    4. Bodden C, Richter SH, Schreiber RS, Kloke V, Gerss J, Palme R, Lesch K-P, Lewejohann L, Kaiser S, Sachser N (2015) Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype. Front Behav Neurosci 9:47.
    5. Brinkmann L, Buff C, Feldker K, Neumeister P, Heitmann CY, Hofmann D, Bruchmann M, Herrmann MJ, Straube T (2018) Inter-individual differences in trait anxiety shape the functional connectivity between the bed nucleus of the stria terminalis and the amygdala during brief threat processing. Neuroimage 166:110–116.
    6. Bröckelmann AK, Steinberg C, Elling L, Zwanzger P, Pantev C, Junghöfer M (2011) Emotion-associated tones attract enhanced attention at early auditory processing: magnetoencephalographic correlates. J Neurosci 31:7801–7810.
    7. Chauveau F, Lange MD, Jüngling K, Lesting J, Seidenbecher T, Pape HC (2012) Prevention of stress-impaired fear extinction through neuropeptide s action in the lateral amygdala. Neuropsychopharmacology 37:1588–1599.
    8. Deckert J, Weber H, Villmann C, Lonsdorf TB, Richter J, Andreatta M, Arias-Vasquez A, Hommers L, Kent L, Schartner C, Cichon S, Wolf C, Schaefer N, von Collenberg CR, Wachter B, Blum R, Schümann D, Scharfenort R, Schumacher J, Forstner AJ, Baumann C, Schiele MA, Notzon S, Zwanzger P, Janzing JGE, Galesloot T, Kiemeney LA, Gajewska A, Glotzbach-Schoon E, Mühlberger A, Alpers G, Fydrich T, Fehm L, Gerlach AL, Kircher T, Lang T, Ströhle A, Arolt V, Wittchen HU, Kalisch R, Büchel C, Hamm A, Nöthen MM, Romanos M, Domschke K, Pauli P, Reif A. (2017) GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder. Mol Psychiatry 22:1431–1439.
    9. Domschke K, Reif A, Weber H, Richter J, Hohoff C, Ohrmann P, Pedersen A, Bauer J, Suslow T, Kugel H, Heindel W, Baumann C, Klauke B, Jacob C, Maier W, Fritze J, Bandelow B, Krakowitzky P, Rothermundt M, Erhardt A, Binder EB, Holsboer F, Gerlach AL, Kircher T, Lang T, Alpers GW, Ströhle A, Fehm L, Gloster AT, Wittchen HU, Arolt V, Pauli P, Hamm A, Deckert J. (2011) Neuropeptide S receptor gene -- converging evidence for a role in panic disorder. Mol Psychiatry 16:938–948.
    10. Domschke K, Gajewska A, Winter B, Herrmann MJ, Warrings B, Mühlberger A, Wosnitza K, Glotzbach E, Conzelmann A, Dlugos A, Fobker M, Jacob C, Arolt V, Reif A, Pauli P, Zwanzger P, Deckert J (2012) ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex. Neuropsychopharmacology 37:759–769.
    11. Gerber B, Yarali A, Diegelmann S, Wotjak C, Pauli P, Fendt M (2014) Pain-relief learning in flies, rats, and man: Basic research and applied perspectives. Learn Mem 21:232. Review.
    12. Gottschalk MG Richter J, Ziegler C, Schiele MA, Mann J, Geiger MJ, Schartner C, Homola GA, Alpers GW, Büchel C, Fehm L, Fydrich T, Gerlach AL, Gloster AT, Helbig-Lang S, Kalisch R, Kircher T, Lang T, Lonsdorf TB, Pané-Farré CA, Ströhle A, Weber H, Zwanzger P, Arolt V, Romanos M, Wittchen HU, Hamm A, Pauli P, Reif A, Deckert J, Neufang S, Höfler M, Domschke K. (2019) Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes. Transl Psychiatry 9:75.
    13. Haaker J, Gaburro S, Sah A, Gartmann N, Lonsdorf TB, Meier K, Singewald N, Pape HC, Morellini F, Kalisch R (2013) Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear. Proc Natl Acad Sci U S A 110: E2428-36.
    14. Haaker J, Maren S, Andreatta M, Merz CJ, Richter J, Richter SH, Meir Drexler S, Lange MD, Jungling K, Nees F, Seidenbecher T, Fullana MA, Wotjak CT, Lonsdorf TB (2019) Making translation work: Harmonizing cross-species methodology in the behavioural neuroscience of Pavlovian fear conditioning. Neurosci Biobehav Rev 107:329–345. Review.
    15. Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu Y-L, Reinscheid RK, Pape HC (2008) Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron 59:298–310.
    16. Jüngling K, Lange MD, Szkudlarek HJ, Lesting J, Erdmann FS, Doengi M, Kugler S, Pape HC (2015) Increased GABAergic Efficacy of Central Amygdala Projections to Neuropeptide S Neurons in the Brainstem During Fear Memory Retrieval. Neuropsychopharmacology 40:2753–2763.
    17. Kampermann L, Wilming N, Alink A, Buchel C, Onat S (2019) Fixation-pattern similarity analysis reveals adaptive changes in face-viewing strategies following aversive learning. Elife 8.
    18. Kamprath K, Romo-Parra H, Haring M, Gaburro S, Doengi M, Lutz B, Pape HC (2011) Short-term adaptation of conditioned fear responses through endocannabinoid signaling in the central amygdala. Neuropsychopharmacology 36:652–663.
    19. Kastner-Dorn AK, Andreatta M, Pauli P, Wieser MJ (2018) Hypervigilance during anxiety and selective attention during fear: Using steady-state visual evoked potentials (ssVEPs) to disentangle attention mechanisms during predictable and unpredictable threat. Cortex 106:120–131.
    20. Kuhn M, Wendt J, Sjouwerman R, Buchel C, Hamm A, Lonsdorf TB (2020) The Neurofunctional Basis of Affective Startle Modulation in Humans: Evidence from Combined Facial Electromyography and Functional Magnetic Resonance Imaging. Biol Psychiatry 87:548–558.
    21. Lange MD, Daldrup T, Remmers F, Szkudlarek HJ, Lesting J, Guggenhuber S, Ruehle S, Jüngling K, Seidenbecher T, Lutz B, Pape HC (2017) Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat. Mol Psychiatry 22:1422–1430.
    22. Lange MD, Jüngling K, Paulukat L, Vieler M, Gaburro S, Sosulina L, Blaesse P, Sreepathi HK, Ferraguti F, Pape HC (2014) Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization. Neuropsychopharmacology 39:2211–2220.
    23. Lonsdorf TB, Klingelhofer-Jens M, Andreatta M, Beckers T, Chalkia A, Gerlicher A, Jentsch VL, Meir Drexler S, Mertens G, Richter J, Sjouwerman R, Wendt J, Merz CJ (2019) Navigating the garden of forking paths for data exclusions in fear conditioning research. Elife 8.
    24. Lonsdorf TB, Merz CJ (2017) More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls. Neurosci Biobehav Rev 80:703–728. Review.
    25. Lueken U, Kuhn M, Yang Y, Straube B, Kircher T, Wittchen H-U, Pfleiderer B, Arolt V, Wittmann A, Strohle A, Weber H, Reif A, Domschke K, Deckert J, Lonsdorf TB (2017) Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach. Transl Psychiatry 7:e1227.
    26. Lueken U, Zierhut KC, Hahn T, Straube B, Kircher T, Reif A, Richter J, Hamm A, Wittchen H-U, Domschke K (2016) Neurobiological markers predicting treatment response in anxiety disorders: A systematic review and implications for clinical application. Neurosci Biobehav Rev 66:143–162. Review.
    27. Mühlberger A, Andreatta M, Ewald H, Glotzbach-Schoon E, Troger C, Baumann C, Reif A, Deckert J, Pauli P (2014) The BDNF Val66Met polymorphism modulates the generalization of cued fear responses to a novel context. Neuropsychopharmacology 39:1187–1195.
    28. Pape HC, Paré D (2010) Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 90:419–463. Review.
    29. Onat S, Buchel C (2015) The neuronal basis of fear generalization in humans. Nat Neurosci 18:1811–1818.
    30. Raczka KA, Gartmann N, Mechias M-L, Reif A, Buchel C, Deckert J, Kalisch R (2010) A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. Mol Psychiatry 15:1067-1074.
    31. Reif A, Richter J, Straube B, Höfler M, Lueken U, Gloster AT, Weber H, Domschke K, Fehm L, Ströhle A, Jansen A, Gerlach A, Pyka M, Reinhardt I, Konrad C, Wittmann A, Pfleiderer B, Alpers GW, Pauli P, Lang T, Arolt V, Wittchen HU, Hamm A, Kircher T, Deckert J. (2014) MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy. Mol Psychiatry 19:122–128.
    32. Ruehle S, Remmers F, Romo-Parra H, Massa F, Wickert M, Wortge S, Haring M, Kaiser N, Marsicano G, Pape HC, Lutz B (2013) Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions. J Neurosci 33:10264–10277.
    33. Schiele MA, Herzog K, Kollert L, Schartner C, Leehr EJ, Böhnlein J, Repple J, Rosenkranz K, Lonsdorf TB, Dannlowski U, Zwanzger D, Reif A, Pauli P, Deckert J, Domschke K (2020a) Extending the vulnerability-stress model of mental disorders: A three-dimensional NPSR1 gene x environment x coping interaction study in anxiety. Br J Psychiatry, doi: 10.1192/bjp.2020.73
    34. Schiele MA, Gottschalk MG, Domschke K (2020c) The applied implications of epigenetics in anxiety, affective and stress-related disorders – A review and synthesis on psychosocial stress, psychotherapy and prevention. Clin Psychol Rev 77:101830. Review.
    35. Schraut KG, Jakob SB, Weidner MT, Schmitt AG, Scholz CJ, Strekalova T, El Hajj N, Eijssen LMT, Domschke K, Reif A, Haaf T, Ortega G, Steinbusch HWM, Lesch KP, Van den Hove DL (2014) Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice. Transl Psychiatry 4:e473.
    36. Segebarth D, Griebel M, Stein N, von Collenberg CR, Martin C, Fiedler D, Comeras LB, Sah A, Schoeler V, Lüffe T, Dürr A, Gupta R, Sasi M, Lillesaar C, Lange MD, Tasan RO, Singewald N, Pape HC, Flath CM, Blum R (2020). On the objectivity, reliability, and validity of deep learning-enabled bioimage analyses. Elife (in press). eLife 2020;9:e59780 doi: 10.7554/eLife.59780.
    37. Waider J, Popp S, Lange MD, Kern R, Kolter JF, Kobler J, Donner NC, Lowe KR, Malzbender JH, Brazell CJ, Arnold MR, Aboagye B, Schmitt-Bohrer A, Lowry CA, Pape HC, Lesch KP (2017) Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice. Transl Psychiatry 7:e1246.
    38. Weber H, Richter J, Straube B, Lueken U, Domschke K, Schartner C, Klauke B, Baumann C, Pané-Farré C, Jacob CP, Scholz CJ, Zwanzger B, Lang T, Lehm L, Jansen A, Konrad C, Fydrich T, Wittman A, Pfleiderer B, Ströhle A, Gerlach AL, Alpers GW, Arolt V, Pauli P, Wittchen HU, Kent L, Hamm A, Kircher T, Deckert J, Reif A (2016) Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing. Mol Psychiatry 21:813–822.
    39. Ziegler C Richter J, Mahr M, Gajewska A, Schiele MA, Gehrmann A, Schmidt B, Lesch KP, Lang T, Helbig-Lang S, Pauli P, Kircher T, Reif A, Rief W, Vossbeck-Elsebusch AN, Arolt V, Wittchen HU, Hamm AO, Deckert J, Domschke K. (2016) MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Transl Psychiatry 6:e773.
    40. Ziegler C, Grundner-Culemann F, Schiele MA, Schlosser P, Kollert L, Mahr M, Gajewska A, Lesch K-P, Deckert J, Kottgen A, Domschke K (2019) The DNA methylome in panic disorder: a case-control and longitudinal psychotherapy-epigenetic study. Transl Psychiatry 9:314.