title: Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle.
abstract: The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT-). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT-. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT-. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders.
authors: Department of Psychology I, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg Würzburg, Germany.
authors: Evelyn
authors: E
authors: Glotzbach-Schoon
authors: Marta
authors: M
authors: Andreatta
authors: Andreas
authors: A
authors: Reif
authors: Heike
authors: H
authors: Ewald
authors: Christian
authors: C
authors: Tröger
authors: Christian
authors: C
authors: Baumann
authors: Jürgen
authors: J
authors: Deckert
authors: Andreas
authors: A
authors: Mühlberger
authors: Paul
authors: P
authors: Pauli
keywords: 5HTTLPR; NPSR1; contextual fear conditioning; fear-potentiated startle; gene × gene interaction
references: Neurosci Lett. 2010 May 3;474(3):154-157
references: 20298749
references: Am Psychol. 2006 Nov;61(8):741-756
references: 17115806
references: Psychopharmacology (Berl). 2008 Aug;199(3):421-37
references: 18058089
references: Neuropharmacology. 2010 Jan;58(1):29-34
references: 19523478
references: Biol Psychiatry. 2002 Nov 15;52(10):927-37
references: 12437934
references: Cogn Affect Behav Neurosci. 2009 Jun;9(2):168-72
references: 19403893
references: Soc Cogn Affect Neurosci. 2011 Sep;6(4):495-506
references: 20693389
references: Psychophysiology. 1998 Nov;35(6):729-36
references: 9844434
references: Acta Psychol (Amst). 2008 Mar;127(3):567-80
references: 18226795
references: Psychiatry Clin Neurosci. 2005 Apr;59(2):119-26
references: 15823155
references: Psychol Sci. 2009 Feb;20(2):198-206
references: 19175757
references: J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57
references: 9881538
references: Cogn Emot. 2012;26(7):1256-72
references: 22551520
references: Biol Psychol. 2012 Feb;89(2):277-82
references: 22061270
references: Science. 1996 Nov 29;274(5292):1527-31
references: 8929413
references: Neuron. 2008 Jul 31;59(2):298-310
references: 18667157
references: Neurosci Biobehav Rev. 1999 May;23(5):743-60
references: 10392663
references: Biol Psychol. 2013 Apr;93(1):159-66
references: 23384512
references: Psychol Rev. 1990 Jul;97(3):377-95
references: 2200076
references: Prog Neurobiol. 1999 Oct;59(2):107-28
references: 10463792
references: J Comp Neurol. 2007 Jan 1;500(1):84-102
references: 17099900
references: Behav Brain Res. 2011 Feb 2;217(1):1-9
references: 20888368
references: Arch Gen Psychiatry. 2003 Jul;60(7):702-8
references: 12860774
references: J Pers Soc Psychol. 1988 Jun;54(6):1063-70
references: 3397865
references: Proc Biol Sci. 2010 Aug 7;277(1692):2411-6
references: 20356893
references: Annu Rev Neurosci. 2004;27:193-222
references: 15217331
references: Neuropharmacology. 2012 Feb;62(2):628-37
references: 21356219
references: Behav Res Ther. 2005 Nov;43(11):1391-424
references: 15885654
references: Psychophysiology. 1996 Nov;33(6):698-710
references: 8961792
references: Science. 2002 Jul 19;297(5580):400-3
references: 12130784
references: Annu Rev Psychol. 2006;57:117-37
references: 16318591
references: Am J Psychiatry. 2008 Jul;165(7):898-904
references: 18347001
references: Behav Brain Res. 2011 Sep 23;222(2):357-62
references: 21497171
references: Nat Neurosci. 2005 Jan;8(1):20-1
references: 15592465
references: Nat Neurosci. 2007 Sep;10(9):1103-9
references: 17726476
references: Biol Psychiatry. 2009 Jul 1;66(1):47-53
references: 19217076
references: Depress Anxiety. 2011 Dec 21;28(12):1048-57
references: 21681867
references: Psychol Sci. 2004 Dec;15(12):822-8
references: 15563327
references: Psychophysiology. 2005 Jan;42(1):1-15
references: 15720576
references: PLoS One. 2009 Jul 07;4(7):e6156
references: 19582153
references: World J Biol Psychiatry. 2014 Jan;15(1):17-25
references: 22404660
references: Transl Psychiatry. 2011 Sep 20;1:e41
references: 22832657
references: Amino Acids. 2011 Oct;41(4):991-6
references: 21861171
references: Neuropsychopharmacology. 2011 Aug;36(9):1879-85
references: 21525857
references: Behav Genet. 1999 Mar;29(2):95-102
references: 10405458
references: J Neurosci. 2008 Sep 3;28(36):9030-6
references: 18768697
references: J Neural Transm (Vienna). 2012 Jun;119(6):709-19
references: 22227740
references: J Abnorm Psychol. 2000 May;109(2):290-8
references: 10895567
references: J Pharmacol Exp Ther. 2005 Dec;315(3):1338-45
references: 16144971
references: Psychopharmacology (Berl). 2011 Mar;214(1):175-96
references: 21225419
references: Trends Cogn Sci. 2006 Apr;10(4):182-91
references: 16530463
references: Psychol Med. 2007 Aug;37(8):1119-29
references: 17407618
references: J Clin Psychiatry. 2010 May;71(5):543-7
references: 20441718
references: PLoS One. 2008 Jul 16;3(7):e2695
references: 18628994
references: J Physiol. 2012 Aug 15;590(16):3701-17
references: 22570383
references: Int J Psychophysiol. 2005 Jul;57(1):5-14
references: 15935258
references: Mol Psychiatry. 2010 Nov;15(11):1045, 1067-74
references: 20628342
references: J Neurosci. 2008 Jun 11;28(24):6211-9
references: 18550763
references: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11981-6
references: 18695238
references: Neuroimage. 2010 Nov 15;53(3):893-8
references: 19962442
references: Mol Psychiatry. 2011 Sep;16(9):938-48
references: 20603625
references: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16033-8
references: 17032778
references: Depress Anxiety. 2011 Dec 21;28(12):1067-73
references: 21818827
references: Brain. 2003 Feb;126(Pt 2):267-75
references: 12538396
references: Psychiatr Ann. 2009 Jun 1;39(6):358-367
references: 19779593
references: Soc Cogn Affect Neurosci. 2013 Mar;8(3):318-25
references: 22258800
references: Biol Psychiatry. 2002 Nov 15;52(10):958-75
references: 12437937
references: Neuroimage. 2011 Mar 1;55(1):389-400
references: 21111828
references: Am Psychol. 2006 Jan;61(1):10-26
references: 16435973
references: Nature. 2010 Jan 7;463(7277):49-53
references: 20010606
references: Neuropsychopharmacology. 2012 Feb;37(3):759-69
references: 22012471
references: Behav Res Ther. 2009 Feb;47(2):111-8
references: 19027893
references: Behav Res Ther. 1986;24(1):1-8
references: 3947307