title: Impaired Pavlovian fear extinction is a common phenotype across genetic lineages of the 129 inbred mouse strain.
abstract: Fear extinction is impaired in psychiatric disorders such as post-traumatic stress disorder and schizophrenia, which have a major genetic component. However, the genetic factors underlying individual variability in fear extinction remain to be determined. By comparing a panel of inbred mouse strains, we recently identified a strain, 129S1/SvImJ (129S1), that exhibits a profound and selective deficit in Pavlovian fear extinction, and associated abnormalities in functional activation of a key prefrontal-amygdala circuit, as compared with C57BL/6J. The first aim of the present study was to assess fear extinction across multiple 129 substrains representing the strain's four different genetic lineages (parental, steel, teratoma and contaminated). Results showed that 129P1/ReJ, 129P3/J, 129T2/SvEmsJ and 129X1/SvJ exhibited poor fear extinction, relative to C57BL/6J, while 129S1 showed evidence of fear incubation. On the basis of these results, the second aim was to further characterize the nature and specificity of the extinction phenotype in 129S1, as an exemplar of the 129 substrains. Results showed that the extinction deficit in 129S1 was neither the result of a failure to habituate to a sensitized fear response nor an artifact of a fear response to (unconditioned) tone per se. A stronger conditioning protocol (i.e. five x higher intensity shocks) produced an increase in fear expression in 129S1, relative to C57BL/6J, due to rapid rise in freezing during tone presentation. Taken together, these data show that impaired fear extinction is a phenotypic feature common across 129 substrains, and provide preliminary evidence that impaired fear extinction in 129S1 may reflect a pro-fear incubation-like process.
authors.affiliation: Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA. campmc@mail.nih.gov
authors.forename: M
authors.initials: M
authors.lastname: Camp
authors.forename: M
authors.initials: M
authors.lastname: Norcross
authors.forename: N
authors.initials: N
authors.lastname: Whittle
authors.forename: M
authors.initials: M
authors.lastname: Feyder
authors.forename: W
authors.initials: W
authors.lastname: D'Hanis
authors.forename: D
authors.initials: D
authors.lastname: Yilmazer-Hanke
authors.forename: N
authors.initials: N
authors.lastname: Singewald
authors.forename: A
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001923:Brain Chemistry / Q000235:genetics; D003213:Conditioning, Psychological / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D014644:Genetic Variation / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009483:Neuropsychological Tests; D010641:Phenotype; D013045:Species Specificity
references.citation: Behav Neurosci. 2002 Aug;116(4):600-11
references.pmid: 12148927
references.citation: Genes Brain Behav. 2002 Jan;1(1):55-69
references.pmid: 12886950
references.citation: Behav Brain Res. 2005 Feb 28;157(2):291-8
references.pmid: 15639180
references.citation: Brain Res. 1997 Oct 10;771(1):1-13
references.pmid: 9383002
references.citation: Mol Psychiatry. 2007 Feb;12(2):120-50
references.pmid: 17160066
references.citation: J Neurosci. 2008 Nov 19;28(47):12147-9
references.pmid: 19020008
references.citation: Nat Rev Drug Discov. 2005 Sep;4(9):775-90
references.pmid: 16138108
references.citation: Comp Med. 2005 Aug;55(4):326-34
references.pmid: 16158908
references.citation: J Neurosci. 2006 Jun 21;26(25):6677-86
references.pmid: 16793875
references.citation: Mamm Genome. 1999 Aug;10(8):836
references.pmid: 10430671
references.citation: Hippocampus. 2005;15(4):502-17
references.pmid: 15744733
references.citation: Learn Mem. 2005 Jul-Aug;12(4):399-406
references.pmid: 16077018
references.citation: J Comp Physiol Psychol. 1969 Mar;67(3):370-5
references.pmid: 5787388
references.citation: Learn Mem. 2004 Nov-Dec;11(6):770-86
references.pmid: 15537742
references.citation: Nat Genet. 2005 May;37(5):532-6
references.pmid: 15852006
references.citation: Learn Mem. 2006 Nov-Dec;13(6):728-33
references.pmid: 17142302
references.citation: Behav Brain Res. 2007 Jan 25;176(2):210-5
references.pmid: 17098297
references.citation: J Gen Psychol. 2002 Oct;129(4):364-400
references.pmid: 12494990
references.citation: Genes Brain Behav. 2004 Jun;3(3):149-57
references.pmid: 15140010
references.citation: Neuropsychopharmacology. 2008 Jan;33(1):56-72
references.pmid: 17882236
references.citation: Nature. 1981 Jul 9;292(5819):154-6
references.pmid: 7242681
references.citation: Cell. 1987 Nov 6;51(3):503-12
references.pmid: 2822260
references.citation: Neuroscience. 1997 Oct;80(4):1087-99
references.pmid: 9284062
references.citation: Behav Res Ther. 1968 Aug;6(3):309-21
references.pmid: 5734549
references.citation: Pharmacol Biochem Behav. 2005 Mar;80(3):427-36
references.pmid: 15740785
references.citation: J Exp Anal Behav. 1973 Jan;19(1):101-11
references.pmid: 16811644
references.citation: Neurosci Biobehav Rev. 2009 Jun;33(6):773-83
references.pmid: 19111570
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7
references.pmid: 16484369
references.citation: J Exp Psychol Anim Behav Process. 2003 Oct;29(4):323-33
references.pmid: 14570519
references.citation: Brain Res. 1982 May 13;239(2):329-47
references.pmid: 7093694
references.citation: Genes Brain Behav. 2009 Feb;8(1):1-4
references.pmid: 18778401
references.citation: Behav Brain Res. 2003 Mar 18;140(1-2):97-106
references.pmid: 12644283
references.citation: Learn Mem. 2000 May-Jun;7(3):170-9
references.pmid: 10837506
references.citation: Nat Genet. 2005 Nov;37(11):1175-80
references.pmid: 16254563
references.citation: Biol Psychiatry. 2009 May 15;65(10):881-6
references.pmid: 19167702
references.citation: Psychopharmacology (Berl). 2008 Oct;200(3):413-24
references.pmid: 18594797
references.citation: Psychopharmacology (Berl). 1997 Jul;132(2):107-24
references.pmid: 9266608
references.citation: Eur J Neurosci. 2004 Aug;20(3):781-90
references.pmid: 15255988
references.citation: Mamm Genome. 1997 Jun;8(6):390-3
references.pmid: 9166580
references.citation: Biol Psychiatry. 2009 Mar 15;65(6):455-63
references.pmid: 18986648
references.citation: Trends Neurosci. 2002 Jul;25(7):336-40
references.pmid: 12079755
references.citation: J Neurosci. 2008 Aug 6;28(32):8074-85
references.pmid: 18685032
references.citation: Nat Genet. 1997 May;16(1):19-27
references.pmid: 9140391
references.citation: Arch Gen Psychiatry. 2001 Nov;58(11):1005-14
references.pmid: 11695946
references.citation: Mamm Genome. 2001 Aug;12(8):651-6
references.pmid: 11471061