title: Traits of fear resistance and susceptibility in an advanced intercross line.
abstract: Genetic variability in the strength and precision of fear memory is hypothesised to contribute to the etiology of anxiety disorders, including post-traumatic stress disorder. We generated fear-susceptible (F-S) or fear-resistant (F-R) phenotypes from an F8 advanced intercross line (AIL) of C57BL/6J and DBA/2J inbred mice by selective breeding. We identified specific traits underlying individual variability in Pavlovian conditioned fear learning and memory. Offspring of selected lines differed in the acquisition of conditioned fear. Furthermore, F-S mice showed greater cued fear memory and generalised fear in response to a novel context than F-R mice. F-S mice showed greater basal corticosterone levels and hypothalamic corticotrophin-releasing hormone (CRH) mRNA levels than F-R mice, consistent with higher hypothalamic-pituitary-adrenal (HPA) axis drive. Hypothalamic mineralocorticoid receptor and CRH receptor 1 mRNA levels were decreased in F-S mice as compared with F-R mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was used to investigate basal levels of brain activity. MEMRI identified a pattern of increased brain activity in F-S mice that was driven primarily by the hippocampus and amygdala, indicating excessive limbic circuit activity in F-S mice as compared with F-R mice. Thus, selection pressure applied to the AIL population leads to the accumulation of heritable trait-relevant characteristics within each line, whereas non-behaviorally relevant traits remain distributed. Selected lines therefore minimise false-positive associations between behavioral phenotypes and physiology. We demonstrate that intrinsic differences in HPA axis function and limbic excitability contribute to phenotypic differences in the acquisition and consolidation of associative fear memory. Identification of system-wide traits predisposing to variability in fear memory may help in the direction of more targeted and efficacious treatments for fear-related pathology.
authors: Department of Psychiatry and Program in Neuroscience, School of Medicine, Uniformed Services University (USU), Bethesda, MD, USA.
authors: Jennifer L
authors: JL
authors: McGuire
authors: Hadley C
authors: HC
authors: Bergstrom
authors: Clarissa C
authors: CC
authors: Parker
authors: Thien
authors: T
authors: Le
authors: Maria
authors: M
authors: Morgan
authors: Haiying
authors: H
authors: Tang
authors: Reed G
authors: RG
authors: Selwyn
authors: Afonso C
authors: AC
authors: Silva
authors: Kwang
authors: K
authors: Choi
authors: Robert J
authors: RJ
authors: Ursano
authors: Abraham A
authors: AA
authors: Palmer
authors: Luke R
authors: LR
authors: Johnson
mesh_terms: D000818:Animals; D003214:Conditioning, Classical; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D005239:Fear; D005793:Generalization, Psychological; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000502:physiology; D007178:Inbreeding; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000502:physiology; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012153:Retention, Psychology
chemical_list: D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D018161:Receptors, Mineralocorticoid; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: AIL; HPA axis; fear conditioning; fear generalisation; hippocampus; manganese-enhanced MRI
references: J Psychiatry Neurosci. 2012 Jul;37(4):241-9
references: 22313617
references: Neuroendocrinology. 1987 Oct;46(4):365-8
references: 3499580
references: Trends Neurosci. 2012 Jan;35(1):24-35
references: 21798604
references: Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):195-200
references: 16368758
references: J Trauma Stress. 2009 Oct;22(5):409-15
references: 19743481
references: Front Syst Neurosci. 2010 Sep 20;4:
references: 20941370
references: Depress Anxiety. 2009;26(11):984-92
references: 19750552
references: Psychopharmacology (Berl). 2006 Jun;186(3):434-41
references: 16052364
references: J Comp Physiol Psychol. 1969 Mar;67(3):370-5
references: 5787388
references: Arch Gen Psychiatry. 1988 Jun;45(6):577-9
references: 2837159
references: Psychoneuroendocrinology. 2013 May;38(5):648-58
references: 22980941
references: Endocr Rev. 1998 Jun;19(3):269-301
references: 9626555
references: Biol Psychiatry. 2011 Mar 15;69(6):556-63
references: 21035787
references: Learn Mem. 2005 Jul-Aug;12(4):375-82
references: 16027176
references: IEEE Trans Med Imaging. 1998 Feb;17(1):87-97
references: 9617910
references: Pavlov J Biol Sci. 1980 Oct-Dec;15(4):177-82
references: 7208128
references: Neuroreport. 2003 Apr 15;14(5):777-80
references: 12692482
references: Behav Brain Res. 2004 Mar 2;149(2):209-15
references: 15129783
references: Eur Psychiatry. 2010 Jun;25(5):278-80
references: 20444578
references: Nat Rev Neurosci. 2004 Nov;5(11):844-52
references: 15496862
references: Behav Genet. 2012 May;42(3):437-48
references: 22237917
references: Eur J Neurosci. 2006 Oct;24(8):2291-8
references: 17042789
references: Science. 1984 Dec 14;226(4680):1342-4
references: 6334362
references: Arch Gen Psychiatry. 2003 Jul;60(7):702-8
references: 12860774
references: Biol Mood Anxiety Disord. 2012 May 18;2:8
references: 22738068
references: Neuron. 2011 Feb 10;69(3):563-71
references: 21315265
references: Behav Res Ther. 2005 Nov;43(11):1391-424
references: 15885654
references: Depress Anxiety. 2011 Jan;28(1):5-17
references: 20734364
references: Psychoneuroendocrinology. 2013 Jun;38(6):863-70
references: 23137715
references: Physiol Rev. 2010 Apr;90(2):419-63
references: 20393190
references: Behav Neurosci. 1998 Feb;112(1):251-4
references: 9517832
references: Neuropharmacology. 2012 Feb;62(2):638-46
references: 21782833
references: J Affect Disord. 2002 Jun;70(1):1-17
references: 12113915
references: Neuroendocrinology. 1989 Aug;50(2):117-23
references: 2550833
references: Neuroimage. 2012 Jan 16;59(2):968-78
references: 21925279
references: Biol Psychol. 2006 Jul;73(1):39-48
references: 16472906
references: Biol Psychiatry. 2000 Mar 15;47(6):512-9
references: 10715357
references: NMR Biomed. 2004 Dec;17(8):532-43
references: 15617052
references: Clin Psychol Rev. 1999 Nov;19(7):789-818
references: 10520436
references: J Neurosci. 2004 Mar 31;24(13):3281-8
references: 15056707
references: Annu Rev Neurosci. 2009;32:289-313
references: 19400714
references: Am J Psychiatry. 2010 Jan;167(1):47-55
references: 19917595
references: Hippocampus. 2004;14(3):301-10
references: 15132429
references: J Abnorm Psychol. 2000 May;109(2):290-8
references: 10895567
references: Front Genet. 2011 Jun 13;2:32
references: 22303328
references: Cell. 2011 Oct 28;147(3):509-24
references: 22036561
references: J Physiol. 1984 Mar;348:493-510
references: 6325673
references: Neuropharmacology. 2012 Feb;62(2):695-704
references: 21377482
references: Neuroimage. 2012 Aug 15;62(2):1208-15
references: 22406355
references: Anxiety Stress Coping. 2013;26(3):241-53
references: 22574657
references: Behav Genet. 1997 Jan;27(1):55-66
references: 9145544
references: Neurosci Res. 2005 Apr;51(4):371-81
references: 15740800
references: Learn Mem. 2009 Jun 24;16(7):460-9
references: 19553384
references: Brain Res. 1990 Feb 12;509(1):80-4
references: 2155045
references: Neurobiol Learn Mem. 2010 Nov;94(4):530-7
references: 20849967
references: Endocr Dev. 2011;20:137-148
references: 21164267
references: Psychosom Med. 2006 Mar-Apr;68(2):307-11
references: 16554398
references: Nat Neurosci. 2009 Jul;12(7):905-12
references: 19543280
references: Psychosom Med. 2008 Apr;70(3):314-8
references: 18378863
references: Mol Psychiatry. 2002;7(3):254-75
references: 11920153
references: Biol Psychiatry. 2010 Sep 15;68(6):544-52
references: 20655508
references: Brain Struct Funct. 2012 Jan;217(1):107-14
references: 21597966
references: Psychoneuroendocrinology. 2012 Mar;37(3):317-31
references: 21802212
references: Horm Behav. 2009 Aug;56(2):232-8
references: 19447109
references: Genes Brain Behav. 2007 Nov;6(8):736-49
references: 17309658
references: Psychiatr Ann. 2009 Jun 1;39(6):358-367
references: 19779593
references: NeuroRx. 2004 Jan;1(1):155-64
references: 15717015
references: Science. 2012 Mar 23;335(6075):1510-3
references: 22362879
references: Biol Psychol. 2013 Jan;92(1):82-9
references: 22406758
references: Annu Rev Neurosci. 2000;23:155-84
references: 10845062
references: J Comp Physiol Psychol. 1969 May;68(1):129-35
references: 5793861
references: Am J Psychiatry. 1999 Apr;156(4):585-8
references: 10200738
references: Am J Psychiatry. 2005 May;162(5):992-4
references: 15863803
references: Schizophr Bull. 2008 Jul;34(4):595-604
references: 18550591
references: Hear Res. 1999 Apr;130(1-2):94-107
references: 10320101
references: Psychoneuroendocrinology. 2012 Jul;37(7):892-902
references: 22094110
references: Psychoneuroendocrinology. 2012 Jul;37(7):1039-47
references: 22204928