title: Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology.
abstract: Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear. Knowledge gained on the biological basis of Pavlovian conditioning has led to the general acceptance that fear extinction may be a useful model in understanding the underlying mechanisms in the pathophysiology of anxiety disorders and may also be a good model for current therapies treating these disorders. Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction. It is also unclear how the neural correlates of fear extinction may mediate sex differences in the etiology, maintenance, and prevalence of psychiatric disorders. In this review, we begin by highlighting the epidemiological differences in incidence rate. We then discuss how estradiol (E2), a primary gonadal hormone, may modulate the mechanisms of fear extinction and mediate some of the sex differences observed in psychiatric disorders.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Cover
authors.affiliation: 1] Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA [2] Department of Psychiatry, Harvard Medical School, Charlestown, MA, USA.
authors.forename: L Y
authors.initials: LY
authors.lastname: Maeng
authors.affiliation: 1] Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA [2] Department of Psychiatry, Harvard Medical School, Charlestown, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lebrón-Milad
authors.affiliation: 1] Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA [2] Department of Psychiatry, Harvard Medical School, Charlestown, MA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Milad
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology*; D001921:Brain / Q000503:physiopathology; D003214:Conditioning, Classical / Q000502:physiology*; D004958:Estradiol / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000503:physiopathology*; D051381:Rats; D012727:Sex Characteristics; D013739:Testosterone / Q000502:physiology
chemical_list: D013739:Testosterone; D004958:Estradiol
references.citation: Neuroscientist. 2014 Oct;20(5):534-45
references.pmid: 24510074
references.citation: Learn Mem. 2014 Jun 17;21(7):347-50
references.pmid: 24939838
references.citation: Pharmacol Rev. 2010 Jun;62(2):155-98
references.pmid: 20392807
references.citation: J Neurosci. 2006 Aug 16;26(33):8517-22
references.pmid: 16914677
references.citation: Neurobiol Learn Mem. 2011 Sep;96(2):378-84
references.pmid: 21740976
references.citation: J Gend Specif Med. 2002 Jan-Feb;5(1):34-40
references.pmid: 11859685
references.citation: Soc Psychiatry Psychiatr Epidemiol. 2014 Mar;49(3):447-57
references.pmid: 24022753
references.citation: Nat Neurosci. 2005 Jul;8(7):925-31
references.pmid: 15937483
references.citation: J Trauma. 2002 Nov;53(5):882-8
references.pmid: 12435938
references.citation: Horm Behav. 2008 Nov;54(5):726-34
references.pmid: 18775724
references.citation: Maturitas. 2007 Apr 20;56(4):447-51
references.pmid: 16963205
references.citation: J Epidemiol Community Health. 1996 Dec;50(6):661-6
references.pmid: 9039386
references.citation: Front Behav Neurosci. 2013 Aug 08;7:102
references.pmid: 23964215
references.citation: Steroids. 2014 Mar;81:49-56
references.pmid: 24240011
references.citation: Arch Gen Psychiatry. 1995 Dec;52(12):1048-60
references.pmid: 7492257
references.citation: Shi Yan Sheng Wu Xue Bao. 2002 Mar;35(1):15-20
references.pmid: 15344311
references.citation: Horm Behav. 1999 Aug;36(1):1-16
references.pmid: 10433882
references.citation: Psychoneuroendocrinology. 2011 Sep;36(8):1239-48
references.pmid: 21454017
references.citation: Int Rev Psychiatry. 2010;22(5):417-28
references.pmid: 21047156
references.citation: Endocrinology. 2012 Jun;153(6):2541-3
references.pmid: 22492307
references.citation: Neuroscience. 2013 Jun 3;239:34-45
references.pmid: 23079626
references.citation: J Neurosci. 2004 Nov 10;24(45):10280-7
references.pmid: 15537900
references.citation: Neurosci Biobehav Rev. 2012 Aug;36(7):1773-802
references.pmid: 22230704
references.citation: J Psychiatr Res. 2013 Nov;47(11):1776-84
references.pmid: 23992769
references.citation: J Am Med Womens Assoc (1972). 2004 Summer;59(3):181-91
references.pmid: 15354371
references.citation: Neurotherapeutics. 2012 Jul;9(3):490-9
references.pmid: 22976615
references.citation: Biol Psychiatry. 2013 Feb 15;73(4):371-8
references.pmid: 23158459
references.citation: J Steroid Biochem Mol Biol. 1991;40(4-6):673-8
references.pmid: 1958565
references.citation: Life Sci. 1994;54(21):PL363-7
references.pmid: 8196472
references.citation: J Psychiatr Res. 1999 May-Jun;33(3):259-64
references.pmid: 10367992
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5567-72
references.pmid: 18391192
references.citation: Am J Psychiatry. 2001 Nov;158(11):1904-10
references.pmid: 11691699
references.citation: Endocrinology. 2012 Feb;153(2):837-46
references.pmid: 22186418
references.citation: Age (Dordr). 2013 Jun;35(3):821-37
references.pmid: 22648398
references.citation: Endocrinology. 1992 Jul;131(1):381-8
references.pmid: 1612018
references.citation: J Clin Psychiatry. 2005 Apr;66(4):428-35; quiz 546
references.pmid: 15816784
references.citation: Brain Res Rev. 2008 Mar;57(2):309-20
references.pmid: 17662459
references.citation: Annu Rev Psychol. 2012;63:129-51
references.pmid: 22129456
references.citation: Front Neurosci. 2013 Apr 16;7:57
references.pmid: 23596385
references.citation: Menopause. 2010 Jul;17(4):823-7
references.pmid: 20531231
references.citation: Neuropsychopharmacology. 2008 Jan;33(1):56-72
references.pmid: 17882236
references.citation: Arch Gen Psychiatry. 2007 May;64(5):566-76
references.pmid: 17485608
references.citation: Arch Gen Psychiatry. 1998 Jul;55(7):626-32
references.pmid: 9672053
references.citation: Biol Psychol. 2013 Apr;93(1):17-23
references.pmid: 23410760
references.citation: Biol Psychiatry. 1995 Dec 15;38(12):814-8
references.pmid: 8750040
references.citation: J Endocrinol. 2010 Feb;204(2):105-14
references.pmid: 19767412
references.citation: CNS Drugs. 2005;19(5):411-27
references.pmid: 15907152
references.citation: J Forensic Nurs. 2012 Sep;8(3):122-30
references.pmid: 22925127
references.citation: Depress Anxiety. 2008;25(10):832-8
references.pmid: 17436312
references.citation: Neuroscience. 2008 Apr 9;152(4):888-902
references.pmid: 18353559
references.citation: J Neuroendocrinol. 2009 Mar;21(4):257-62
references.pmid: 19207809
references.citation: J Physiol Pharmacol. 2013 Apr;64(2):129-42
references.pmid: 23756388
references.citation: Science. 2010 Jun 4;328(5983):1288-90
references.pmid: 20522777
references.citation: Learn Mem. 2003 Jul-Aug;10(4):270-4
references.pmid: 12888545
references.citation: Eur J Neurosci. 2010 Feb;31(4):599-612
references.pmid: 20384807
references.citation: Neurobiol Learn Mem. 2014 Sep;113:101-8
references.pmid: 24560771
references.citation: Am J Epidemiol. 2003 Jun 1;157(11):1015-22
references.pmid: 12777365
references.citation: Neuron. 2012 Nov 21;76(4):804-12
references.pmid: 23177964
references.citation: J Psychiatry Neurosci. 2008 Jul;33(4):331-43
references.pmid: 18592034
references.citation: Neuroscience. 2009 Dec 15;164(3):887-95
references.pmid: 19761818
references.citation: Biol Psychiatry. 1999 Apr 1;45(7):817-26
references.pmid: 10202568
references.citation: Psychopharmacology (Berl). 2012 Jun;221(3):527-35
references.pmid: 22143579
references.citation: Front Endocrinol (Lausanne). 2011 Nov 22;2:77
references.pmid: 22654827
references.citation: Trends Endocrinol Metab. 2006 Mar;17(2):55-64
references.pmid: 16480891
references.citation: J Neurosci. 2006 Sep 13;26(37):9503-11
references.pmid: 16971534
references.citation: Biol Psychiatry. 2002 Aug 15;52(4):305-11
references.pmid: 12208637
references.citation: Reprod Biol Endocrinol. 2003 Jul 09;1:52
references.pmid: 12904263
references.citation: Front Neural Circuits. 2013 Oct 18;7:149
references.pmid: 24151456
references.citation: Arch Gen Psychiatry. 2008 Jul;65(7):805-15
references.pmid: 18606953
references.citation: Am J Geriatr Psychiatry. 2001 Fall;9(4):393-9
references.pmid: 11739065
references.citation: Brain Res. 2014 Jan 16;1543:128-42
references.pmid: 24231554
references.citation: J Psychiatr Res. 1998 Nov-Dec;32(6):335-45
references.pmid: 9844949
references.citation: BMC Pregnancy Childbirth. 2002 Nov 19;2(1):8
references.pmid: 12437774
references.citation: Int Rev Psychiatry. 2010;22(5):437-52
references.pmid: 21047158
references.citation: Biol Mood Anxiety Disord. 2012 Feb 07;2:3
references.pmid: 22738383
references.citation: Novartis Found Symp. 2000;230:20-6; discussion 27-40
references.pmid: 10965500
references.citation: Horm Behav. 2008 Jun;54(1):185-93
references.pmid: 18413151
references.citation: Hippocampus. 2002;12(5):578-84
references.pmid: 12440573
references.citation: Biol Psychiatry. 2013 Jun 1;73(11):1045-53
references.pmid: 23348009
references.citation: J Endocrinol. 2007 May;193(2):311-21
references.pmid: 17470522
references.citation: Neuroscience. 2012 Jan 27;202:131-46
references.pmid: 22133892
references.citation: J Biol Chem. 2001 Apr 27;276(17):13615-21
references.pmid: 11278408
references.citation: Synapse. 2006 Sep 15;60(4):280-7
references.pmid: 16786530
references.citation: Neurobiol Learn Mem. 2013 Nov;106:56-65
references.pmid: 23891713
references.citation: Biol Psychiatry. 2009 Dec 15;66(12):1075-82
references.pmid: 19748076
references.citation: Pharmacol Biochem Behav. 2012 Aug;102(2):191-5
references.pmid: 22546276
references.citation: Neuron. 2012 Jun 7;74(5):801-8
references.pmid: 22681685
references.citation: Brain Res Mol Brain Res. 1998 Feb;54(1):175-80
references.pmid: 9526077
references.citation: Int J Neuropsychopharmacol. 2013 May;16(4):825-33
references.pmid: 22704253
references.citation: Biochem Soc Trans. 2012 Feb;40(1):139-46
references.pmid: 22260680
references.citation: J Neurosci. 1999 Jul 15;19(14):5792-801
references.pmid: 10407020
references.citation: J Neuroendocrinol. 2008 Jul;20(7):893-903
references.pmid: 18445128
references.citation: Endocrinology. 1995 May;136(5):2320-4
references.pmid: 7720680
references.citation: J Clin Endocrinol Metab. 1996 Oct;81(10):3578-83
references.pmid: 8855804
references.citation: Neurobiol Learn Mem. 2010 Nov;94(4):488-98
references.pmid: 20828630
references.citation: J Comp Neurol. 1997 Dec 1;388(4):507-25
references.pmid: 9388012
references.citation: J Neurosci. 1990 Dec;10(12):4035-9
references.pmid: 2269895
references.citation: J Clin Psychiatry. 1999;60 Suppl 6:20-4
references.pmid: 10235121
references.citation: J Clin Endocrinol Metab. 2013 Sep;98(9):3829-38
references.pmid: 23836935
references.citation: Neuron. 2004 Sep 16;43(6):897-905
references.pmid: 15363399
references.citation: Psychoneuroendocrinology. 1992;17(1):87-93
references.pmid: 1319072
references.citation: J Psychiatry Neurosci. 2013 Sep;38(5):341-8
references.pmid: 23611176
references.citation: Neuroscience. 2010 Sep 29;170(1):54-66
references.pmid: 20619320
references.citation: J Psychiatr Res. 2013 Jan;47(1):64-71
references.pmid: 23107307
references.citation: Neuroimage. 2014 Apr 15;90:24-32
references.pmid: 24365676
references.citation: J Neurobiol. 1998 Sep 5;36(3):357-78
references.pmid: 9733072
references.citation: Arch Gen Psychiatry. 2001 Jun;58(6):529-34
references.pmid: 11386980
references.citation: Am J Psychiatry. 2012 Apr;169(4):415-23
references.pmid: 22318762
references.citation: Cereb Cortex. 2002 Feb;12(2):116-28
references.pmid: 11739260
references.citation: Neuroreport. 2009 Mar 25;20(5):517-20
references.pmid: 19247210
references.citation: Hum Brain Mapp. 2014 Jul;35(7):3249-61
references.pmid: 24302681
references.citation: Front Biosci (Landmark Ed). 2011 Jan 01;16:1560-73
references.pmid: 21196248
references.citation: Neuroimage. 2006 Aug 1;32(1):457-64
references.pmid: 16644236
references.citation: Biol Psychiatry. 2012 Jul 1;72(1):19-24
references.pmid: 22502987
references.citation: Biol Psychiatry. 2007 Sep 1;62(5):446-54
references.pmid: 17217927
references.citation: J Neurosci. 2004 Jun 23;24(25):5704-10
references.pmid: 15215292
references.citation: Biol Psychiatry. 2011 Nov 15;70(10):920-7
references.pmid: 21762880
references.citation: Front Endocrinol (Lausanne). 2011 Oct 10;2:43
references.pmid: 22701110
references.citation: J Neurosci. 2009 Jul 1;29(26):8474-82
references.pmid: 19571138
references.citation: J Neurophysiol. 2011 Jun;105(6):3054-66
references.pmid: 21471396
references.citation: Mol Pharmacol. 2003 Jan;63(1):44-52
references.pmid: 12488535
references.citation: J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):143-50
references.pmid: 17643294
references.citation: J Neurosci. 2001 Aug 15;21(16):RC162
references.pmid: 11473133
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):895-902
references.pmid: 20416352
references.citation: Neuroscience. 2010 Jul 14;168(3):652-8
references.pmid: 20412837
references.citation: Arch Gen Psychiatry. 2006 Apr;63(4):415-24
references.pmid: 16585471
references.citation: J Trauma Stress. 2013 Oct;26(5):537-47
references.pmid: 24151000
references.citation: Neuroscience. 2013 Jun 3;239:295-303
references.pmid: 23211562
references.citation: J Abnorm Psychol. 2012 Feb;121(1):282-8
references.pmid: 21842958
references.citation: Physiol Behav. 2012 Mar 20;105(5):1168-74
references.pmid: 22226989
references.citation: Pharmacol Biochem Behav. 2004 Jul;78(3):473-81
references.pmid: 15251256
references.citation: Genes Brain Behav. 2012 Jul;11(5):503-12
references.pmid: 22530815
references.citation: Neurosci Lett. 1999 Feb 12;261(1-2):17-20
references.pmid: 10081916
references.citation: Can J Psychiatry. 2006 Feb;51(2):100-13
references.pmid: 16989109
references.citation: Anat Rec (Hoboken). 2011 Nov;294(11):1913-9
references.pmid: 21972199
references.citation: Endocrinology. 1998 Dec;139(12):5070-81
references.pmid: 9832446
references.citation: J Neurosci. 2005 May 18;25(20):5066-78
references.pmid: 15901789
references.citation: Curr Opin Neurobiol. 2012 Aug;22(4):717-23
references.pmid: 22424846
references.citation: Neuropsychopharmacology. 2014 Aug;39(9):2161-9
references.pmid: 24625752
references.citation: Horm Behav. 2008 Aug;54(2):286-93
references.pmid: 18455727
references.citation: Eur J Neurosci. 2006 Jul;24(1):261-9
references.pmid: 16882022
references.citation: Acta Psychiatr Scand. 2005 Apr;111(4):291-9
references.pmid: 15740465
references.citation: Brain Res. 2006 Dec 18;1126(1):176-82
references.pmid: 16934233
references.citation: J Neurosci. 2005 Oct 5;25(40):9309-16
references.pmid: 16207891
references.citation: J Clin Psychiatry. 2001 May;62(5):332-6
references.pmid: 11411813
references.citation: J Affect Disord. 2012 Sep;140(1):92-6
references.pmid: 22537684
references.citation: Lancet. 1996 Apr 6;347(9006):930-3
references.pmid: 8598756