Regulatory mechanisms of fear extinction and depression-like behavior.
Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression.
Tronson
Natalie C
NC
Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. tronson@northwestern.edu
Schrick
Christina
C
Fischer
Andre
A
Sananbenesi
Farahnaz
F
Pagès
Gilles
G
Pouysségur
Jacques
J
Radulovic
Jelena
J
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003863:Depression / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000172:deficiency; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013550:Swimming
D004791:Enzyme Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3
Neurobiol Learn Mem. 2004 Sep;82(2):128-41
15341798
J Neurochem. 2004 Oct;91(2):462-70
15447679
J Comp Physiol Psychol. 1969 Mar;67(3):370-5
5787388
Eur J Pharmacol. 1978 Oct 1;51(3):291-4
568552
Science. 1989 Aug 25;245(4920):866-9
2772638
Clin Neuropharmacol. 1992;15 Suppl 1 Pt A:208A-209A
1498813
Biol Psychiatry. 2006 Jun 15;59(12):1151-9
16566899
Biol Psychiatry. 2006 Jun 15;59(12):1136-43
16797263
Behav Brain Res. 2006 Oct 2;173(1):104-11
16828176
Science. 2006 Aug 25;313(5790):1141-4
16931766
Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8205-9
1381507
J Neurochem. 1993 Dec;61(6):2303-10
8245981
Hippocampus. 1995;5(4):349-62
8589798
Oncogene. 1997 Apr 10;14(14):1635-42
9135064
J Biol Chem. 1998 Jul 17;273(29):18623-32
9660836
J Neurosci. 1998 Sep 15;18(18):7452-61
9736664
Behav Brain Res. 1998 Oct;95(2):179-89
9806438
J Clin Psychiatry. 1998;59 Suppl 18:10-7
9840193
J Immunol. 1999 Mar 1;162(5):3013-21
10072553
Mol Psychiatry. 2007 Jul;12(7):656-70
17264839
Science. 1999 Nov 12;286(5443):1374-7
10558995
J Neurosci. 2000 Aug 15;20(16):5906-14
10934237
Depress Anxiety. 2000;12 Suppl 1:2-19
11098410
Behav Brain Res. 1999 Oct;104(1-2):1-12
11125727
Learn Mem. 2001 Jan-Feb;8(1):11-9
11160759
Depress Anxiety. 2001;13(2):57-71
11301922
J Neurochem. 2001 May;77(3):916-28
11331420
Cell Signal. 2001 Nov;13(11):777-85
11583913
Brain Res Mol Brain Res. 2001 Oct 19;94(1-2):15-24
11597761
Nat Neurosci. 1998 Nov;1(7):602-9
10196568
J Neurosci. 1999 Jun 1;19(11):4337-48
10341237
J Neurosci. 1999 Jun 15;19(12):5016-25
10366634
J Neurosci. 2004 Dec 1;24(48):10846-57
15574735
J Neurosci. 2004 Dec 8;24(49):11029-34
15590919
Psychopharmacology (Berl). 2005 Jan;177(3):245-55
15609067
Behav Brain Res. 2005 Feb 28;157(2):291-8
15639180
Nat Neurosci. 2005 May;8(5):664-72
15834420
Am J Psychiatry. 2005 May;162(5):970-6
15863800
Neurosci Biobehav Rev. 2005;29(4-5):547-69
15893822
Neurosci Biobehav Rev. 2005;29(4-5):867-89
15899517
J Neurochem. 2005 Jun;93(6):1551-60
15935071
Endocrinology. 2005 Jul;146(7):2903-10
15817663
Nat Neurosci. 2005 Jul;8(7):925-31
15937483
Behav Brain Res. 2005 Nov 7;164(2):222-30
16095730
Annu Rev Psychol. 2006;57:117-37
16318591
Nat Neurosci. 2006 Feb;9(2):167-9
16415868
Learn Mem. 2006 May-Jun;13(3):349-58
16705140
Biol Psychiatry. 2006 Jun 15;59(12):1160-71
16457783
Neurobiol Learn Mem. 2007 Jan;87(1):149-58
16979915
Behav Brain Res. 2006 Dec 15;175(2):233-40
17050000
J Neurosci. 2006 Dec 6;26(49):12700-7
17151273
J Neurosci. 2007 Jan 17;27(3):684-91
17234600
Biol Psychiatry. 2007 Mar 1;61(5):661-70
16945347
Nat Rev Neurosci. 2007 Mar;8(3):194-205
17311006
Mol Cell Neurosci. 2007 May;35(1):76-88
17350282
J Biol Chem. 2001 Nov 23;276(47):43871-8
11571286
Neuroscientist. 2002 Apr;8(2):122-31
11954557
Mol Psychiatry. 2002;7 Suppl 1:S46-56
11986995
Nature. 2002 May 16;417(6886):292-5
12015604
Neuron. 2002 May 30;34(5):807-20
12062026
J Neurosci. 2002 Jun 15;22(12):4860-8
12077183
Biochem Pharmacol. 2002 Sep;64(5-6):755-63
12213567
Neuron. 2002 Nov 14;36(4):567-84
12441048
Mol Pharmacol. 2003 Jan;63(1):128-35
12488545
Mol Cell Neurosci. 2002 Nov;21(3):463-76
12498787
Hippocampus. 2003;13(1):53-8
12625457
J Neurosci. 2003 Aug 13;23(19):7311-6
12917364
J Neurosci. 2003 Sep 10;23(23):8310-7
12967993
EMBO Rep. 2003 Oct;4(10):964-8
14502223
Brain Res. 2003 Nov 21;991(1-2):195-205
14575892
J Neurosci. 2003 Dec 10;23(36):11436-43
14673008
Behav Brain Res. 2004 Feb 4;149(1):17-31
14739006
J Neurosci. 2004 Feb 25;24(8):1962-6
14985438
Nat Neurosci. 2004 Jun;7(6):635-42
15133516