NF-kappaB activity affects learning in aversive tasks: possible actions via modulation of the stress axis.
The role of altered activity of nuclear factor kappaB (NF-kappaB) in specific aspects of motivated behavior and learning and memory was examined in mice lacking the p50 subunit of the NF-kappaB/rel transcription factor family. Nfkb1-deficient mice are unable to produce p50 and show specific susceptibilities to infections and inflammatory challenges, but the behavioral phenotype of such mice has been largely unexamined, owing in large part to the lack of understanding of the role of NF-kappaB in nervous system function. Here we show that Nfkb1 (p50) knockout mice more rapidly learned to find the hidden platform in the Morris water maze than did wildtype mice. The rise in plasma corticosterone levels after the maze test was greater in p50 knockout than in wildtype mice. In the less stressful Barnes maze, which tests similar kinds of spatial learning, the p50 knockout mice performed similarly to control mice. Adrenalectomy with corticosterone replacement eliminated the differences between p50 knockout and wildtype mice in the water maze. Knockout mice showed increased levels of basal anxiety in the open-field and light/dark box tests, suggesting that their enhanced escape latency in the water maze was due to activation of the stress (hypothalamic-pituitary-adrenal) axis leading to elevated corticosterone production by strongly but not mildly anxiogenic stimuli. The results suggest that, as in the immune system, p50 in the nervous system normally serves to dampen NF-kappaB-mediated intracellular activities, which are manifested physiologically through elevated stress responses to aversive stimuli and behaviorally in the facilitated escape performance in learning tasks.
Lehmann
Michael L
ML
Section on Functional Neuroanatomy, National Institute of Mental Health, NIH, Bethesda, MD 20892-3724, USA. Michael.lehmann@nih.gov
Brachman
Rebecca A
RA
Listwak
Samuel J
SJ
Herkenham
Miles
M
D000315:Adrenalectomy; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D003345:Corticosterone / Q000097:blood; D024202:Electrophoretic Mobility Shift Assay; D005106:Exploratory Behavior / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*
D054360:Chemokine CXCL1; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D003345:Corticosterone
Nat Med. 1999 May;5(5):554-9
10229233
Genes Brain Behav. 2002 Jan;1(1):55-69
12886950
Hippocampus. 2004;14(6):677-83
15318326
J Biol Chem. 2004 Nov 26;279(48):49995-50003
15465827
Cell. 1995 Jan 27;80(2):321-30
7834752
Behav Brain Res. 2004 Oct 5;154(2):577-84
15313047
Mol Cell Biol. 2000 Dec;20(24):9113-9
11094063
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16364-9
17053075
Synapse. 2000 Feb;35(2):151-9
10611641
Mol Cell. 2002 Mar;9(3):625-36
11931769
J Neurosci. 1999 Oct 15;19(20):8856-65
10516305
Mol Cell Biol. 1994 Jun;14(6):3981-92
8196637
Trends Neurosci. 1997 Jun;20(6):252-8
9185306
Am J Pathol. 2005 Mar;166(3):695-708
15743782
J Neurosci Methods. 1984 May;11(1):47-60
6471907
Behav Brain Res. 2009 Mar 2;198(1):247-51
18996418
J Neurosci. 2007 Dec 5;27(49):13436-45
18057202
Cancer Cell. 2004 Sep;6(3):203-8
15380510
Trends Neurosci. 2005 Jan;28(1):37-43
15626495
J Neuropathol Exp Neurol. 2008 Mar;67(3):223-30
18344913
Exp Neurol. 2002 Aug;176(2):277-88
12359170
Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9458-62
15190179
Neurosci Biobehav Rev. 1985 Spring;9(1):37-44
2858080
J Neurosci Methods. 1999 Feb 1;87(1):87-95
10065997
Brain Res Bull. 1982 Jun;8(6):609-12
6890398
Behav Brain Res. 1995 Jan 23;66(1-2):225-30
7755894
Science. 1992 Jun 5;256(5062):1452-6
1604322
Neuroscience. 2006;139(3):965-78
16533569
J Comp Physiol Psychol. 1979 Feb;93(1):74-104
221551
Learn Mem. 2000 May-Jun;7(3):170-9
10837506
Brain Res. 2008 Nov 13;1240:22-30
18817763
Brain Res. 2006 Aug 9;1104(1):39-44
16814269
J Clin Invest. 1992 Jul;90(1):121-9
1634604
Cell. 2002 Apr;109 Suppl:S81-96
11983155
Annu Rev Immunol. 1998;16:225-60
9597130
Genome Res. 1996 Oct;6(10):986-94
8908518
Eur J Neurosci. 2005 May;21(10):2845-52
15926932
Genes Dev. 2004 Sep 15;18(18):2195-224
15371334
Psychopharmacology (Berl). 1997 Jul;132(2):107-24
9266608
Physiol Behav. 2001 Jan;72(1-2):271-81
11240006
Behav Brain Res. 2009 Mar 2;198(1):58-68
19022298
Neuron. 2007 Sep 20;55(6):942-57
17880897
Behav Brain Res. 2002 Nov 15;136(2):489-501
12429412
J Biol Chem. 2002 Nov 29;277(48):46720-9
12351629
J Neurosci. 2008 Apr 9;28(15):3911-9
18400889
Mol Pharmacol. 2004 May;65(5):1286-92
15102957
Nat Neurosci. 2003 Oct;6(10):1072-8
12947408