title: Stress-response pathways are altered in the hippocampus of chronic alcoholics.
abstract: The chronic high-level alcohol consumption seen in alcoholism leads to dramatic effects on the hippocampus, including decreased white matter, loss of oligodendrocytes and other glial cells, and inhibition of neurogenesis. Examining gene expression in post mortem hippocampal tissue from 20 alcoholics and 19 controls allowed us to detect differentially expressed genes that may play a role in the risk for alcoholism or whose expression is modified by chronic consumption of alcohol. We identified 639 named genes whose expression significantly differed between alcoholics and controls at a False Discovery Rate (FDR) ≤ 0.20; 52% of these genes differed by at least 1.2-fold. Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 (FKBP5), UDP glycosyltransferase 8 (UGT8), urea transporter (SLC14A1), zinc transporter (SLC39A10), Interleukin 1 receptor type 1 (IL1R1), thioredoxin interacting protein (TXNIP), and many metallothioneins. Pathways related to inflammation, hypoxia, and stress showed activation, and pathways that play roles in neurogenesis and myelination showed decreases. The cortisol pathway dysregulation and increased inflammation identified here are seen in other stress-related conditions such as depression and post-traumatic stress disorder and most likely play a role in addiction. Many of the detrimental effects on the hippocampus appear to be mediated through NF-κB signaling. Twenty-four of the differentially regulated genes were previously identified by genome-wide association studies of alcohol use disorders; this raises the potential interest of genes not normally associated with alcoholism, such as suppression of tumorigenicity 18 (ST18), BCL2-associated athanogene 3 (BAG3), and von Willebrand factor (VWF).
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Jeanette N
authors: JN
authors: McClintick
authors: Xiaoling
authors: X
authors: Xuei
authors: Jay A
authors: JA
authors: Tischfield
authors: Alison
authors: A
authors: Goate
authors: Tatiana
authors: T
authors: Foroud
authors: Leah
authors: L
authors: Wetherill
authors: Marissa A
authors: MA
authors: Ehringer
authors: Howard J
authors: HJ
authors: Edenberg
mesh_terms: D000328:Adult; D000368:Aged; D057229:Alcoholics; D000437:Alcoholism / Q000503:physiopathology*; D005260:Female; D063990:Gene Ontology; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D055495:Neurogenesis; D059467:Transcriptome
chemical_list: D016328:NF-kappa B
keywords: Alcoholism; Cortisol; GWAS; Gene expression; Hippocampus; Inflammation; NF-κB; Stress
references: Pharmacol Biochem Behav. 2009 Sep;93(3):230-6
references: 19409922
references: Alcohol Alcohol. 2009 Mar-Apr;44(2):115-27
references: 18940959
references: Curr Opin Neurobiol. 2013 Aug;23(4):513-20
references: 23434064
references: Alcohol Clin Exp Res. 2007 Apr;31(4):537-45
references: 17374032
references: Neuropsychopharmacology. 2012 Jan;37(2):557-66
references: 21956439
references: Exp Neurol. 2010 Jun;223(2):267-81
references: 19699201
references: J Alzheimers Dis. 2005 Nov;8(2):139-45; discussion 209-15
references: 16308482
references: Am J Psychiatry. 2007 Aug;164(8):1149-59
references: 17671276
references: J Pharmacol Exp Ther. 1995 Nov;275(2):790-7
references: 7473168
references: Trends Pharmacol Sci. 2010 Jul;31(7):318-25
references: 20537734
references: Brain Behav Immun. 2011 Jun;25 Suppl 1:S4-S12
references: 21402143
references: Addict Biol. 2009 Jul;14(3):366-70
references: 19298317
references: Alcohol. 2009 Nov;43(7):491-8
references: 19913192
references: Alcohol Clin Exp Res. 1999 Jan;23(1):164-8
references: 10029219
references: Ann N Y Acad Sci. 2013 Apr;1282:39-70
references: 23170934
references: Psychol Med. 1997 Nov;27(6):1381-96
references: 9403910
references: JAMA. 2008 Mar 19;299(11):1291-305
references: 18349090
references: Cell. 2009 Apr 3;137(1):47-59
references: 19345186
references: Addict Biol. 2006 Sep;11(3-4):386-96
references: 16961766
references: Nat Neurosci. 2005 Nov;8(11):1442-4
references: 16251985
references: Alcohol Clin Exp Res. 2011 May;35(5):963-75
references: 21314694
references: Alcohol Clin Exp Res. 2000 Dec;24(12):1873-82
references: 11141048
references: Glia. 2012 May;60(6):948-64
references: 22431236
references: Alcohol. 2010 Mar;44(2):171-83
references: 20116196
references: Mamm Genome. 2008 May;19(5):352-65
references: 18563486
references: Nat Clin Pract Endocrinol Metab. 2008 Sep;4(9):496-505
references: 18695699
references: PLoS One. 2011;6(7):e19210
references: 21818250
references: Cell Metab. 2012 Aug 8;16(2):250-64
references: 22883233
references: J Neurosci Methods. 2007 Jul 30;163(2):295-309
references: 17512057
references: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9070-5
references: 18591672
references: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references: 12582260
references: Hippocampus. 2010 May;20(5):596-607
references: 19554644
references: J Neurochem. 2004 Sep;90(5):1050-8
references: 15312160
references: Exp Neurol. 2012 Jan;233(1):12-21
references: 21281629
references: Brain Res. 2008 Jul 11;1219:1-7
references: 18534562
references: Genes Brain Behav. 2008 Aug;7(6):677-89
references: 18397380
references: Alcohol Clin Exp Res. 2011 Feb;35(2):376-85
references: 21083670
references: BMC Bioinformatics. 2006 Jan 31;7:49
references: 16448562
references: Neurosci Res. 2004 Aug;49(4):379-85
references: 15236863
references: J Neurosci. 2008 Jan 2;28(1):264-78
references: 18171944
references: Hippocampus. 1997;7(1):78-87
references: 9138671
references: Arch Gen Psychiatry. 1999 Apr;56(4):356-63
references: 10197833
references: PLoS One. 2012;7(4):e33575
references: 22511924
references: J Biol Chem. 1997 Nov 14;272(46):29364-71
references: 9361018
references: Genes Brain Behav. 2005 Feb;4(1):20-30
references: 15660665
references: J Neuroendocrinol. 2006 Aug;18(8):629-31
references: 16867184
references: Endocrinology. 2010 Sep;151(9):4332-43
references: 20668026
references: Nat Immunol. 2010 Feb;11(2):136-40
references: 20023662
references: Alcohol Clin Exp Res. 2012 Mar;36(3):509-16
references: 21895712
references: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6368-73
references: 16618939
references: Immunol Lett. 2010 Jun 15;131(1):11-8
references: 20398702
references: Arch Gen Psychiatry. 2009 Jul;66(7):773-84
references: 19581569
references: J Neurosci Res. 2005 May 15;80(4):529-38
references: 15846778
references: Biometals. 2009 Dec;22(6):995-1009
references: 19513589
references: Alcohol Clin Exp Res. 2010 May;34(5):840-52
references: 20201924
references: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2669-74
references: 20133768
references: Alcohol Clin Exp Res. 2003 Mar;27(3):410-23
references: 12658106
references: BMC Genomics. 2011 Feb 21;12:124
references: 21338521
references: Mol Psychiatry. 2013 Nov;18(11):1218-24
references: 23089632
references: J Neurosci Res. 2003 Jun 15;72(6):756-67
references: 12774316
references: Hum Mol Genet. 2008 Apr 1;17(7):963-70
references: 18079108
references: Alcohol Clin Exp Res. 1999 May;23(5):757-8
references: 10371392
references: J Pharmacol Exp Ther. 2002 May;301(2):774-84
references: 11961084
references: Cell Tissue Bank. 2008 Sep;9(3):205-16
references: 18543078
references: Alcohol Clin Exp Res. 2007 Sep;31(9):1460-6
references: 17625000
references: Am J Med Genet B Neuropsychiatr Genet. 2011 Jan;156B(1):44-58
references: 21184583
references: Mol Psychiatry. 2014 May;19(5):560-7
references: 23689534
references: Science. 2003 Dec 5;302(5651):1760-5
references: 14615545
references: Alcohol. 2007 Mar;41(2):95-132
references: 17517326
references: Brain Behav Immun. 2011 Jun;25 Suppl 1:S92-S105
references: 21266194
references: Neuroscience. 2010 May 5;167(2):361-71
references: 20153402
references: J Neurochem. 2002 May;81(4):802-13
references: 12065639
references: Behav Brain Res. 2000 May;109(2):177-86
references: 10762687
references: J Neurochem. 2005 Apr;93(2):359-70
references: 15816859
references: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5082-7
references: 20202923
references: Mol Psychiatry. 2009 Mar;14(3):261-8
references: 18180755
references: Alcohol Clin Exp Res. 2010 Jul;34(7):1291-302
references: 20477762
references: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6626-31
references: 21464311
references: J Neuroinflammation. 2012 Jun 18;9:130
references: 22709825
references: Int J Psychophysiol. 2006 Mar;59(3):210-7
references: 16360227
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references: 12883005
references: Mol Cell Neurosci. 2012 Aug;51(1-2):43-52
references: 22884903
references: Neurobiol Dis. 2009 Oct;36(1):1-10
references: 19501165
references: Mol Psychiatry. 2006 Nov;11(11):1016-24
references: 16924269
references: Alcohol. 2004 Apr;32(3):223-41
references: 15282116
references: Neuropsychopharmacology. 2006 Jul;31(7):1574-82
references: 16292326
references: Psychiatry Res. 2013 May 30;207(3):225-8
references: 23123147
references: Twin Res Hum Genet. 2010 Feb;13(1):10-29
references: 20158304
references: Oncogene. 2003 Jun 26;22(26):4035-46
references: 12821938
references: Hippocampus. 2006;16(3):296-304
references: 16411241
references: Addict Biol. 2012 Jan;17(1):108-20
references: 21309947
references: Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S186-95
references: 19560279
references: J Neurosci. 2005 Mar 2;25(9):2255-66
references: 15745951