Ethanol-responsive brain region expression networks: implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice.
Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factor Bdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.
Kerns
Robnet T
RT
Department of Pharmacology/Toxicology and the Center for Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Ravindranathan
Ajay
A
Hassan
Sajida
S
Cage
Mary P
MP
York
Tim
T
Sikela
James M
JM
Williams
Robert W
RW
Miles
Michael F
MF
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D019295:Computational Biology / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D046228:Microarray Analysis / Q000379:methods; D015999:Multivariate Analysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013045:Species Specificity; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D002492:Central Nervous System Depressants; D000431:Ethanol
Trends Neurosci. 1999 Apr;22(4):173-9
10203855
J Neurosci. 1999 May 15;19(10):4110-22
10234039
Mech Dev. 1999 May;83(1-2):39-52
10381566
Pharmacogenetics. 1999 Oct;9(5):607-17
10591541
J Mol Biol. 2000 Mar 31;297(3):599-606
10731414
Mech Dev. 2000 Jun;94(1-2):183-7
10842069
Cell. 2000 Jul 7;102(1):109-26
10929718
Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11038-43
11005875
Neuron. 2000 Oct;28(1):53-67
11086983
Mol Pharmacol. 2000 Dec;58(6):1593-600
11093800
Alcohol Clin Exp Res. 2000 Dec;24(12):1873-82
11141048
Nat Neurosci. 2001 Mar;4(3):289-96
11224546
Brain Res. 2001 Apr 6;897(1-2):139-49
11282367
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
Alcohol Clin Exp Res. 2001 Jun;25(6):810-8
11410715
Genome Res. 2001 Aug;11(8):1425-33
11483584
Behav Genet. 2001 Jan;31(1):79-91
11529277
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13355-60
11687615
Jpn J Pharmacol. 2001 Oct;87(2):104-9
11700008
J Neurosci. 2001 Dec 1;21(23):RC184
11717387
FASEB J. 2002 Jan;16(1):27-35
11772933
Development. 2002 Feb;129(4):917-33
11861475
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3990-5
11891330
J Mol Biol. 2002 Mar 22;317(2):225-35
11902839
J Pharmacol Exp Ther. 2002 Apr;301(1):66-70
11907158
J Neurosci. 2002 May 15;22(10):4153-62
12019333
Blood. 2002 Sep 15;100(6):2056-62
12200366
J Clin Invest. 2002 Nov;110(9):1233-4
12417559
J Biol Chem. 2003 Mar 14;278(11):9630-8
12524444
Am J Med Genet B Neuropsychiatr Genet. 2003 Feb;117B(1):39-45
12555233
Science. 2003 Mar 21;299(5614):1889-92
12649481
Cell Tissue Res. 2003 Mar;311(3):333-42
12658441
Pharmacol Toxicol. 2002 Dec;91(6):404-13
12688386
Nat Biotechnol. 2003 Jul;21(7):818-21
12794640
Mol Cell Neurosci. 2003 May;23(1):107-20
12799141
J Neurosci. 2003 Jun 1;23(11):4491-8
12805289
Genes Brain Behav. 2002 Jan;1(1):35-45
12886948
Genome Biol. 2003;4(10):R70
14519205
Cell. 2003 Dec 12;115(6):655-66
14675531
Mamm Genome. 2003 Nov;14(11):733-47
14722723
Neurochem Res. 2004 Feb;29(2):357-69
15002731
Int Rev Neurobiol. 2004;59:425-44
15006497
Neuroinformatics. 2003;1(4):343-57
15043220
Neurosci Lett. 2004 Apr 22;360(1-2):106-8
15082190
Nat Neurosci. 2004 Jul;7(7):699-700
15208631
BMC Bioinformatics. 2004 Oct 08;5:147
15473905
J Neurosci. 2004 Nov 17;24(46):10542-52
15548669
Trends Pharmacol Sci. 1992 May;13(5):177-84
1604710
Acta Neuropathol. 1989;79(2):200-4
2596268
Alcohol Clin Exp Res. 1995 Apr;19(2):269-78
7625557
Behav Neurosci. 1994 Aug;108(4):789-803
7986372
Am J Psychiatry. 1994 Feb;151(2):184-9
8296886
Behav Genet. 1993 Mar;23(2):213-22
8512534
Protein Sci. 1993 Apr;2(4):489-97
8518727
J Pharmacol Exp Ther. 1996 May;277(2):613-23
8627538
FASEB J. 1996 Jul;10(9):1050-7
8801166
Physiol Rev. 1997 Jan;77(1):1-20
9016298
J Cell Biol. 1997 Jun 16;137(6):1355-67
9182667
Science. 1997 Oct 3;278(5335):58-63
9311927
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14349-54
9405615
J Neurochem. 1998 Jan;70(1):224-32
9422366
J Pharmacol Exp Ther. 1998 Jan;284(1):258-68
9435186
Cell. 1998 Jun 12;93(6):997-1007
9635429
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
9843981
Nature. 1998 Nov 26;396(6709):366-9
9845072
Mamm Genome. 1998 Dec;9(12):983-90
9880664