"These findings provide a wealth of new insights into the molecular determinants of excessive drinking, which could lead to a better understanding of alcoholism," notes NIAAA Director Ting-Kai Li, M.D. "They also underscore the value that animal models bring to the investigation of complex human disorders such as alcohol dependence."
Mice that have been selectively bred to have either a high or low preference for alcohol have been a mainstay of alcohol research for many years, allowing investigators to study diverse behavioral and physiological characteristics of alcohol dependence. In the current study, NIAAA grantee Susan E. Bergeson, Ph.D., of the University of Texas (UT) at Austin, and a multi-site team of scientists participating in NIAAA's Integrative Neuroscience Initiative on Alcoholism (INIA) used microarray techniques to study gene expression in the brains of these animals. Microarrays are powerful tools that investigators use for comprehensive analyses of gene activity.
"Microarrays allow us to look at the full complement of genes that are active in the brains of animals bred to exhibit very different alcohol drinking behaviors," said Dr. Bergeson, an Assistant Professor of Neurobiology in UT's Waggoner Center for Alcohol and Addiction Research. When a gene is activated, cellular machinery transcribes certain parts of the gene's DNA into messenger RNA (mRNA), which is the body's template for creating proteins. The complete set of transcribed mRNA in a tissue is termed the "transcriptome."
Dr. Bergeson and her INIA colleagues examined brain transcriptomes of nine strains of mice, each differing in their voluntary alcohol consumption.
"By measuring total gene expression in brains of each of the mouse models we could explore which transcripts are consistently changed in different genetic models of high and low alcohol intake and thereby define the transcriptional signatures of genetic predisposition to high and low alcohol consumption," said Dr. Bergeson.
The researchers employed novel statistical techniques to identify nearly 4,000 differentially expressed genes between the high and low alcohol drinking mouse strains and to narrow the focus to 75 primary candidate genes. In addition, a comparison of the mouse data with human genetic studies revealed that genes with significant expression differences reside in chromosomal regions that previously were shown to be associated with human alcoholism.
Numerous pathways, as well as genes whose functions are currently unknown, may contribute to the genetic predisposition to drink high amounts of alcohol, notes Dr. Bergeson. "Our results will allow us to begin to focus on targets never previously implicated in excessive drinking. For example, genetic studies have shown that chromosome 9 contains genes that may regulate alcohol consumption in mice. Our analyses allowed us to narrow our focus from thousands of genes in that region to twenty."
"This first microarray-based analysis of a behavioral trait reveals many new research opportunities and exemplifies the rich collaborative potential of NIAAA's INIA consortium," adds Dr. Li.
The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.
Reference: Mulligan, MK, et al. Toward Understanding the Genetics of Alcohol Drinking Through Transcriptome Meta-analysis, Proceedings of the National Academy of Sciences 2006 103/16: 6368-6373.