On the cutting edge of brain gene analysis

December 13, 2000

On the cutting edge of brain gene analysis Alcohol's primary target is the central nervous system, where it influences neurotransmission to produce intoxication. Chronic alcohol abuse produces tolerance, dependence and neurotoxicity. Although changes in brain gene expression are believed responsible for these effects, research that appears in the December issue of Alcoholism: Clinical & Experimental Research (ACER) is the first to use an exciting new technique called gene array technology to study gene expression in human alcoholism.

"A critical question in addiction," said R. Adron Harris, director of the Waggoner Center for Alcohol and Addiction Research at the University of Texas at Austin and lead author of the study, "is how the reprogramming of the brain leads to long-lasting, severe, life-threatening dependence. This study provides insight regarding the molecular neurocircuitry of the frontal cortex that is altered in alcoholism. A key point here is that we study the superior frontal cortex. This is also called the 'executive cortex' because it is critical for judgement and decision making, tasks that are corrupted in addiction. Just as a computer virus can change the programming of specific functions, our data show that chronic alcohol abuse can change the molecular programming and circuitry of the frontal cortex."

All of our cells have exactly the same deoxyribonucleic acid (DNA), which means they all have the same genes. The reason that different cells can appear and work so differently with the same genes (giving us, for example, unique eyes, skin, hair, etc.) is that only some genes are used or 'turned on' in each cell. This is called gene expression. The sequence of events is for DNA, or genes, to make ribonucleic acid (RNA), also called a "message," which is then used to make proteins. These proteins determine the appearance and function of each cell and, in turn, the proteins' existence depends on gene expression. Thus, gene expression is a normal function of all cells and is well regulated to avoid mistakes.

"Drugs can change gene expression and thereby disturb normal functions of the cell and tissue," explained Harris. "Alcohol can change gene expression in the brain and this is believed to be responsible for many of the hallmarks of addiction, such as tolerance, physical dependence, and craving as well as the consequences of chronic alcoholism, such as neurotoxicity (brain damage). The problem has been to find which genes are 'incorrectly' turned on or off in the brains of human alcoholics. This is because there are about 50,000 genes and any of these may be important. Previously, it was impossible to analyze more than a handful of these genes." Gene array technology has now changed that.

"Gene expression measurements that use arrays can simultaneously detect expression of thousands of gene products," said Boris Tabakoff, chair of the Department of Pharmacology at the University of Colorado School of Medicine. "This is a novel and fruitful approach for understanding patterns of changes produced by various disease processes. This particular study clearly demonstrates the power of the technique."

A gene array is a small glass microscope slide that has thousands of different DNA samples attached to the glass. Knowing that DNA makes RNA, and wanting to know which genes have been turned on to make RNA, researchers measured the level of thousands of RNAs in the brain. RNA samples were extracted from post-mortem samples of superior frontal cortex of 10 alcoholics and 10 non-alcoholics, and measured by two different types of microarrays (the Affymetrix and Genome systems). Using two microarrays - a more complicated, challenging and expensive venture than just one - provided more complete gene coverage and enhanced the reliability and replication of the findings.

"The key," said Harris, "is that RNA can be converted to a complimentary DNA called 'cDNA' with a fluorescent or colored 'tag' that will very selectively bind to or partner with its corresponding DNA. We can put a drop of this brain cDNA on the gene array and each spot of DNA that shows a colored tag will indicate that it is a gene that is turned on in the brain. Thus, each gene or 'DNA element' on the array has a color that reflects how much the gene is turned on in the alcoholic relative to the control."

In the ACER study, more than 4,000 genes in brain tissue were analyzed simultaneously. Of these, 163 (or roughly 4%) were found to differ by 40 percent or more between the alcoholics and non-alcoholics. The genes that seemed to change were those related to the generation of white matter in brain, and it was thought by the authors that the results may indicate that alcohol has a particularly damaging (or down regulating) effect on the generation of this white matter (which is called myelin). Myelin forms an insulation (or sheath) between information-carrying cells of the brain, and loss of white matter may result in cognitive deficiencies. These findings not only provide evidence for an extensive reprogramming of brain gene expression due to alcoholism, but also identify several functional clusters of genes that are particularly affected by this disease.

"Alcoholism is a major health problem in the US," said Harris, "yet there are few treatment options. This is due to our lack of understanding of the process of addiction. Alcoholism is a brain disease, and the brain is still a frontier for biological research. This study is a beginning to unraveling the undesirable changes in the brain produced by chronic exposure to alcohol. Such studies will, eventually, result in new and better treatments for alcoholism and other addictions."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Joanne M. Lewohl of the Waggoner Center for Alcohol and Addiction Research at the University of Texas at Austin, and the Department of Biochemistry at the University of Queensland, Australia; Long Wang, Michael F. Miles, and Li Zhang of the Ernest Gallo Clinic and Research Center at the University of California at San Francisco; and Peter R. Dodd of the Department of Biochemistry at the University of Queensland. The study was funded by the Waggoner Foundation, the Texas Commission on Alcohol and Drug Abuse, the National Institutes of Health, the National Health and Medical Research Council of Australia, and the State of California through the University of California at San Francisco.

Alcoholism: Clinical & Experimental Research

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.