Overview: Uncovering the genetics of how the brain adapts to alcoholLay summary of Center Activities
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) has established the Portland Alcohol Research Center at the Portland VA Medical Center (VAMC) and the Oregon Health & Science University (OHSU). The PARC has been funded by NIAAA to support research through 2015.
The center supports the coordinated research efforts of 20 scientists at the VA and OHSU, and one scientist at the University of Pittsburgh, in areas ranging from behavioral neuroscience to molecular biology. More than 60 people are working on different aspects of the research. The PARC is one of 27 alcohol research centers funded by NIAAA, which is the primary source of all funding for alcohol research in the United States. Dr. John Crabbe is the center Director.
A major emphasis of the research is using animal models to study the genetic contributions to alcohol and drug sensitivity. It is clear from human studies that a predisposition to alcoholism, alcohol dependence and substance abuse is influenced by many different genes. Identifying the specific genes responsible in humans is quite difficult for a number of practical and ethical reasons.
The PARC is focused on the genetics of how the brain adapts to alcohol. Genetic mapping techniques have allowed a large group of investigators collaboratively to identify the location of individual genes affecting responses to alcohol in mice. The PARC is unique in its focus on gene mapping and discovering the function of many such genes relevant for how the brain responds to chronic alcohol.
For many diseases, inheriting a single deleterious gene is sufficient to cause the disease. An example is Huntington's Disease -- to the best of our knowledge, inheritance of this disease is hardly influenced by non-genetic (environmental) factors such as diet, family social and economic characteristics, or the influence of peers. For alcohol dependence, like other complex behavioral traits, the picture is more complex. While there is a clear influence of genetics on whether individuals become dependent on alcohol, there are also apparently many genes at work. The inheritance of some combination of risk-promoting genes appears to increase the chance of becoming an alcoholic, but the role of environmental factors is equally important.
What has been unclear up until now is which genes specifically lead to increased or decreased risk for alcohol dependence. Of the many thousands of human genes, only a handful are important. Although we know that a close relative of an alcoholic is at increased risk for the disease, this is an "average" statement. In other words, that person's chance of having inherited the risk-promoting genes is greater than normal, but we don't know whether he or she has actually inherited those genes. Therefore, it is currently impossible to advise anyone about his or her real, individual risk.
Using gene mapping strategies, the PARC group has located a number of genes on mouse chromosomes that influence alcohol susceptibility traits. Drs. Kari Buck, John Belknap, John Crabbe, and Pamela Metten have been able to identify individual mice with high or low genetic risk for severe alcohol withdrawal reactions. Somewhere in a very small region of Mouse Chromosomes 1 and 4, there are particular genes which lead to severe alcohol withdrawal. On Chromosome 11, they have found another gene that appears to reduce alcohol withdrawal severity.
Mpdz: first identified location
One gene in particular, Mpdz, is an important focus. Our scientists expect to be able to identify the human versions of Mpdz and the other mouse susceptibility genes because of the great similarity between mouse and human genomes. These results have excited interest in the scientific community because they represent the first time that the locations of specific genes influencing an alcohol response have been identified.
Center scientists are using these and other methods to study a number of alcohol's effects in mice. Drs. John Belknap, Robert Hitzemann, Tamara Phillips, Pamela Metten and John Crabbe are studying different aspects of alcohol's rewarding effects, such as the preference to drink alcohol over water. They have already located genes affecting alcohol drinking on mouse chromosomes 2 and 9. Their new work involves the examination of not only the precise location of the important genes in the genome, but also the activity of those genes (i.e., whether they are actively working to produce the protein they make that affects the brain). These steps will help identify the specific genes responsible, which in turn will direct progress in research with human subjects.
Links to impulsivity
Drs. Suzanne Mitchell, Chris Cunningham and Tamara Phillips are developing new ways to measure impulsive behavior in mice to see how impulsivity, a temperamental risk factor for alcoholism in humans, affects alcohol responses. is collaborating with Drs. Chris Cunningham and John Crabbe to study the initial sensitivity of infant rhesus monkeys to alcohol and impulsivity measures as young adult and see if these baseline measures predict how much alcohol they will drink as adults. Some monkeys, like people, develop patterns of abusive drinking that resemble alcohol dependent humans when offered access to alcohol.
The PARC also supports a program of small pilot grants to explore emerging areas of alcohol research. In 2012, the Center is funding three projects. Dr. Claudio Mello is utilizing an avian zebra finch model to investigate a mechanism that links ethanol consumption to retinoic acid-linked gene expression and cognitive decline. In another pilot project, Dr. Bonnie Nagel is looking at brain function and behavior related to emotional processing in youth with a Family History Positive (FHP) for alcohol use disorders (AUD). By using functional magnetic resonance imaging to examine brain activity and behavior in FHP and Family History Negative (FHN) youth prior to heavy alcohol use, this study seeks to identify neural markers and behaviors associated with familial alcoholism, which may relate to the increased risk for developing AUDs. Finally, Dr. Tamara Phillips is investigating how nicotinic acetylcholine receptors (nAChR) may be a common site of action for ethanol and nicotine, and how an nAChR agonist, the smoking cessation drug varenicline (Chantix), may be a candidate for the treatment of alcohol dependence.
The PARC remains focused on the etiology and prediction of risk of alcohol dependence and other specific alcohol-related health problems (e.g., withdrawal seizures). The genetic risk and protective markers that we are studying will be of utility in the future for prevention of alcoholism.
The first theme of the PARC is to use behavioral genomics strategies-- through studies of gene mapping and expression and development of new genetic animal models, we are identifying genes underlying ethanol’s ability to cause neuroadaptation, that is, adaptations in the way the brain works. The second main PARC theme is to explore mechanisms underlying and traits related to ethanol neuroadaptation.
Two specific hypotheses have emerged from the synthesis of PARC and related projects' findings. The first is the intriguing idea that withdrawal and drinking may be influenced by some of the same genes. The second hypothesis is that high impulsivity is a significant genetic risk factor for high alcohol drinking. Multiple research components, core components, and a pilot project address these themes and hypotheses. A separate component is focused on education and outreach, especially on bringing information about alcohol and the brain to elementary-to-high school age children, due to the risk of alcohol causing permanent changes in the brain particularly early in life.
Current Projects and Cores
Several research projects focus intensively on mapping quantitative trait loci (QTLs) for alcohol preference and withdrawal genes in mice. We have vigorously pursued one QTL and have successfully mapped the first quantitative trait gene (QTG) for an alcohol-related behavioral response, Mpdz, which influences alcohol withdrawal severity. Multiple other QTLs are also being pursued along similar lines. Our gene finding approaches have evolved to include a major emphasis on mapping QTGs whose effects on the trait are derived from differences in regulation of gene expression. This effort has led to a significant expansion in our bioinformatics efforts.
One new component is developing novel mouse models for impulsive behavior, establishing their genetic basis, and relating them to alcohol consumption. Another new component takes advantage of access to a large colony of rhesus monkeys, all of whom have been genotyped in a full-genome linkage scan and tested at 3 months old for temperament-related traits (e.g., anxiety). These animals are given an alcohol challenge at 1 year old to determine individual differences in alcohol-induced ataxia and anxiolysis. We have now begun to test them for alcohol self-administration.
Cores support the research projects to coordinate efforts. The Animal and Phenotyping Core breeds specialized mouse genotypes for mapping studies and maintains many standard strains and selectively bred lines for studies. It also provides an ethanol inhalation core facility for dependence-related studies.
The Molecular Genetics Unit provides genotyping, QTL mapping, and functional assays for testing candidate QT Genes. As the tools for finding genes have become more sophisticated, the PARC has had to develop more complex systems for dealing with the resulting data. Centralized data banks for the linkage markers used in the mapping studies, gene expression array data, behavioral sensitivity scores, and locations of genes affecting alcohol responses as they are discovered are being maintained by the Center's Bioinformatics and Biostatistics Unit. Together, those Units form the Molecular and Bioinformatics Core.
Education and Outreach
PARC investigators have been training pre- and post-doctoral fellows and medical students in alcoholism and alcohol research for more than 30 years. A component dedicated to education and outreach also trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with students from elementary to high school.
by Mark Rutledge-Gorman
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