Browsing by Subject "Alcoholism--Genetic aspects"

Now showing 1 - 3 of 3

Brain region gene expression responds discretely to chronic alcohol withdrawal with specific disruption of the hippocampus during intoxication
(2005) Berman, Ari Ethan; Bergeson, Susan E.
Alcoholism is a chronic, progressive and heritable disease that affects millions of Americans and costs the United States hundreds of billions of dollars per year in medical expenditures, property damage, and loss of productivity. Alcohol dependence is the result of long-lasting cellular and molecular changes in the brain that are initiated and maintained by the repeated ingestion of intoxicating amounts of alcohol. Withdrawal symptoms from alcohol occur when alcohol intake is reduced or halted and the brain enters a period of extended hyperactivity. Animal models for alcohol-related behaviors were previously developed and characterized in both mice and rats, including mouse strains that were particularly sensitive to alcohol withdrawal. Mice from a strain that is highly sensitive to withdrawal from alcohol, DBA/2J, were given a chronic dose of ethanol by inhalation and comparative microarray analysis was performed. A suite of microarray analysis software was written to facilitate the large amount of data collected from this experiment, and a robust web-based database system, the Alcohol Research Integrator, was developed to serve both as a storage and as a high-level analysis medium. Here we show that detectable gene expression changes occur in a discrete fashion between gross anatomical brain regions at various stages of withdrawal, and that the hippocampus shows a markedly greater level of gene expression change during intoxication than any of the other brain regions suggesting a particular vulnerability to the intoxicating effects of alcohol.
Studies of the global gene expression changes in alcoholic human brain and blood
(2005) Liu, Jianwen, 1978-; Harris, R. Adron; Mayfield, R. Dayne (Roy Dayne), 1958-
Alcohol is known as a drug subject to addiction. Long-term excessive drinking may cause alcohol tolerance, dependence, and craving. Neuroadaptations underlying these effects are likely due to changes at the gene expression level in the brain. Previous gene expression studies in the post-mortem human brain of alcoholics demonstrated that several gene families were altered by alcohol abuse (Lewohl et al. 2000; Mayfield et al. 2002). However, it is not clear how individual variability contributes to the observed changes. In addition, most changes in alcoholic human brain were relatively small. It is not clear if patterns of gene expression have sufficient power to discriminate control from alcoholic individuals. Around 10~15% of alcohol abusers develop liver cirrhosis. It is still unknown how concomitant liver cirrhosis may alter gene expression level in alcoholic human brain on a global scale. In the present study, microarray analysis was first performed on both frontal and motor cortex. A clustering analysis of cases suggested that patterns of gene expression changes in the frontal cortex were more consistent than these in motor cortex. Therefore the subsequent studies were focused on the frontal cortex. The sample size was increased to 14 uncomplicated alcoholics and 13 controls. A total of 532 genes were identified as differentially expressed. Those genes were involved in several functional groups, including myelination, ubiquitination, apoptosis and cell adhesion. In addition, several of those genes have been suggested to be involved in the development of other neural diseases. Expression profiling of the frontal cortex from seven cirrhotic alcoholics was conducted to examine how concomitant liver cirrhosis influences gene expression in human brain. Both glial and neuronal cells were affected at the transcriptional level in cirrhotic alcoholics relative to non-cirrhotic alcohol abusers. Gene expression profiling was also performed in alcoholic blood to identify potential biomarkers for alcohol abuse. Initial studies indicated that gene expression levels were also affected in the blood of alcoholics. In conclusion, a consistent re-programming of gene expression occurs in the brain of alcohol abusers with and without concomitant liver cirrhosis. Similar changes may also exist in the blood of alcoholics.
Transcriptomics and the genetics of alcohol consumption in mice
(2007-12) Mulligan, Megan Kathleen, 1977-; Bergeson, Susan E.; Harris, R. Adron
Alcoholism is a complex disease determined by both genetic and environmental components that exerts a devastating economic and social impact worldwide. The complexity of this disease makes the elucidation of candidate genes for the susceptibility to alcoholism difficult in human populations, however, mouse model systems replicate many aspects of the disease and represent an excellent system for the investigation of the genetic contributions to alcoholism. One component of alcoholism that can be investigated in mouse models is the predisposition to high alcohol consumption. Selectively bred and inbred mice differ markedly in the level of voluntary alcohol intake using a two-bottle choice paradigm. The phenotype of voluntary alcohol consumption in mice is a complex trait and a genetic comparison between mouse models with similar levels of alcohol intake should identify genes that contribute to the predisposition for alcohol consumption. Three different studies were completed at the University of Texas and candidate genes involved in the predisposition to high alcohol consumption in mice were identified through the use of brain transcriptome analysis. In the first study, 3,800 transcripts were identified that were divergent between 3 selected lines and 6 isogenic strains of mice known to differ in voluntary alcohol consumption. This list was filtered to reveal candidate genes associated with alcohol preference on mouse chromosome 9: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, Zfp291. In the second study, analysis of voluntary alcohol intake and brain gene expression between two closely related inbred mouse substrains separated for nearly fifty years revealed divergent alcohol consumption as well as genetic variation between the substrains. Finally, the third study revealed dominant and overdominant patterns of expression in an F1 hybrid that voluntarily consumed more alcohol than either inbred parental strain. The microarray datasets analyzed here represent an important first step in the elucidation of the genetic determinants of high alcohol consumption in mice and will be influential in the discovery of genes that play a role in vulnerability to alcoholism in humans.