During the current period of support, we used microarrays to define changes in gene expression in brain (prefrontal cortex and amygdala) and blood of alcoholic and non-alcoholic subjects. We have also profiled the expression of miRNAs in brain and propose that they are 'master switches,'responsible for many of the gene expression changes. In the proposed research, we will expand these findings in three areas. First, based on our preliminary studies of the GABAB receptor, we propose that regulation of some genes by chronic alcohol consumption is splice variant specific. Second, we will determine if the extent of changes in gene expression seen in human alcoholics are also present in three widely used mouse models of alcohol consumption. Because these mouse models are used for medication development, it is essential to determine the genetic factors that underlie neurochemical responses characteristic of alcoholism in these models. Third, selected miRNAs that were changed in frontal cortex of human alcoholics will be delivered to mouse brain to determine which gene networks are altered by these miRNAs. We propose that a single miRNA can produce selective changes in gene expression that change alcohol consumption.
Three Specific Aims are proposed: 1) next generation sequencing will reveal novel splice variants of differentially expressed transcripts in human brain, and subsequent RT-PCR analysis will define splice-specific regulation of gene expression in alcoholism, 2) some expression changes in functional groups of genes found in the amygdala and frontal cortex of human alcoholics will be seen in these same brain regions using mouse models of excessive alcohol consumption, and 3) overexpression of select miRNAs in mouse brain will alter drinking phenotypes, and these changes will be correlated with specific patterns of gene expression in the prefrontal cortex and amygdala.
We propose that alcohol-induced changes in brain function are due to alterations in gene expression and we will explore these changes with several innovative approaches to alcohol research, including next generation sequencing of selected brain transcripts and delivery of alcohol-related miRNAs to brain. This work will provide new opportunities for gene-based diagnosis and treatment of alcohol dependence.
|McCarthy, Gizelle M; Warden, Anna S; Bridges, Courtney R et al. (2017) Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addict Biol :|
|Harris, R Adron; Bajo, Michal; Bell, Richard L et al. (2017) Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. J Neurosci 37:1139-1155|
|Mayfield, Jody; Harris, R Adron (2017) The Neuroimmune Basis of Excessive Alcohol Consumption. Neuropsychopharmacology 42:376|
|Mayfield, R Dayne (2017) Emerging roles for ncRNAs in alcohol use disorders. Alcohol 60:31-39|
|Warden, Anna S; Mayfield, R Dayne (2017) Gene expression profiling in the human alcoholic brain. Neuropharmacology 122:161-174|
|Warden, Anna; Truitt, Jay; Merriman, Morgan et al. (2016) Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep 6:27618|
|Most, Dana; Leiter, Courtney; Blednov, Yuri A et al. (2016) Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption. Neuropsychopharmacology 41:538-48|
|Wolfe, Sarah A; Workman, Emily R; Heaney, Chelcie F et al. (2016) FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties. Nat Commun 7:12867|
|Mayfield, J; Arends, M A; Harris, R A et al. (2016) Genes and Alcohol Consumption: Studies with Mutant Mice. Int Rev Neurobiol 126:293-355|
|Warden, Anna; Erickson, Emma; Robinson, Gizelle et al. (2016) The neuroimmune transcriptome and alcohol dependence: potential for targeted therapies. Pharmacogenomics 17:2081-2096|
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