Chronic alcohol abuse produces lasting changes in brain function that are manifested as tolerance, physical dependence, craving, and other behavioral changes. The Mayfield Project will test the overall hypothesis that these changes are due to the co-ordinated regulation of alcohol-responsive genes by small non-coding RNAs. This Project will explore the role of these regulatory RNAs using several innovative approaches to alcohol research, including profiling of all known miRNAs, next generation sequencing of unique small RNAs, prediction and validation of microRNAs (miRNAs):mRNA target interactions, expression patterns of miRNAs which may act in combination to regulate mRNA expression and delivery of selected alcohol-related miRNAs to brain.
Three Specific Aims are proposed:
Aim 1 will test the hypothesis that miRNA expression profiling and next generation sequencing will identify unique alcohol-sensitive small RNAs in the nucleus accumbens and ventral tegmental area of mouse brain. Subsequent RT-PCR analysis will validate and define which of these are involved in mediating the effects of alcohol consumption in mouse models.
Aim 2 will test the hypothesis that differentially expressed miRNAs are co-ordinately expressed and act in combination by direct interaction with their predicted targets to regulate gene expression. The changes in expression that occur as a result of miRNA regulation are functionally important and may underlie alcohol's actions in the brain.
Aim 3 will test the hypothesis that over-expression of select miRNAs in mouse brain, either individually or in combination, will alter drinking phenotypes, and these changes will be correlated with specific patterns of gene expression in the nucleus accumbens and ventral tegmental area of mouse brain.

Public Health Relevance

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 novel miRNAs, functional analysis of alcohol-responsive miRNAs including delivery of these miRNAs to brain. This work will provide new opportunities for gene-based diagnosis and treatment of alcohol dependence.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Austin
United States
Zip Code
Cornelison, Garrett L; Pflanz, Natasha C; Tipps, Megan E et al. (2016) Identification and characterization of heptapeptide modulators of the glycine receptor. Eur J Pharmacol 780:252-9
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
Marballi, K; Genabai, N K; Blednov, Y A et al. (2016) Alcohol consumption induces global gene expression changes in VTA dopaminergic neurons. Genes Brain Behav 15:318-26
Farris, S P; Arasappan, D; Hunicke-Smith, S et al. (2015) Transcriptome organization for chronic alcohol abuse in human brain. Mol Psychiatry 20:1438-47
Osterndorff-Kahanek, Elizabeth A; Becker, Howard C; Lopez, Marcelo F et al. (2015) Chronic ethanol exposure produces time- and brain region-dependent changes in gene coexpression networks. PLoS One 10:e0121522
Farris, Sean P; Pietrzykowski, Andrzej Z; Miles, Michael F et al. (2015) Applying the new genomics to alcohol dependence. Alcohol 49:825-36
Farley, Nicole-Marie M; Mihic, S John (2015) Allosteric modulation of the glycine receptor activated by agonists differing in efficacy. Brain Res 1606:95-101
Farris, Sean P; Harris, Robert A; Ponomarev, Igor (2015) Epigenetic modulation of brain gene networks for cocaine and alcohol abuse. Front Neurosci 9:176
Most, D; Ferguson, L; Blednov, Y et al. (2015) The synaptoneurosome transcriptome: a model for profiling the emolecular effects of alcohol. Pharmacogenomics J 15:177-88
Cornelison, Garrett L; Mihic, S John (2014) Contaminating levels of zinc found in commonly-used labware and buffers affect glycine receptor currents. Brain Res Bull 100:1-5

Showing the most recent 10 out of 16 publications