An underlying premise of the INIA-Stress consortium is that progression to abusive ethanol consumption is, at least in part, accompanied and perhaps caused by alterations in an organism's response to stress, including the stress of excessive ethanol intake/withdrawal. We propose that changes in brain gene expression networks are an important part of allostatic mechanisms leading to progressive ethanol consumption and aberrant responses to stress. We have previously used genetic and genomic approaches across brain regions of BXD recombinant inbred panel to define robust gene networks regulated by acute ethanol and relate these to ethanol behaviors, particularly regarding responses to stress. We have also identified significant overlap in expression responses to acute ethanol in mice and altered gene expression patterns seen in a primate model of excessive ethanol intake (SIP) developed by Dr. Grant, the PI of the INIA-Stress consortium. Furthermore, very recent pilot array studies in BXD mice exposed to multiple cycles of the chronic intermittent ethanol vapor (CIE) model of excessive ethanol consumption have identified remarkable homology with results from acute ethanol exposure and our data from cynomolgus macaque. Those studies have generated gene networks that allow testing initial major hub genes for their possible role in modifying ethanol consumption and response to stress in the CIE model. For example, we recently identified Gsk3p as an important regulator of ethanol consumption and withdrawal-induced anxiety, using AAV viral vector gene delivery studies. Based on these findings, we propose the following Organizing Hypothesis: Altered ethanol drinking and stress/endocrine phenotypes in the mouse CIE and monkey SIP models result from (and cause) adaptive responses in brain gene expression networks, resulting in a new allostatic set point.
The aims of this project will define new gene networks underlying allostatic changes in the CIE and monkey SIP models by expression profiling of CIE treatment across the BXD mouse panel and Rhesus Macaque samples of Dr. Grant (Project 1), co-analysis of results with RNA-Seq data of Dr. Williams' Project 10, and testing of candidates, including Gsk3P, using viral vector gene delivery.

Public Health Relevance

The studies proposed here can identify novel targets for future therapeutic development and contribute to our overall understanding of the neurobiology underlying the interaction between stress and ethanol during the transition to excessive ethanol consumption. Studies on one candidate gene already identified, Gsk3?, hold direct promise for future medication development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016667-09
Application #
8790926
Study Section
Special Emphasis Panel (ZAA1-DD (51))
Program Officer
Reilly, Matthew
Project Start
2007-02-15
Project End
2017-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
9
Fiscal Year
2015
Total Cost
$250,193
Indirect Cost
$82,840
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
O'Brien, Megan A; Weston, Rory M; Sheth, Nihar U et al. (2018) Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice. Front Genet 9:402
van der Vaart, Andrew; Meng, Xianfang; Bowers, M Scott et al. (2018) Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence. Neuropsychopharmacology 43:2521-2531
Lopez, Marcelo F; Miles, Michael F; Williams, Robert W et al. (2017) Variable effects of chronic intermittent ethanol exposure on ethanol drinking in a genetically diverse mouse cohort. Alcohol 58:73-82
Adkins, Amy E; Hack, Laura M; Bigdeli, Tim B et al. (2017) Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. Alcohol Clin Exp Res 41:911-928
Porcu, Patrizia; O'Buckley, Todd K; Lopez, Marcelo F et al. (2017) Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains. Alcohol 58:107-125
van der Vaart, Andrew D; Wolstenholme, Jennifer T; Smith, Maren L et al. (2017) The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort. Alcohol 58:93-106
Bogenpohl, James W; Mignogna, Kristin M; Smith, Maren L et al. (2017) Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets. Methods Mol Biol 1488:531-549
Wolstenholme, Jennifer T; Mahmood, Tariq; Harris, Guy M et al. (2017) Intermittent Ethanol during Adolescence Leads to Lasting Behavioral Changes in Adulthood and Alters Gene Expression and Histone Methylation in the PFC. Front Mol Neurosci 10:307
Rinker, Jennifer A; Fulmer, Diana B; Trantham-Davidson, Heather et al. (2017) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol 58:33-45
Zuo, Lingjun; Tan, Yunlong; Li, Chiang-Shan R et al. (2016) Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 171:1057-1071

Showing the most recent 10 out of 39 publications