Ethanol and stress exert a wide spectrum of neuropharmacological and neurophysiological effects that leave both molecular and cellular imprints in the CNS. While some targets of ethanol and stress in the brain have been defined, particularly shifts in neurotransmitter tone, much of the influence of ethanol is mediated by subtle and non-specific modification of allosteric interactions and downstream events that will remain hard to pinpoint and manipulate. The joint effects of ethanol and stress also vary a great deal depending on genetic differences. In this INIA renewal we will use new genomic methods to understand much more about differential vulnerability to alcohol and stress and molecular targets. We exploit a diverse group of strains of mice (BXDs) that model many aspects of human genetic complexity.
In Aim 1 we evaluate predisposing differences in gene expression and splicing and the effects that individual differences have on responses to stress and to eventual alcohol consumption.
In aim 2 we will study the effects of chronic intermittent ethanol exposure (and animal model of binge drinking) on voluntary alcohol consumption. Here we are asking how the combination of stress and alcohol alters gene expression patterns in an almost permanent way to induce quick relapse when access to ethanol is provided.
In aim 3 we will integrate, test, and translate our results from aims 1 and 2 to understand more about the complex molecular and cellular networks that contribute to both vulnerability and allostatic changes in brain function. We will exploit extensive human data sets to test the translational relevance of finding in murine populations.

Public Health Relevance

This U01 project of INIAStress will be of high significance in understanding at least two critical features of alcoholism: (1) the underlying genetics and neurogenetics of susceptibility to stress and alcohol, and (2) the imprints of allostatic load on gene expression (including alternative isoform usage and production of noncoding RNAs) in different CNS regions and in strains with markedly different responses to alcohol and stress.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA013499-13
Application #
8601673
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Reilly, Matthew
Project Start
2002-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38103
Neuner, Sarah M; Garfinkel, Benjamin P; Wilmott, Lynda A et al. (2016) Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging. Neurobiol Aging 46:58-67
Alam, Gelareh; Miller, Diane B; O'Callaghan, James P et al. (2016) MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains. Neurotoxicology 55:40-7
Lopez, Marcelo F; Miles, Michael F; Williams, Robert W et al. (2016) Variable effects of chronic intermittent ethanol exposure on ethanol drinking in a genetically diverse mouse cohort. Alcohol :
Shi, Xiao; Walter, Nicole A R; Harkness, John H et al. (2016) Genetic Polymorphisms Affect Mouse and Human Trace Amine-Associated Receptor 1 Function. PLoS One 11:e0152581
Porcu, Patrizia; O'Buckley, Todd K; Lopez, Marcelo F et al. (2016) Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains. Alcohol :
Wang, Xusheng; Pandey, Ashutosh K; Mulligan, Megan K et al. (2016) Joint mouse-human phenome-wide association to test gene function and disease risk. Nat Commun 7:10464
Delprato, A; Bonheur, B; Algéo, M-P et al. (2015) Systems genetic analysis of hippocampal neuroanatomy and spatial learning in mice. Genes Brain Behav 14:591-606
Bubier, Jason A; Phillips, Charles A; Langston, Michael A et al. (2015) GeneWeaver: finding consilience in heterogeneous cross-species functional genomics data. Mamm Genome 26:556-66
Padula, Audrey E; Griffin 3rd, William C; Lopez, Marcelo F et al. (2015) KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction. Neuropsychopharmacology 40:1928-39
Cook, Melloni N; Baker, Jessica A; Heldt, Scott A et al. (2015) Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions. Physiol Genomics 47:308-17

Showing the most recent 10 out of 105 publications