The aims of this project for the currently funded period employed genetically engineered mouse lines. The overarching goal of these studies was to elucidate neurobiological mechanisms that contribute to an increased vulnerability to alcohol use disorders, with a focus on both hippocampal/amygdala GABAergic synaptic transmission (Aims 1-2) and epigenetics (Aim 3). As noted in earlier progress reports, some methodological challenges were encountered in re-establishing the breeding colonies of global and conditional Kl mice. Because of the delays in establishing the needed mouse lines, Aims 1&2 will continue essentially as originally described into the extension phase. Studies of the epigenetic effects of ethanol (Aim 3) will continue to focus on characterizing the effects of ethanol on histone modifications in mice following acute and chronic ethanol exposure and following ethanol withdrawal. The provocative discovery by the PI of transgenerational alterations in ethanol-induced behaviors and drinking following paternal preconception ethanol exposure has provided a need to significantly expand the experimental focus of this grant in an exciting new direction. Our results suggest that an individual's ethanol phenotype is dictated in part by his father's history of ethanol exposure prior to conceiving that individual. Remarkably, these transgenerational effects of ethanol appear to only affect male offspring. These exciting observations suggest that ethanol is an epimutagen (i.e., it alters the epigenetic program) that impacts germ cells in an enduring fashion. To further investigate the hypothesis that an individual's drinking and neurobiological sensitivity to ethanol are due in part to parental preconception ethanol exposure, we will (1) characterize the model in greater detail, (2) undertake studies to reveal the mechanism(s) that mediate these effects, (3) examine if these effects represent true transgenerational epigenetic inheritance, (4) develop a rat model of paternal preconception ethanol exposure, and (5) conduct neurobiological studies to better understand the phenotype.

Public Health Relevance

EtOH addiction remains an imposing medical and socio-economic concern for our society. Elucidating the molecular and neurophysiological substrates that underlie EtOH addiction and the consequences of paternal preconception ethanol exposure will facilitate the development of more effective treatment strategies for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AA010422-19
Application #
8839369
Study Section
Special Emphasis Panel (NSS)
Program Officer
Reilly, Matthew
Project Start
2015-05-01
Project End
2020-04-20
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
19
Fiscal Year
2015
Total Cost
$463,697
Indirect Cost
$103,811
Name
University of Pittsburgh
Department
Anesthesiology
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Rompala, Gregory R; Mounier, Anais; Wolfe, Cody M et al. (2018) Heavy Chronic Intermittent Ethanol Exposure Alters Small Noncoding RNAs in Mouse Sperm and Epididymosomes. Front Genet 9:32
Zamudio-Bulcock, Paula A; Homanics, Gregg E; Woodward, John J (2018) Loss of Ethanol Inhibition of N-Methyl-D-Aspartate Receptor-Mediated Currents and Plasticity of Cerebellar Synapses in Mice Expressing the GluN1(F639A) Subunit. Alcohol Clin Exp Res 42:698-705
Rompala, Gregory R; Simons, Alison; Kihle, Brooke et al. (2018) Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner. Front Behav Neurosci 12:257
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Rompala, Gregory R; Finegersh, Andrey; Slater, Michelle et al. (2017) Paternal preconception alcohol exposure imparts intergenerational alcohol-related behaviors to male offspring on a pure C57BL/6J background. Alcohol 60:169-177
Hill, Shirley Y; Rompala, Gregory; Homanics, Gregg E et al. (2017) Cross-generational effects of alcohol dependence in humans on HRAS and TP53 methylation in offspring. Epigenomics 9:1189-1203
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den Hartog, Carolina R; Gilstrap, Meghin; Eaton, Bethany et al. (2017) Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors. Front Neurosci 11:84
Mahnke, Amanda H; Miranda, Rajesh C; Homanics, Gregg E (2017) Epigenetic mediators and consequences of excessive alcohol consumption. Alcohol 60:1-6
Skelly, M J; Ariwodola, O J; Weiner, J L (2017) Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala. Neuropharmacology 113:231-240

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