Binge drinking of alcohol is highly prevalent during adolescence, which is an important period of emotional maturation in the brain. The extended amygdala, which includes central nucleus of amygdala (CeA), medial nucleus of amygdala (MeA), nucleus accumbens (NAc) shell, and bed nucleus of stria terminalis (BNST) circuitries, has been shown to be involved in the processes that regulate emotion, anxiety, and alcoholism. Ethanol produces anxiolytic effects in both animals and humans and adolescents are less sensitive to the sedative and anxiolytic effects of ethanol. Epigenetic mechanisms, such as histone acetylation and DNA methylation, have been shown to play a role in neuromaturation by regulating gene expression and synaptic remodeling during brain development. Several genes, such as brain-derived neurotrophic factor (BDNF), activity regulated cytoskeleton-associated (Arc) protein, and NMDA receptor subunits (NR2A&2B) are involved in regulating dendritic spine density (DSD) in the brain and are epigenetically controlled by histone acetylation and DNA methylation. The link between epigenetic mechanisms and neuronal plasticity associated with adaptational mechanisms to adolescent intermittent ethanol (AIE) exposure and its role in alcoholism and anxiety at adulthood is currently unknown. This proposal is based on the hypothesis that ethanol-induced perturbation of DNA methylation or histone acetylation (H3&H4) during adolescence may produce long-lasting changes in the expression of genes, such as BDNF, Arc, and NR2A &2B receptor subunits, that may be involved in altering synaptic plasticity (dendritic spine density) in the extended amygdala, thereby promoting the development of anxiety-like and alcohol-drinking behaviors in adulthood. To test this hypothesis, we propose to investigate whether chromatin remodeling (histone acetylation and DNA methylation) in the extended amygdala during AIE regulates the molecular mechanisms of synaptic plasticity, such as changes in gene expression and dendritic spine density in adolescent rats, and if these changes can lead to abnormal synaptic plasticity during neuromaturation that persists at adulthood and causes these rats to exhibit anxiety-like and alcohol-drinking behaviors. Thus, the proposed studies will provide an important clue about AlE-induced epigenetic modifications in the extended amygdala as a neurobiological substrate for vulnerability towards anxiety and alcoholism in adulthood.

Public Health Relevance

Binge alcohol drinking occurs at a high rate among adolescents, which can lead to anxiety and alcohol abuse disorders during adulthood. The proposed research will help to identify novel epigenetic and molecular targets that can be used to develop future pharmacotherapies to treat adults comorbid with alcoholism and anxiety, due to exposure to alcohol during adolescence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA019971-03
Application #
8316437
Study Section
Special Emphasis Panel (ZAA1-DD (11))
Program Officer
Bechtholt-Gompf, Anita
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$370,435
Indirect Cost
$134,489
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kyzar, Evan J; Banerjee, Ritabrata (2016) Targeted Epigenetic Modulation of Gene Expression in the Brain. J Neurosci 36:9283-5
Sakharkar, Amul J; Vetreno, Ryan P; Zhang, Huaibo et al. (2016) A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. Brain Struct Funct 221:4691-4703
Pandey, Subhash C (2016) A Critical Role of Brain-Derived Neurotrophic Factor in Alcohol Consumption. Biol Psychiatry 79:427-9
Kyzar, Evan J; Floreani, Christina; Teppen, Tara L et al. (2016) Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology. Front Neurosci 10:222
Kyzar, Evan J; Zhang, Huaibo; Sakharkar, Amul J et al. (2016) Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood. Addict Biol :
Teppen, Tara L; Krishnan, Harish R; Zhang, Huaibo et al. (2016) The Potential Role of Amygdaloid MicroRNA-494 in Alcohol-Induced Anxiolysis. Biol Psychiatry 80:711-719
Pandey, Subhash C; Sakharkar, Amul J; Tang, Lei et al. (2015) Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood. Neurobiol Dis 82:607-19
Blum, Kenneth; Febo, Marcelo; Smith, David E et al. (2015) Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation. J Child Adolesc Psychopharmacol 25:286-92
Kyzar, Evan J; Pandey, Subhash C (2015) Molecular mechanisms of synaptic remodeling in alcoholism. Neurosci Lett 601:11-9
Centanni, Samuel W; Teppen, Tara; Risher, Mary-Louise et al. (2014) Adolescent alcohol exposure alters GABAA receptor subunit expression in adult hippocampus. Alcohol Clin Exp Res 38:2800-8

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