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.
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.
|Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L et al. (2014) The epigenetic landscape of alcoholism. Int Rev Neurobiol 115:75-116|
|Sakharkar, Amul J; Tang, Lei; Zhang, Huaibo et al. (2014) Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats. Int J Neuropsychopharmacol 17:2057-67|
|You, Chang; Zhang, Huaibo; Sakharkar, Amul J et al. (2014) Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment. Int J Neuropsychopharmacol 17:313-22|
|Sakharkar, Amul J; Zhang, Huaibo; Tang, Lei et al. (2014) Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviours. Int J Neuropsychopharmacol 17:1207-20|
|Zhang, Xiaolu; Kusumo, Handojo; Sakharkar, Amul J et al. (2014) Regulation of DNA methylation by ethanol induces tissue plasminogen activator expression in astrocytes. J Neurochem 128:344-9|
|Arora, Devinder S; Nimitvilai, Sudarat; Teppen, Tara L et al. (2013) Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Neuropsychopharmacology 38:1674-84|
|Moonat, Sachin; Sakharkar, Amul J; Zhang, Huaibo et al. (2013) Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol Psychiatry 73:763-73|
|Sakharkar, Amul J; Zhang, Huaibo; Tang, Lei et al. (2012) Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. Alcohol Clin Exp Res 36:61-71|
|Pandey, Subhash C (2012) TLR4-MyD88 signalling: a molecular target for alcohol actions. Br J Pharmacol 165:1316-8|