A variety of factors, including genetic traits, may mediate the development of alcohol-drinking behaviors. Evidence also indicates that negative reinforcing factors, such as high anxiety levels, may play an important role in alcohol use and abuse. However, the epigenetic and signaling mechanisms that may be involved in the comorbidity of anxiety and alcoholism remain unclear. Animal lines, such as selectively bred alcohol-preferring (P) and non-preferring (NP) rats, appear to be suitable models to study the molecular basis of the genetic predisposition to anxiety and alcoholism. Our laboratory recently demonstrated that brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc) expression, and dendritic spine density (DSD) were lower in the central (CeA) and medial nucleus of amygdala (MeA) but not basolateral amygdala (BLA) of P rats as compared with NP rats. Despite correlational evidence, it is unknown if decreased BDNF signaling in the amygdaloid circuitry of P rats is responsible for heightened anxiety-like and excessive alcohol- drinking behaviors. It is also unknown how the expression of Arc and various exons of BDNF and its receptor, tyrosine kinase B (trkB)-linked signaling [cAMP responsive-element binding protein (CREB) and extracellular regulated protein kinases 1/2 (Erk1/2)] are regulated and if BDNF signaling modulates synaptic plasticity in the amygdala resulting in the phenotypes of anxiety and alcohol-drinking behaviors of P rats compared with NP rats. One epigenetic regulatory mechanism which has been shown to play a role in the regulation of gene expression is DNA methylation. DNA methyltransferases (DNMT) catalyze DNA methylation allowing for the binding of methyl-CpG-binding proteins and recruitment of several transcriptional suppressors to DNA, thereby decreasing gene transcription. Several genes, such as BDNF, trkB, and Arc, involved in synaptic plasticity are epigenetically controlled by DNA methylation. The association between DNMTs, synaptic plasticity-associated gene expression, and DSD in the amygdala of P and NP rats and its role in anxiety and alcohol-drinking behaviors are currently unknown. The proposal is based on the hypothesis that innately higher DNMT levels will produce DNA hypermethylation-mediated decreases in the expression of BDNF, trkB and Arc leading to decreased DSD in the amygdala and deficits in the BDNF system that may be operative in the predisposition to anxiety and alcoholism. Two novel approaches have been proposed to test the above hypothesis. One approach proposes to investigate DNA methylation mechanisms in the amygdaloid brain circuitry (CeA and MeA) by determining DNMT (DNMT1, DNMT3a, and DNMT3b) expression and DNA methylation, and how changes in DNA methylation may coordinate shifts in the expression of genes (BDNF, trkB and Arc) that regulate synaptic plasticity (DSD) and result in a predisposition to anxiety and alcoholism. Another approach is to examine the effects of systemic treatment with a newly identified trkB receptor agonist (7, 8-dihydroxyflavone) or intra-amygdaloid (CeA or MeA) infusion with BDNF on BDNF-trkB signaling (Erk1/2, CREB, Arc, and DSD) and on anxiety-like and alcohol-drinking behaviors using P and NP rats as an animal model. The proposed studies will provide new information on the epigenetic and cellular mechanisms of synaptic plasticity in the amygdala that may be involved in the comorbidity of anxiety and alcoholism.
Several factors, such as genetic traits, may be involved in the development of alcoholism. In addition, it has been shown that innate high anxiety levels promote higher alcohol consumption. This proposal will enhance our understanding of the brain epigenetic and signaling mechanisms associated with the comorbidity of anxiety and alcoholism and will identify novel cellular targets that can be used to develop future therapeutic agents in treating alcohol-abuse disorders with and without anxiety disorders.
|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|
|Gavin, David P; Kusumo, Handojo; Zhang, Huaibo et al. (2016) Role of Growth Arrest and DNA Damage-Inducible, Beta in Alcohol-Drinking Behaviors. Alcohol Clin Exp Res 40:263-72|
|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|
|Kyzar, Evan J; Pandey, Subhash C (2015) Molecular mechanisms of synaptic remodeling in alcoholism. Neurosci Lett 601:11-9|
|Gavin, David P; Kusumo, Handojo; Sharma, Rajiv P et al. (2015) Gadd45b and N-methyl-D-aspartate induced DNA demethylation in postmitotic neurons. Epigenomics 7:567-79|
|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|
Showing the most recent 10 out of 24 publications