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Stress, epigenetics, and alcoholism.

Moonat S, Pandey SC - Alcohol Res (2012)

Bottom Line: Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders.Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria.Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes.

View Article: PubMed Central - PubMed

Affiliation: University of Illinois, Chicago, IL, USA.

ABSTRACT
Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism.

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Related in: MedlinePlus

A hypothetical model for the role of brain-derived neurotrophic factor (BDNF) signaling and chromatin remodeling in central amygdaloid brain regions in the regulation of anxiety induced by acute ethanol and ethanol withdrawal. BDNF binding to tyrosine receptor kinase B (TrkB) triggers several signaling cascades that culminate in the activation of transcription factors, Elk-1 and cAMP-responsive element binding protein (CREB). Under normal conditions, histone deacetylase (HDAC) levels and histone acetylation are adequate to allow for normally regulated chromatin structure and gene transcription. Acute ethanol exposure inhibits HDAC, resulting in increased histone acetylation and an open chromatin conformation. This may lead to increased transcription of BDNF as well as higher levels of a protein, activity-regulated cytoskeleton associated protein (Arc), thereby increasing dendritic spine density. The modulation of these synaptic factors results in anxiety-reducing (i.e., anxiolytic) behavioral effects. In contrast during withdrawal from chronic ethanol exposure HDAC activity increases, resulting in a reduction of histone acetylation that in turn closes the chromatin conformation and reduces gene transcription. The resulting low BDNF levels decrease Arc and dendritic spine density, all of which are associated with anxiety-like behaviors. This model is further supported by the fact that exogenous infusion of BDNF into the CeA reduces anxiety-like behaviors in ethanol withdrawn rats and is associated with increased BDNF and Arc levels (Moonat et al. 2010; Pandey et al. 2008a, 2008b).
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f3-arcr-34-4-495: A hypothetical model for the role of brain-derived neurotrophic factor (BDNF) signaling and chromatin remodeling in central amygdaloid brain regions in the regulation of anxiety induced by acute ethanol and ethanol withdrawal. BDNF binding to tyrosine receptor kinase B (TrkB) triggers several signaling cascades that culminate in the activation of transcription factors, Elk-1 and cAMP-responsive element binding protein (CREB). Under normal conditions, histone deacetylase (HDAC) levels and histone acetylation are adequate to allow for normally regulated chromatin structure and gene transcription. Acute ethanol exposure inhibits HDAC, resulting in increased histone acetylation and an open chromatin conformation. This may lead to increased transcription of BDNF as well as higher levels of a protein, activity-regulated cytoskeleton associated protein (Arc), thereby increasing dendritic spine density. The modulation of these synaptic factors results in anxiety-reducing (i.e., anxiolytic) behavioral effects. In contrast during withdrawal from chronic ethanol exposure HDAC activity increases, resulting in a reduction of histone acetylation that in turn closes the chromatin conformation and reduces gene transcription. The resulting low BDNF levels decrease Arc and dendritic spine density, all of which are associated with anxiety-like behaviors. This model is further supported by the fact that exogenous infusion of BDNF into the CeA reduces anxiety-like behaviors in ethanol withdrawn rats and is associated with increased BDNF and Arc levels (Moonat et al. 2010; Pandey et al. 2008a, 2008b).

Mentions: The activation of these cascades, particularly the MAPK pathway, ultimately results in the recruitment and phosphorylation of two transcription factors, CREB and Elk-1, which in turn enhance the expression of a gene, activity-regulated cytoskeleton-associated (Arc) immediate-early gene,1 (see figure 3) (Bramham et al. 2008; Pandey et al. 2008b; Ramanan et al. 2005; Ying et al. 2002). Arc protein plays a role in the induction of a process, long-term potentiation, and is believed to result in the proliferation of dendritic spines (Huang et al. 2007; Messaoudi et al. 2007; Pandey et al. 2008b; Ying et al. 2002). Thus, BDNF plays an important role in the regulation of synaptic plasticity by activating TrkB-coupled signaling and causing induction of Arc immediate-early gene.


Stress, epigenetics, and alcoholism.

Moonat S, Pandey SC - Alcohol Res (2012)

A hypothetical model for the role of brain-derived neurotrophic factor (BDNF) signaling and chromatin remodeling in central amygdaloid brain regions in the regulation of anxiety induced by acute ethanol and ethanol withdrawal. BDNF binding to tyrosine receptor kinase B (TrkB) triggers several signaling cascades that culminate in the activation of transcription factors, Elk-1 and cAMP-responsive element binding protein (CREB). Under normal conditions, histone deacetylase (HDAC) levels and histone acetylation are adequate to allow for normally regulated chromatin structure and gene transcription. Acute ethanol exposure inhibits HDAC, resulting in increased histone acetylation and an open chromatin conformation. This may lead to increased transcription of BDNF as well as higher levels of a protein, activity-regulated cytoskeleton associated protein (Arc), thereby increasing dendritic spine density. The modulation of these synaptic factors results in anxiety-reducing (i.e., anxiolytic) behavioral effects. In contrast during withdrawal from chronic ethanol exposure HDAC activity increases, resulting in a reduction of histone acetylation that in turn closes the chromatin conformation and reduces gene transcription. The resulting low BDNF levels decrease Arc and dendritic spine density, all of which are associated with anxiety-like behaviors. This model is further supported by the fact that exogenous infusion of BDNF into the CeA reduces anxiety-like behaviors in ethanol withdrawn rats and is associated with increased BDNF and Arc levels (Moonat et al. 2010; Pandey et al. 2008a, 2008b).
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860391&req=5

f3-arcr-34-4-495: A hypothetical model for the role of brain-derived neurotrophic factor (BDNF) signaling and chromatin remodeling in central amygdaloid brain regions in the regulation of anxiety induced by acute ethanol and ethanol withdrawal. BDNF binding to tyrosine receptor kinase B (TrkB) triggers several signaling cascades that culminate in the activation of transcription factors, Elk-1 and cAMP-responsive element binding protein (CREB). Under normal conditions, histone deacetylase (HDAC) levels and histone acetylation are adequate to allow for normally regulated chromatin structure and gene transcription. Acute ethanol exposure inhibits HDAC, resulting in increased histone acetylation and an open chromatin conformation. This may lead to increased transcription of BDNF as well as higher levels of a protein, activity-regulated cytoskeleton associated protein (Arc), thereby increasing dendritic spine density. The modulation of these synaptic factors results in anxiety-reducing (i.e., anxiolytic) behavioral effects. In contrast during withdrawal from chronic ethanol exposure HDAC activity increases, resulting in a reduction of histone acetylation that in turn closes the chromatin conformation and reduces gene transcription. The resulting low BDNF levels decrease Arc and dendritic spine density, all of which are associated with anxiety-like behaviors. This model is further supported by the fact that exogenous infusion of BDNF into the CeA reduces anxiety-like behaviors in ethanol withdrawn rats and is associated with increased BDNF and Arc levels (Moonat et al. 2010; Pandey et al. 2008a, 2008b).
Mentions: The activation of these cascades, particularly the MAPK pathway, ultimately results in the recruitment and phosphorylation of two transcription factors, CREB and Elk-1, which in turn enhance the expression of a gene, activity-regulated cytoskeleton-associated (Arc) immediate-early gene,1 (see figure 3) (Bramham et al. 2008; Pandey et al. 2008b; Ramanan et al. 2005; Ying et al. 2002). Arc protein plays a role in the induction of a process, long-term potentiation, and is believed to result in the proliferation of dendritic spines (Huang et al. 2007; Messaoudi et al. 2007; Pandey et al. 2008b; Ying et al. 2002). Thus, BDNF plays an important role in the regulation of synaptic plasticity by activating TrkB-coupled signaling and causing induction of Arc immediate-early gene.

Bottom Line: Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders.Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria.Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes.

View Article: PubMed Central - PubMed

Affiliation: University of Illinois, Chicago, IL, USA.

ABSTRACT
Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism.

Show MeSH
Related in: MedlinePlus