Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

Jangra, Ashok; Sriram, Chandra Shaker; Pandey, Suryanarayan; Choubey, Priyansha; Rajput, Prabha; Saroha, Babita; Bezbaruah, Babul Kumar; Lahkar, Mangala

doi:10.1159/000449486

Cited by 20 publications

(12 citation statements)

References 104 publications

(140 reference statements)

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“…Epigenetic regulation underlies drug-induced adaptations. Post-translational modification of histone and dynamic changes of chromatin remodeling proteins alter the expression of specific genes in the brain’s reward circuitry, and thus mediate the actions of drugs of abuse (Ajonijebu et al , 2018; Godino et al , 2015; Jangra et al , 2016; Maze et al , 2010; Qiang et al , 2011; Renthal et al , 2007). An attractive scenario of drug addiction is the rejuvenation hypothesis, in which drugs of abuse elicit developmental and/or even embryonic mechanisms to produce abnormally robust and durable forms of memories associated with addiction (Dong and Nestler, 2014; Huang et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

et al. 2018

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Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior.

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Section: Introductionmentioning

confidence: 99%

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

et al. 2018

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“…Chromatin remodeling in the form of histone acetylation, deacetylation, methylation, and demethylation all play a role in transcription by modulating access to the DNA. Genes coding for chromatin remodeling enzymes are important in the discussion of gene networks, not only because they have been implicated through gene network analysis in alcohol behavior across species [19, 51, 97, 109, 120, 129–131], but because they possess the capability to coordinate gene networks. Histone acetylation via histone acetyltransferases (HATs) can provide access to DNA in a coordinated and long-lasting fashion, resulting in a network of transcripts becoming upregulated, while histone deacetylases (HDACs) mediate the opposite function.…”

Section: Part 2: Gene Network Implicated In Alcohol Behavior In the Flymentioning

confidence: 99%

Studying alcohol use disorder using Drosophila melanogaster in the era of ‘Big Data’

et al. 2019

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Our understanding of the networks of genes and protein functions involved in Alcohol Use Disorder (AUD) remains incomplete, as do the mechanisms by which these networks lead to AUD phenotypes. The fruit fly ( Drosophila melanogaster ) is an efficient model for functional and mechanistic characterization of the genes involved in alcohol behavior. The fly offers many advantages as a model organism for investigating the molecular and cellular mechanisms of alcohol-related behaviors, and for understanding the underlying neural circuitry driving behaviors, such as locomotor stimulation, sedation, tolerance, and appetitive (reward) learning and memory. Fly researchers are able to use an extensive variety of tools for functional characterization of gene products. To understand how the fly can guide our understanding of AUD in the era of Big Data we will explore these tools, and review some of the gene networks identified in the fly through their use, including chromatin-remodeling, glial, cellular stress, and innate immunity genes. These networks hold great potential as translational drug targets, making it prudent to conduct further research into how these gene mechanisms are involved in alcohol behavior.

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“…Long-term, stable consequences of chronic alcohol abuse are thought to be due to stable changes of gene expression resulting from epigenetic alterations within particular regions of the brain [26][27][28]. For example, in rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex.…”

Section: Alcoholmentioning

confidence: 99%

The Role of DNA Repair and the Epigenetic Markers Left after Repair in Neurologic Functions, Including Memory and Learning

Bernstein¹,

Bernstein²

2019

DNA Repair- An Update

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In eukaryotic cell nuclei, DNA is wrapped around and firmly associated with histone proteins, forming chromatin. When DNA is damaged, the chromatin structure needs to be loosened to allow repair enzymes to gain access to the damage. This requires modifying the histone proteins. These modifications, called epigenetic alterations, do not alter the base-pair sequence. Repair-associated epigenetic alterations are usually transient, removed when no longer needed for repair. However, some remain after repair. In the human brain, long-lasting novel epigenetic alterations appear to account for the persistence of addictions to such substances as alcohol, nicotine and cocaine. Certain neurodegenerative diseases are caused by inherited mutations in genes necessary for DNA repair. Deficient DNA repair in these diseases is associated with extensive epigenetic alterations that likely have a role in the disease phenotype. Persistent epigenetic alterations due to DNA repair processes, both histone modifications and methylations of DNA, can also have positive consequences. Stimulation of brain activity (e.g. learning and memory formation) is often accompanied by the generation of DNA damage in neuronal DNA, followed by repair associated with persistent epigenetic alterations. In particular, recent research has shown the need for non-homologous end joining and base excision repair in memory formation.

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Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

Cited by 20 publications

References 104 publications

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

Studying alcohol use disorder using Drosophila melanogaster in the era of ‘Big Data’

The Role of DNA Repair and the Epigenetic Markers Left after Repair in Neurologic Functions, Including Memory and Learning

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