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Striatal Modulation of Epigenetic DNA Demethylation in Reward Learning

奖励学习中表观遗传 DNA 去甲基化的纹状体调节

基本信息

批准号：
9461801
负责人：
Faraz Ali Sultan
金额：
$ 0.06万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9461801
关键词：
Acute Animals Area Base Excision Repairs Behavior Behavioral Behavioral Paradigm Brain CRISPR/Cas technology Cells Chromatin Chronic Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Corpus striatum structure DNA DNA Damage DNA Methylation Discipline Dopamine Drug Addiction Drug abuse Effectiveness Elements Enzymes Epigenetic Process Event GADD45 protein GADD45A gene GADD45B Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Growth Healthcare Systems Hippocampus (Brain)In Vitro Intervention Learning Light Longevity Medical Memory Midbrain structure Modeling Modification Molecular Molecular Profiling Neurons Nucleus Accumbens Output Oxides Pharmaceutical Preparations Physiological Physiological Adaptation Property Quality of life Regulation Relapse Reporter Research Rewards Rodent Role Sensory Signal Transduction Site Synaptic plasticity System Technology Testing Thymine Transcript Transcriptional Regulation Ventral Striatum Ventral Tegmental Area Withdrawal addiction base demethylation drug of abuse epigenetic regulation epigenome experience histone modification in vivo information processing insight interest methylome neurotransmission new technology next generation sequencing novel oxidation psychostimulant reward circuitry reward processing senescence

项目摘要

Project Summary The neuroepigenetic model of learning and memory posits that a number of critical epigenetic changes in the active neuron regulate its firing properties in an acute or chronic manner and thereby provide the cell with a form of molecular memory. Driven in part by salient sensory experiences, these changes can potentially modulate behavior for the entire remaining lifespan of the animal. Because drug addiction is a state of chronic maladaptation dependent on broad molecular and physiological plasticity, the neuroepigenetic hypothesis of addiction is an emerging area of research. Psychostimulant reward in rodents has been shown to modulate the neuronal chromatin state. Dynamic DNA methylation in the nucleus accumbens, a central hub of reward processing that integrates drug-induced dopaminergic neurotransmission from the midbrain, was also shown to regulate cocaine sensitization and contextual reward memory. However, little is known about the role or mechanism of demethylation in the striatum. Recent evidence points to a sequential mechanism of demethylation involving oxidation of 5-methylcytosine and subsequent base-excision and repair to the default unmethylated base. This proposal will examine the breadth and functionality of DNA demethylation in the nucleus accumbens in reward learning and gene expression. A dissociated primary culture of striatal neurons will be used to examine the effect of dopamine on transcription and associated DNA methylation. Additionally, multiplex transcriptional control with CRISPR technologies will be used for global regulation of demethylation factors to determine the role of demethylation on learning-related gene expression and cocaine reward behavior. Finally, because the role of site-specific epigenetic dynamics in the brain is poorly understood, this study will utilize a novel fusion construct to direct single-locus demethylation in the striatum. The results of this proposal will expand the current understanding of molecular mechanisms by which drugs of abuse hijack the reward system and, in the long term, will offer novel insights into the potential effectiveness of epigenetic manipulation in addiction therapy.

项目总结