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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：
9321583
负责人：
Faraz Ali Sultan
金额：
$ 5.92万
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：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321583
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.

项目摘要学习和记忆的神经表观遗传学模型假设，大脑中许多关键的表观遗传学变化活性神经元以急性或慢性的方式调节其放电特性，从而为细胞提供分子记忆的形式。这些变化在一定程度上是由显著的感官体验驱动的，可能在动物的整个剩余寿命中调节行为。因为吸毒是一种慢性的状态适应不良依赖于广泛的分子和生理可塑性，神经表观遗传学假说上瘾是一个新兴的研究领域。啮齿类动物的心理刺激奖赏已被证明可以调节神经元染色质状态。奖赏中枢伏核的动态DNA甲基化整合药物诱导的中脑多巴胺能神经传递的过程也被证明调节可卡因敏感化和情境奖赏记忆。然而，人们对这个角色或纹状体去甲基化的机制。最近的证据指出了一种顺序机制去甲基化，包括5-甲基胞嘧啶的氧化和随后的碱基切除和修复到默认状态未甲基化的碱基。这项提案将研究DNA去甲基化的广度和功能伏核在奖赏学习和基因表达中的作用。纹状体神经元的原代分离培养将用于检测多巴胺对转录和相关DNA甲基化的影响。另外，结合CRISPR技术的多重转录控制将用于全球去甲基化调控决定去甲基化对学习相关基因表达和可卡因奖赏作用的因素行为。最后，由于对特定部位的表观遗传动力在大脑中的作用知之甚少，这研究将利用一种新的融合结构来指导纹状体中的单基因座去甲基化。这样做的结果提案将扩大目前对滥用药物劫持毒品的分子机制的理解奖励制度，从长远来看，将为表观遗传的潜在有效性提供新的见解上瘾治疗中的操控。