Roles for histone monoaminylation in cocaine-induced transcriptional and behavioral plasticity

组蛋白单胺化在可卡因诱导的转录和行为可塑性中的作用

• 批准号: 9915869
• 负责人: Ian S. Maze
• 金额: $ 50.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915869
• 关键词: Addictive Behavior; Adult; Affect; Behavior; Behavioral; Binding; Biochemical; Biochemistry; Biology; Brain; Brain region; Cell Nucleus; Chemicals; Chemosensitization; Chromatin; Chronic; Cocaine; Cytoplasmic Protein; Data; Development; Discipline; Disease; Doctor of Philosophy; Dopamine; Drug Addiction; Drug abuse; Enzymes; Epigenetic Process; Future; Gene Expression; Genetic Transcription; Genomics; Goals; Histone H3; Histones; Human; Individual; Investigation; Life; Mammalian Cell; Mediating; Mental disorders; Molecular; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitters; Norepinephrine; Nuclear; Physiological; Play; Post-Translational Protein Processing; Production; Proteins; Psychostimulant dependence; Reader; Regulation; Relapse; Rewards; Rodent; Rodent Model; Role; Serotonin; Structure; Substance Addiction; Substance abuse problem; System; Therapeutic Intervention; Tissues; Treatment Efficacy; Ventral Tegmental Area; Volition; Withdrawal; addiction; behavioral plasticity; cell type; covalent bond; drug seeking behavior; effective therapy; genome-wide; insight; monoamine; neuronal patterning; neurotransmission; novel; programs; psychostimulant; reward circuitry; shift work; substance abuse treatment; transglutaminase 2; vesicular monoamine transporter

Project Summary: Maze, IS, Ph.D. Persistent changes in neuronal gene expression promote physiological alterations implicated in a wide variety of human neurodevelopmental and adult psychiatric disorders. More recently, cell-type and brain region specific `epigenetic' mechanisms have been demonstrated to regulate transcriptional programs contributing to addiction-like behaviors; however, our understanding of how these mechanisms mediate life-long addiction remains limited. Monoaminergic neurotransmission in the central nervous system plays a critical role in psychostimulant-induced neural plasticity, with alterations in monoamine production/function being implicated in both the development and treatment of substance abuse disorders. Although packaging of monoamines by the vesicular monoamine transporter is essential for numerous aspects of reward, recent data have demonstrated the additional presence of `reserve' pools of extravesicular monoamines in the nucleus of monoamine producing neurons. Dopamine, as well as other monoamines, has previously been shown to form covalent bonds with certain cytoplasmic proteins catalyzed by the tissue Transglutaminase 2 enzyme. We recently identified histone proteins – histones are highly abundant, post-translationally modified proteins, which constitute the building blocks of eukaryotic chromatin and form the fundamental repeating units of transcription in mammalian cells – as robust substrates for monoaminylation in brain. Our data indicate that histone H3 dopaminylation likely acts to potentiate binding of adjacent histone posttranslational modification (PTM) interacting proteins (`readers') and may play a direct and critical role in dopaminergic neuronal transcription. Furthermore, our data demonstrate that chronic withdrawal from volitional administration of extended access to cocaine in rodents results in high levels of dopamine accumulation in the nucleus of dopamine producing neurons in the ventral tegmental area (an important structure within the mesolimbic reward circuitry), as well as increased cytoplasmic to nuclear shuttling of TGM2, the H3 dopaminylase. Take together, these data suggest that persistent states of addiction may result from increased genomic enrichment of H3 dopaminylation, potentiation of aberrant transcriptional plasticity and increased drug seeking behaviors. Using a unique combination of chromatin biochemistry, chemical biology, genome-wide and functional neurobiological approaches, we plan to fully characterize the functions of histone dopaminylation, both in the context of normal neuronal function and in ethologically valid rodent models of drug abuse; understanding these highly novel molecular phenomena promises to provide new insights into the underlying mechanisms of drug addiction, and aims to identify novel targets for the development of more effective therapeutics. Lastly, given the fundamental role other monoaminergic systems (e.g., serotonin, norepinephrine) in addiction, we believe that this `paradigm shifting' work will serve as a launching pad for countless future investigations aimed at fully delineating the `epigenetic' mechanisms at play in the development of substance abuse disorders.

项目概要：迷宫，IS，博士 神经元基因表达的持续变化促进了多种生理学改变， 人类神经发育和成人精神疾病的研究。最近，细胞类型和大脑区域 已经证明特定的“表观遗传”机制调节转录程序， 成瘾样行为;然而，我们对这些机制如何介导终身成瘾的理解 仍然有限。中枢神经系统中的单胺能神经传递在中枢神经系统中起关键作用。 精神兴奋剂诱导的神经可塑性，涉及单胺产生/功能的改变 在药物滥用障碍的发展和治疗方面。虽然包装单胺， 囊泡单胺转运蛋白对奖赏的许多方面都是必不可少的，最近的数据表明， 证明了额外存在的“储备”池的囊外单胺在核 单胺神经元多巴胺，以及其他单胺，以前已被证明是形成 由组织转谷氨酰胺酶2酶催化与某些细胞质蛋白质形成共价键。我们 最近鉴定的组蛋白-组蛋白是高度丰富的，后修饰的蛋白质， 构成真核细胞染色质的结构单元，并形成转录的基本重复单位 在哺乳动物细胞中-作为脑中单胺化的稳定底物。我们的数据表明组蛋白H3 多巴胺化可能起增强相邻组蛋白翻译后修饰（PTM）结合的作用 相互作用蛋白（“阅读器”），并可能在多巴胺能神经元转录中发挥直接和关键的作用。 此外，我们的数据表明，长期退出自愿管理的扩展访问， 可卡因在啮齿类动物中导致高水平的多巴胺积累在多巴胺产生核中， 腹侧被盖区的神经元（中脑边缘奖励回路中的重要结构），以及 增加TGM 2（H3多巴胺酶）的细胞质到细胞核的穿梭。综合来看，这些数据表明 成瘾的持续状态可能是由于H3多巴胺化的基因组富集增加， 增强异常转录可塑性和增加药物寻求行为。使用唯一 结合染色质生物化学、化学生物学、全基因组和功能神经生物学 方法，我们计划充分表征组蛋白多巴胺化的功能，无论是在正常的背景下， 神经元功能和行为学上有效的药物滥用啮齿动物模型;了解这些高度新颖的 分子现象有望为药物成瘾的潜在机制提供新的见解， 旨在确定新的目标，以开发更有效的治疗方法。最后，考虑到基本 其它单胺能系统（例如，5-羟色胺，去甲肾上腺素）成瘾，我们认为，这种“范式” “转移”工作将作为一个发射台，为无数的未来调查，旨在充分划定 “表观遗传”机制在药物滥用障碍的发展中起作用。