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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：迷宫，IS，博士学位。神经元基因表达的持续变化促进了各种各样的身体改变人类神经发育和成人精神病。最近，细胞类型和大脑区域已经证明了特定的“表观遗传学”机制来调节转录程序类似成瘾的行为；但是，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心理刺激诱导的神经可塑性，单胺产生/功能的改变。在滥用药物的发展和治疗中。虽然单胺包装囊泡单胺转运蛋白对于奖励的许多方面至关重要，最近的数据具有证明了在产生神经元的单胺。多巴胺以及其他单胺，以前已显示出形成与组织转谷氨酰胺酶2酶催化的某些细胞质蛋白的共价键。我们最近确定的组蛋白蛋白 - 组蛋白是高度丰富的翻译后修饰蛋白，这是构成真核染色质的基础，并形成基本重复单位在哺乳动物细胞中 - 作为大脑中单氨基化的鲁棒底物。我们的数据表明Hisstone H3 多巴胺基化可能对相邻组蛋白后翻译后修饰（PTM）的潜在结合起来相互作用的蛋白质（“读者”），并且可能在多巴胺能神经元转录中起着直接而关键的作用。此外，我们的数据表明，长期从自愿施用扩展访问权限啮齿动物中的可卡因导致多巴胺产生核中多巴胺的积累高水平腹侧盖区域的神经元（中边奖励电路中的重要结构）以及 TGM2，H3多巴胺基酶的细胞质增加到核穿梭。一起，这些数据暗示成瘾的持续状态可能是由于H3多巴胺基化基因组富集的增加而导致的，增强异常转录可塑性和增加药物的行为。使用唯一染色质生物化学，化学生物学，全基因组和功能性神经生物学的组合方法，我们计划在正常的背景下完全表征组蛋白多巴胺基化的功能神经元功能以及在伦理上有效的药物滥用模型；了解这些高度新颖分子现象有望为药物成瘾的潜在机制提供新的见解，并提供旨在确定开发更有效疗法的新目标。最后，考虑到基本角色其他单胺能系统（例如5-羟色胺，去甲肾上腺素）在成瘾中，我们相信这种范式转移的工作将作为无数未来调查的发射台，旨在完全描述在滥用药物障碍的发展中，“表观遗传”机制发挥了作用。