Transcriptional Mechanisms of Addiction-related Neural Plasticity

成瘾相关神经可塑性的转录机制

• 批准号: 9902386
• 负责人: Christopher W Cowan
• 金额: $ 39.62万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902386
• 关键词: AMPA Receptors; Abstinence; Acute; Addictive Behavior; Adult; Behavior; Brain; Cell physiology; Chronic; Cocaine; Cocaine Dependence; Complex; Cytoskeleton; Data; Development; Disease; Dose; Drug Addiction; Drug usage; Endocytosis; Environment; Excitatory Synapse; Exhibits; FMR1; Feedback; Food; Genetic Transcription; Glutamates; Goals; Grant; Knockout Mice; Lead; Literature; Locomotion; Mediating; Messenger RNA; Modeling; Molecular; Motor; Mus; Neuronal Plasticity; Neurons; Nucleus Accumbens; Palate; Pathway interactions; Pattern; Pharmaceutical Preparations; Process; Protein Biosynthesis; Proteins; Psychological reinforcement; RNA chemical synthesis; RNA-Binding Proteins; Recycling; Regulation; Relapse; Rewards; Role; Self Administration; Series; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Intervention; Volition; addiction; base; behavior change; behavioral plasticity; behavioral response; cell type; density; drug abstinence; drug development; drug reward; excitatory neuron; experience; experimental study; in vivo; insight; loss of function; multidisciplinary; neuron loss; new therapeutic target; response; transcription factor

Project Summary/Abstract A major challenge for treating drug addiction is the poor understanding of the molecular mechanisms by which drug use produces persistent changes in brain function that facilitate compulsive drug seeking and taking behaviors even after long periods of abstinence. We showed that MEF2 transcription factors regulate excitatory synapse density by promoting structural and functional synapse elimination in a process involving the Fragile X Mental Retardation Protein (FMRP) – an RNA-binding protein that regulates dendritic protein synthesis and glutamatergic synaptic strength and density in the brain. FMRP acts to regulate multiple cocaine-induced behaviors and glutamatergic synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) shell. FMRP associates with hundreds of neuronal mRNAs, including the mRNA for the activity-regulated cytoskeleton-associated protein (Arc). In our preliminary studies, we find that Arc is induced in the NAc by cocaine and is a negative-regulator of NAc MSN glutamatergic synaptic transmission, and loss of Arc enables the development of sensitized cocaine bheaviors, including motor, reward and possibly sensitivity to low-dose cocaine in the mouse IV self-administration model. As such, our central hypothesis is that Arc RNA and protein synthesis in the NAc functions to antagonize glutamatergic synaptic plasticity on MSNs, and loss of Arc produces a synapse plasticity environment that facilitates sensitized cocaine behaviors. We will test and refine our central hypothesis with the following specific aims: Specific Aim 1: Analyze the regulation of Arc by cocaine in the adult NAc. In this aim, we will investigate the dynamic, cell-type specific regulation of Arc mRNA and protein in the adult NAc after acute and chronic cocaine (non-contingent and contingent) administration. Specific Aim 2: Determine the role of Arc in sensitized cocaine behaviors. In this aim, we will build upon our recent preliminary data to test for the role of Arc in the adult NAc for the development of non-contingent and contingent drug behaviors. Specific Aim 3: Determine the role of Arc in regulating cocaine-modulated NAc MSN excitatory synaptic transmission. Using a cell type-specific approach, we will investigate the role of Arc in mediating cocaine-induced (non-contingent and contingent) MSN glutamatergic synaptic strength and number with the hypothesis that Arc limits the sensitized cocaine behaviors by promoting AMPAR endocytosis of D1R+ MSNs in the adult NAc.

项目概要/摘要 治疗药物成瘾的一个主要挑战是对药物成瘾的分子机制了解甚少。 吸毒会导致大脑功能发生持续变化，从而促进强迫性药物寻求和服用 即使在长期禁欲之后的行为。我们发现 MEF2 转录因子调节 通过在涉及的过程中促进结构和功能性突触消除来提高兴奋性突触密度 脆性 X 智力迟钝蛋白 (FMRP) – 一种调节树突蛋白的 RNA 结合蛋白 大脑中的合成和谷氨酸突触的强度和密度。 FMRP 旨在监管多种 可卡因诱导的行为和细胞核中型多棘神经元（MSN）上的谷氨酸突触 伏隔核 (NAc) 壳。 FMRP 与数百种神经元 mRNA 相关，包括 活性调节细胞骨架相关蛋白（Arc）。在我们的初步研究中，我们发现电弧是诱发的 NAc 中可卡因的作用，是 NAc MSN 谷氨酸突触传递的负调节剂，并且是 NAc MSN 谷氨酸突触传递的负调节剂，并且是 Arc 能够促进可卡因敏感行为的发展，包括运动、奖赏和可能的敏感性 小鼠 IV 自我给药模型中的低剂量可卡因。因此，我们的中心假设是 Arc RNA NAc 中的蛋白质合成功能可以拮抗 MSN 上的谷氨酸突触可塑性，并丧失 Arc 产生突触可塑性环境，促进可卡因敏感行为。我们将测试并 通过以下具体目标完善我们的中心假设： 具体目标 1：分析可卡因对成人 NAc 中 Arc 的调节作用。为了这个目标，我们将调查 急性和慢性后成人 NAc 中 Arc mRNA 和蛋白质的动态、细胞类型特异性调节 可卡因（非偶然性和偶然性）管理。 具体目标 2：确定 Arc 在可卡因致敏行为中的作用。为了这个目标，我们将在此基础上 我们最近的初步数据测试了 Arc 在成人 NAc 中对非偶然发展的作用 和偶然的药物行为。 具体目标 3：确定 Arc 在调节可卡因调节的 NAc MSN 兴奋性中的作用 突触传递。使用特定于细胞类型的方法，我们将研究 Arc 在介导中的作用 可卡因诱导的（非偶然性和偶然性）MSN 谷氨酸突触强度和数量 假设 Arc 通过促进 D1R+ MSN 的 AMPAR 内吞作用来限制可卡因致敏行为 在成人NAc中。