Transcriptional Mechanisms of Addiction-related Neural Plasticity

项目摘要/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缺乏了解。 吸毒会导致大脑功能的持续变化，从而促进强迫性寻求和服药 即使在长时间禁欲后也会有这种行为。我们发现MEF2转录因子调节 促进结构和功能突触消除的兴奋性突触密度 脆性X智力低下蛋白(FMRP)--一种调节树突状细胞蛋白的RNA结合蛋白 大脑中的合成和谷氨酸能突触强度和密度。FMRP采取行动监管多个 可卡因诱导的行为和核团中棘神经元上的谷氨酸能突触 伏隔(NAC)壳。FMRP与数百个神经元mRNAs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Arc是由 在NAC由可卡因和负性调节的NAC MSN谷氨酸能突触传递，并失去 ARC使致敏的可卡因受体得以发展，包括运动、奖励和可能的敏感性 以小鼠静脉注射小剂量可卡因建立自我给药模型。因此，我们的中心假设是Arc RNA 和NAC中蛋白质合成的功能，以对抗MSN上的谷氨酸能突触可塑性，以及 ARC产生一个突触可塑性环境，促进致敏的可卡因行为。我们将测试和 用以下具体目标来完善我们的中心假设： 具体目的1：分析可卡因对成年NAC中Arc的调节。为了达到这个目的，我们将调查 急性和慢性成年NAC中Arc mRNA和蛋白的动态、细胞型特异性调节 可卡因(非或有和或有)管理。 具体目标2：确定Arc在致敏可卡因行为中的作用。为了实现这一目标，我们将在 我们最近的初步数据检验了Arc在成人NAC中对于非偶然性发展的作用 和偶发毒品行为。 具体目标3：确定Arc在可卡因调制的NAC MSN兴奋性调节中的作用 突触传递。使用特定细胞类型的方法，我们将研究Arc在调节 可卡因诱导(非偶发和偶发)MSN谷氨酸能突触强度和数目与 Arc通过促进D1R+MSN的AMPAR内吞作用限制可卡因致敏行为的假说 在成年的NAC。

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.