Role of FMRP in Cocaine-Dependent Behavioral Plasticity

FMRP 在可卡因依赖性行为可塑性中的作用

• 批准号: 8606280
• 负责人: Christopher W Cowan
• 金额: $ 19.75万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606280
• 关键词: Role; FMRP; Cocaine; Dependent; Behavioral

DESCRIPTION (provided by applicant): Identifying key molecules that mediate brain reward plasticity remains an important goal of current drug abuse research. We recently identified a key role for the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in regulating protein synthesis in dendrites, as an essential downstream component of MEF2-dependent synapse elimination. Moreover, we observed significant deficits in cocaine-induced behavioral plasticity in FMRP-deficient mice. Taken together with the recently documented role for MEF2 in repeated cocaine-induced structural and functional plasticity, our findings in the Fmr1 KO mice suggest an important role for synapse elimination as a process that promotes long-lasting behavioral plasticity associated with chronic cocaine use. In this proposal, we will test the hypothesis that FMRP mediates an acute process of synapse elimination/remodeling in the NAc that is required for behavioral plasticity associated with repeated cocaine exposure. To this end, we propose the following: Specific Aim 1: Our preliminary findings indicate that Fmr1-/- mice have significantly reduced cocaine sensitization and place preference to cocaine. As these are developmental knockout mice, the precise populations of cells where FMRP exerts its function on cocaine-induced behaviors is not clear. To this end, we will take a two-pronged approach: 1) we will express WT FMRP in the nucleus accumbens (NAc) using viral- mediated gene delivery in the Fmr1 KO mice and test for functional rescue of cocaine behaviors, and 2) we will selectively knockout the Fmr1 gene in the NAc using viral-mediated gene delivery of Cre recombinase in adult conditional Fmr1 knockout mice and test the requirement for FMRP in the adult NAc during cocaine-induced behavioral plasticity. Specific Aim 2: Our recent findings revealed that FMRP is strictly required for MEF2-dependent regulation of synapse number in hippocampal pyramidal neurons, and NAc expression of active MEF2 enhances both sensitized locomotion and place preference to cocaine. Therefore, we will test the hypothesis that FMRP functions in the NAc to mediate MEF2-induced sensitized behavioral responses to cocaine. To this end, we will use established viral-mediated gene delivery to determine whether MEF2-modulated behavioral responses to cocaine require FMRP function in vivo using Fmr1-/- mice and established behavioral assays. Specific Aim 3: We previously demonstrated that inhibition of MEF2 activity is necessary and sufficient to regulate the chronic cocaine-induced increase in NAc MSN spine density. Since we found that FMRP is required for MEF2-regulated excitatory synapse density in hippocampal neurons, we will test the hypothesis that the cocaine-induced increase in NAc spine density requires FMRP in vivo. Using established spine imaging methods, we will assess the basal and chronic cocaine-regulated NAc spine density in Fmr1 KO mice.

描述（由申请人提供）：确定介导大脑奖励可塑性的关键分子仍然是当前药物滥用研究的重要目标。我们最近确定了脆弱的X智力低下蛋白（FMRP）的关键作用，这是一种参与调节树突中蛋白质合成的RNA结合蛋白，是MEF2依赖性突触消除的必不可少的下游成分。此外，我们观察到可卡因诱导的FMRP缺陷小鼠的行为可塑性的明显缺陷。总而言之，MEF2在重复可卡因诱导的结构和功能可塑性中的作用，我们在FMR1 KO小鼠中的发现表明，突触消除突触消除的重要作用是促进与慢性可卡因使用相关的长期行为可塑性的过程。在该提案中，我们将检验以下假设：FMRP介导了NAC中的突触消除/重塑的急性过程，这是与重复可卡因暴露有关的行为可塑性所需的。为此，我们提出以下内容：特定目标1：我们的初步发现表明FMR1 - / - 小鼠的可卡因敏感性大大降低，并偏爱可卡因。由于这些是发展性敲除小鼠，因此FMRP在可卡因诱导的行为上发挥功能的细胞的精确种群尚不清楚。 To this end, we will take a two-pronged approach: 1) we will express WT FMRP in the nucleus accumbens (NAc) using viral- mediated gene delivery in the Fmr1 KO mice and test for functional rescue of cocaine behaviors, and 2) we will selectively knockout the Fmr1 gene in the NAc using viral-mediated gene delivery of Cre recombinase in adult conditional Fmr1 knockout在可卡因诱导的行为可塑性期间，小鼠并测试成人NAC中FMRP的需求。 具体目的2：我们最近的发现表明，在海马锥体神经元中，MEF2依赖性的突触数的调节严格需要FMRP，而主动MEF2的NAC表达则增强了敏感性的运动和对可卡因的偏好。因此，我们将检验以下假设：FMRP在NAC中起作用以介导MEF2诱导的对可卡因的敏化行为反应。为此，我们将使用已建立的病毒介导的基因递送来确定MEF2调节对可卡因的行为反应是否需要使用FMR1 - / - 小鼠在体内和已建立的行为分析中进行FMRP功能。 具体目的3：我们先前证明，对MEF2活性的抑制是必要且足以调节慢性可卡因诱导的NAC MSN脊柱密度的增加。由于我们发现海马神经元中由MEF2调节的兴奋性突触密度需要FMRP，因此我们将测试可卡因诱导的NAC脊柱密度增加的假设，需要体内FMRP。使用已建立的脊柱成像方法，我们将评估FMR1 KO小鼠中的基础和慢性可卡因调节的NAC脊柱密度。