Actin Dynamics and Spine Remodeling in Ethanol-Induced Plasticity
Actin Dynamics and Spine Remodeling in Ethanol-Induced Plasticity
批准号:
8019403
负责人:
L Judson Chandler
金额:
$7.1万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-02-10 至 2011-01-31
关键词:
3-DimensionalActinsAlcohol dependenceAlcohol-Related DisordersAlcoholismBehaviorBiochemicalBrainBrain regionBreathingCell modelChronicComplexComputer softwareDendritic SpinesDevelopmentElectrophysiology (science)EthanolEventExcitatory SynapseF-ActinFluorescent DyesFundingG ActinGlutamate ReceptorGlutamatesGoalsHomer proteinImageIn VitroKnockout MiceLeadLearningLinkMeasuresMembraneModelingModificationMolecularMolecular ModelsMorphologyN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNR2B NMDA receptorNatureNeuronsNuclear TranslocationPhysical DependencePlayProceduresProcessProtein DynamicsResearchRisk FactorsRoleScaffolding ProteinSeriesShapesSignal TransductionSignaling MoleculeSiteSynapsesSynaptic plasticitySystemTestingThree-Dimensional ImagingTranslationsVertebral columnaddictionalcohol behavioralcohol cravingalcohol exposurealcohol related problemalcohol responsealcohol seeking behaviorbasebehavioral tolerancechronic alcohol ingestiondensitydrug of abuseeffective therapyexperiencegene gungenetic regulatory proteinin vivoin vivo Modelmemory processmolecular modelingmouse modelneurotransmissionnovelnovel strategiesnovel therapeutic interventionpostsynapticpresynaptic density protein 95public health relevanceresponsescaffoldvapor
中文摘要
描述(由申请人提供):棘的大小、形状和数量的改变被认为是神经元回路中经验依赖性变化的重要组成部分,并可能在成瘾的可塑性中发挥重要作用。活动依赖性可塑性的细胞模型表明,谷氨酸受体的亚细胞定位的变化与突触后密度的分子重组和棘形态和/或密度的改变有关。谷氨酸受体的NMDA亚型在突触可塑性中起核心作用,并且是乙醇的已知靶点。慢性乙醇消耗导致神经元功能的适应性变化,表现为耐受性、身体依赖性和成瘾性。我们最近发现的一个潜在的适应性机制是选择性靶向含有NR2B的NMDA受体的突触。这种增加与突触后密度处支架蛋白PSD-95定位的相应增加以及树突棘大小的肌动蛋白依赖性增加相关并依赖于此。这些观察结果使我们提出了一种兴奋性突触处乙醇诱导的可塑性的分子模型,其中突触后密度处含NR2B的NMDA受体和PSD-95的增加为调节棘肌动蛋白动力学、蛋白质翻译和突触可塑性的信号分子的募集和激活提供了扩展的支架平台。该更新申请将利用生物化学、共聚焦成像和电生理学程序,使用定义明确的长期乙醇暴露体外和体内模型来检验该假设。具体目标是:(1)检验棘肌动蛋白动力学的调节响应于慢性乙醇暴露而改变的假设;(2)检验慢性乙醇暴露增加树突棘大小的假设;(3)检验慢性乙醇暴露增强调节活性依赖性棘重塑的防御调节蛋白的PSD依赖性关联的假设;(4)检验慢性乙醇诱导的突触可塑性的发展需要PSD支架-信号传导复合物的假设,所述PSD支架-信号传导复合物可以支持基于肌动蛋白的脊柱重塑。这是一个新的和及时的建议,是一致的积累的证据表明,脊髓肌动蛋白的突触能调制的PSD在酒精中毒和酒精相关行为的可塑性中起着至关重要的作用。公共卫生相关性酒精中毒的特征是渴望酒精和强迫性酒精寻求行为。这些行为的持久性和顽固性可能类似于学习和记忆过程,这可能是加法行为的基础。因此,确定酒精暴露导致大脑异常和不适当的突触连接的过程可能会导致有效治疗酒精中毒和酒精相关疾病的新方法。
英文摘要
DESCRIPTION (provided by applicant): Modifications of the size, shape, and number of spines is thought to be an important component of experience-dependent changes in neuronal circuits and may play an important role in the plasticity of addiction. Cellular models of activity-dependent plasticity have shown that changes in the subcellular localization of glutamate receptors are associated with a molecular reorganization of the postsynaptic density and alterations in spine morphology and/or density. The NMDA subtype of glutamate receptors play a central role in synaptic plasticity and are known targets of ethanol. Chronic ethanol consumption results in adaptive changes in neuronal function that manifest as tolerance, physical dependence and addiction. A potential adaptive mechanism we recently identified is the selective targeting of NR2B-containing NMDA receptors to the synapse. This increase is associated with, and dependent upon, a corresponding increase in the localization of the scaffolding protein PSD-95 at the postsynaptic density, and with an actin-dependent increase in the size of dendritic spines. These observations lead us to propose a molecular model for ethanol- induced plasticity at excitatory synapses in which increases in NR2B-containing NMDA receptors and PSD-95 at the postsynaptic density provides an expanded scaffolding platform for the recruitment and activation of signaling molecules that regulate spine actin dynamics, protein translation and synaptic plasticity. This renewal application will utilize biochemical, confocal imaging and electrophysiology procedures to test this hypothesis using well-defined in-vitro and in- vivo models of chronic ethanol exposure. The specific aims are to: (1) Test the hypothesis that modulation of spine actin dynamics is altered in response to chronic ethanol exposure; (2) Test the hypothesis that chronic ethanol exposure increases the size of dendritic spines; (3) Test the hypothesis that chronic ethanol exposure enhances the PSD-dependent association of translational-regulatory-proteins that modulate activity-dependent spine remodeling; (4) Test the hypothesis that the development of chronic ethanol-induced synaptic plasticity requires a PSD scaffolding-signaling complex that can support actin-based spine remodeling. This is a novel and timely proposal that is consistent with accumulating evidence that glutamatergic modulation of spine actin by the PSD plays a critical role in the plasticity of alcoholism and alcohol-related behaviors. PUBLIC HEALTH RELEVANCE Alcoholism is characterized by craving for alcohol and compulsive alcohol-seeking behavior. The persistence and intractable nature of these behaviors may be analogous to learning and memory processes that may underlie the hardwiring of the additive behavior. Thus, determining the processes by which alcohol exposure leads to aberrant and inappropriate synaptic connections of the brain may lead to novel approaches to effective treatments of alcoholism and alcohol related disorders.
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