Actin Dynamics and Spine Remodeling in Ethanol-Induced Plasticity

乙醇诱导可塑性中的肌动蛋白动力学和脊柱重塑

基本信息

批准号：
8019403
负责人：
L Judson Chandler
金额：
$ 7.1万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-10 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8019403
关键词：
3-Dimensional Actins Alcohol dependence Alcohol-Related Disorders Alcoholism Behavior Biochemical Brain Brain region Breathing Cell model Chronic Complex Computer software Dendritic Spines Development Electrophysiology (science)Ethanol Event Excitatory Synapse F-Actin Fluorescent Dyes Funding G Actin Glutamate Receptor Glutamates Goals Homer protein Image In Vitro Knockout Mice Lead Learning Link Measures Membrane Modeling Modification Molecular Molecular Models Morphology N-Methyl-D-Aspartate Receptors N-Methylaspartate NR2B NMDA receptor Nature Neurons Nuclear Translocation Physical Dependence Play Procedures Process Protein Dynamics Research Risk Factors Role Scaffolding Protein Series Shapes Signal Transduction Signaling Molecule Site Synapses Synaptic plasticity System Testing Three-Dimensional Imaging Translations Vertebral column addiction alcohol behavior alcohol craving alcohol exposure alcohol related problem alcohol response alcohol seeking behavior base behavioral tolerance chronic alcohol ingestion density drug of abuse effective therapy experience gene gun genetic regulatory protein in vivo in vivo Model memory process molecular modeling mouse model neurotransmission novel novel strategies novel therapeutic intervention postsynaptic presynaptic density protein 95 public health relevance response scaffold vapor

项目摘要

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.

描述（由申请人提供）：刺的大小，形状和数量的修改被认为是与经验相关的神经元电路变化的重要组成部分，并且可能在成瘾的可塑性中起重要作用。活性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脊柱形态和/或密度的变化有关。谷氨酸受体的NMDA亚型在突触可塑性中起着核心作用，并且是乙醇的已知靶标。慢性乙醇消耗会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。我们最近确定的潜在自适应机制是将含NR2B的NMDA受体的选择性靶向到突触。这种增加与脚手架后密度下的脚手架蛋白PSD-95的定位相应增加，并取决于肌动蛋白链球刺的大小增加。这些观察结果使我们提出了一个分子模型，用于兴奋性突触时乙醇诱导的可塑性，其中含NR2B的NMDA受体的增加和PSD-95在突触后密度上增加了scaffer的脚手架平台，可扩大si累的信号分子的招募和激活，从而调节脊柱塑料，质子构成刺激性，并构成刺激性塑料。这种更新的应用将利用生化，共聚焦成像和电生理程序，使用慢性乙醇暴露的体外和体内模型来检验这一假设。具体目的是：（1）检验以下假设：脊柱肌动蛋白动力学的调节会因慢性乙醇暴露而改变；（2）检验以下假设：慢性乙醇暴露会增加树突状刺的大小；（3）检验以下假设：慢性乙醇暴露增强了调节活性依赖性脊柱重塑的转化调节蛋白的PSD依赖性关联；（4）检验以下假设：慢性乙醇诱导的突触可塑性的发展需要PSD脚手架信号复合物，该复合物可以支持基于肌动蛋白的脊柱重塑。这是一个新颖及时的建议，与积累的证据一致，表明通过PSD对脊柱肌动蛋白调节的证据在酒精中毒和与酒精有关的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饮酒行为。这些行为的持久性和棘手的性质可能类似于学习和记忆过程，这些学习和记忆过程可能是累加行为的硬化。因此，确定酒精暴露导致大脑的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。