Modulation of Synaptic Vesicles in Neurotransmission, Plasticity and Addiction

突触小泡在神经传递、可塑性和成瘾中的调节

• 批准号: 7660582
• 负责人: Qi Zhang
• 金额: $ 13.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660582
• 关键词: Address; Affect; Behavior; Behavioral; Cells; Chemosensitization; Clinical; Cocaine; Data; Dopamine; Drug Addiction; Electron Microscope; Foundations; Genes; Glutamates; Health; Hippocampus (Brain); Hour; Image; Knock-in Mouse; Knock-out; Knowledge; Laboratories; Learning; Light; Location; Measures; Mediating; Memory; Midbrain structure; Mission; Modification; Molecular; Molecular Profiling; Monitor; National Institute of Drug Abuse; Neurologic; Neurons; Neurotransmitters; Nicotine; Optics; Pharmaceutical Preparations; Play; Presynaptic Terminals; Probability; Proteins; Public Health; Qi; Quantum Dots; RNA Interference; Reporting; Research; Research Personnel; Resolution; Retrieval; Rewards; Role; Running; Societies; Synapses; Synaptic Vesicles; Synaptic plasticity; Ventral Tegmental Area; Vesicle; addiction; base; career; cocaine exposure; dopaminergic neuron; genetic manipulation; indexing; insight; nanoscale; neuronal circuitry; neurotransmission; neurotransmitter release; overexpression; postsynaptic; presynaptic; programs; protein function; spatiotemporal; synaptotagmin VII; tool

DESCRIPTION (provided by applicant): Clinical and laboratory data have converged on the idea that drug addiction is the usurpation of synaptic plasticity that normally supports reward-related learning and memory. For example, repeated cocaine exposure induces multiple forms of synaptic plasticity in the neuronal circuitry for reward learning. Synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength. It includes presynaptic change on the quantity of neurotransmitter released and postsynaptic change on how effectively cells respond to those neurbtransmitters. Our view of post -synaptic plasticity is greatly advanced owing to pharmacological and electrophysiological tools with high selectivity and sensitivity. However, presynaptic plasticity, also closely involved in addiction, is less appreciated, in part due to the lack of ways to directly monitor synaptic vesicles releasing neurotransmitter. Taking advantage of its nanoscale size and superior photoproperties, I developed a quantum -dot-based approach that can directly report the behavior of single presynaptic vesicles in cultured hippocampal neurons for minutes or even hours. I discovered that vesicles with high release probability prefer a mode of fast and reversible reuse (kiss-and-run, K&R) and the potentiation of neurotransmission was achieved by the increase of K&R. To understand how the fusion and retrieval of synaptic vesicles and the presynaptic release of neurotransmitter are altered in drug addiction, I propose to: (1) investigate the modification of vesicle release associated with presynaptic plasticity, (2) identify the protein regulators of vesicle release that mediate presynaptic plasticity, and (3) illustrate how vesicular release of dopamine is regulated and how addictive drugs affect it. Given the importance of synaptic vesicles in presynaptic plasticity and the significance of presynaptic plasticity in drug addiction, understanding how synaptic vesicles are malfunctioned in drug addiction may prove beneficial in the treatment of one of society's most intractable health problems. PUBLIC HEALTH REVELANCE: This project aims to explore the molecular and cellular mechanisms that regulate neurotransmission in the presynaptic terminals and to understand how they are perturbed by addictive substances. It will advance our knowledge about the neurological foundation of drug addiction, which is well aligned with the mission of the National Institute of Drug Abuse.

描述（由申请人提供）：临床和实验室数据已经融合了这样的想法，即药物成瘾是突触可塑性的篡夺，通常支持奖励相关的学习和记忆。例如，重复的可卡因暴露在神经元电路中诱导多种形式的突触可塑性，以进行奖励学习。突触可塑性是两个神经元之间连接或突触的能力。它包括释放的神经递质数量的突触前变化，以及对细胞对这些NeurbTransmitters的有效反应的释放后变化。由于具有高选择性和敏感性的药理和电生理工具，我们对突触后可塑性的看法大大提高了。然而，突触前的可塑性（也与成瘾都密切相关），部分原因是由于缺乏直接监测神经递质释放的突触囊泡的方法。利用其纳米级的大小和优异的光透明质，我开发了一种基于量子 - dot的方法，该方法可以直接报告培养的海马神经元中单突前囊泡的行为，几分钟甚至数小时。我发现具有较高释放概率的囊泡更喜欢一种快速和可逆的再利用模式（Kiss-and-Run，K＆R），并且通过增加K＆R来实现神经传递的增强。要了解突触囊泡的融合和检索以及神经递质的突触前释放在药物成瘾中的改变，我建议：（1）研究与突触前可塑性相关的囊泡释放的修饰，（2）介导囊泡释放的蛋白质调节剂，并介导了促进了促成刺激性的塑料和3个vES的（3）vesiantial sivellatient and（3）vesiratient and vesic sivellatient and vesiratient and vesiratient and（3）vesiratient和3）。上瘾的药物会影响它。鉴于突触囊泡在突触前可塑性中的重要性以及突触前可塑性在药物成瘾中的重要性，因此了解突触囊泡在药物成瘾中如何出现突触囊泡可能证明对治疗社会最棘手的健康问题之一。 公共卫生启示：该项目旨在探索调节突触前终端中神经传递的分子和细胞机制，并了解它们如何被上瘾的物质扰动。它将提高我们对药物成瘾的神经系统基础的了解，这与美国国家药物滥用研究所的使命保持一致。