COBRE: UMMC: ALTERATIONS OF CORTICAL SYNAPTIC MARKERS IN ALCOHOL DEPENDENCE

COBRE：UMMC：酒精依赖性皮质突触标记物的变化

• 批准号: 7610487
• 负责人: JOSE JAVIER MIGUEL-HIDALGO
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610487
• 关键词: Abstinence; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Anterior; Antioxidants; Astrocytes; Autopsy; Chromosome Pairing; Chronic; Computer Retrieval of Information on Scientific Projects Database; Consumption; Disease remission; Elements; Environment; Funding; Grant; Homeostasis; Human; Institution; Knowledge; Measures; Modeling; Neurons; Prefrontal Cortex; Proteins; Rattus; Relapse; Research; Research Personnel; Resources; Rodent; Rodent Model; Source; Structure; Synapses; Synaptophysin; Testing; Therapeutic Intervention; United States National Institutes of Health; Withdrawal; alcohol preferring rats; human subject; neurotransmitter release; neurotrophic factor; protective effect; synaptic function; synaptotagmin; syntaxin; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Functional and structural changes in the prefrontal cortex of alcohol-dependent subjects are presumably associated with alterations in the basic structural unit of information transmission: the synapse. This involves the neuronal elements of the synapse and the glial support essential for its homeostasis. Thus, alterations in the structure and function of synapses, and the glial environment, namely astrocytes, are to be expected in the prefrontal cortex of alcohol-dependent subjects. However, very little knowledge exists on changes in synaptic proteins involved in neurotransmitter release and changes in the glial support of the synapses following chronic alcoholism. Therefore, in the present project it is hypothesized that significant alterations in the distribution of the synoptic proteins synaptophysin, synaptotagmin, syntaxin and SNAP-25 will be observed in the postmortem dorsolateral, orbitofrontal and anterior cingulate prefrontal cortex (all showing functional alterations in alcohol-dependence) of alcohol-dependent human subjects as compared to controls. Parallel changes should occur in astrocytic markers associated with synapses. It is further proposed that in a rodent model of alcohol-dependence with periods of withdrawal and relapse the synaptic changes observed will be comparable with those present in human alcohol-dependent subjects. Furthermore, it is predicted that synaptic and glial alterations in the animal model will be reversed or greatly reduced by neuroprotective treatments to alcohol-dependent experimental rodents. The hypotheses above will be tested with the following specific aims: Specific aim 1: To examine the distribution of synaptic proteins and astroglial markers in the prefrontal cortex of a rat model of alcohol-dependence using controls and alcohol preferring rats divided into the following main groups: rats with induced alcohol-dependence, rats with induced alcohol dependence and a period of remission, rats with induced alcohol-dependence and a period of withdrawal before relapsing to alcohol, rats with long term consumption and a period of abstinence of two months, rats not treated with alcohol. Specific aim 2: to assess the protective effects of treatment with neurotrophic factors and antioxidants on the distribution of synaptic proteins and astrocytic markers in the animal model. This will be done measuring and comparing the changes of synaptic proteins in treated animals with alcohol dependence versus alcohol-dependent rodents without treatment. Specific aim 3: To examine the distribution and content of synaptic proteins and astroglial in three regions of the prefrontal cortex in alcohol-dependent subjects with remission, alcohol-dependent subjects without remission and non-psychiatric controls. Thus, this proposal aims to assess in animal models of alcohol-dependence the ability of therapeutic interventions in preserving normal synaptic function.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 酒精依赖受试者的前额叶皮层的功能和结构变化可能与信息传递的基本结构单位突触的改变有关。这涉及到突触的神经元成分和对其稳态至关重要的神经胶质支持。因此，在酒精依赖受试者的前额叶皮层中，突触的结构和功能以及神经胶质环境（即星形胶质细胞）的改变是可以预期的。然而，很少有知识存在的神经递质释放和神经胶质支持的突触后慢性酒精中毒的突触蛋白的变化。因此，在本项目中，假设与对照组相比，在酒精依赖的人类受试者的死后背外侧、眶额和前扣带前额叶皮层（均显示酒精依赖的功能改变）中将观察到突触蛋白突触体素、突触结合蛋白、突触融合蛋白和SNAP-25的分布的显著改变。与突触相关的星形胶质细胞标记物也会发生类似的变化。进一步提出，在具有戒断期和复发期的酒精依赖啮齿动物模型中，观察到的突触变化将与人类酒精依赖受试者中存在的突触变化相当。此外，预测动物模型中的突触和神经胶质改变将通过对酒精依赖性实验啮齿动物的神经保护治疗而逆转或大大减少。具体目的1：使用对照组和酒精偏好大鼠，检查酒精依赖大鼠模型的前额叶皮层中突触蛋白和星形胶质细胞标志物的分布，将酒精偏好大鼠分为以下主要组：诱导酒精依赖大鼠，诱导酒精依赖和缓解期大鼠，具有诱导的酒精依赖性和在酒精复发之前戒断一段时间的大鼠，具有长期消费和两个月的戒断期的大鼠，未用酒精处理的大鼠。具体目标2：评估神经营养因子和抗氧化剂治疗对动物模型中突触蛋白和星形胶质细胞标记物分布的保护作用。这将通过测量和比较经治疗的酒精依赖动物与未经治疗的酒精依赖啮齿动物中突触蛋白的变化来完成。具体目标3：检测酒精依赖缓解者、酒精依赖未缓解者和非精神病对照者前额叶皮质3个区域突触蛋白和星形胶质细胞的分布和含量。因此，该建议旨在评估酒精依赖动物模型中治疗干预在保持正常突触功能方面的能力。