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: 7381912
• 负责人: JOSE JAVIER MIGUEL-HIDALGO
• 金额: $ 14.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381912
• 关键词: COBRE; UMMC; ALTERATIONS; CORTICAL; SYNAPTIC

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。酒精依赖者前额皮质的功能和结构变化可能与信息传递的基本结构单元：突触的变化有关。这涉及突触的神经元元件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皮质中，突触的结构和功能以及神经胶质环境（即星形胶质细胞）会发生变化。然而，对于慢性酒精中毒后参与神经递质释放的突触蛋白的变化以及突触神经胶质支持的变化，人们知之甚少。因此，在本项目中，假设在死后背外侧、眶额和前扣带回前额皮质中观察到突触蛋白、突触结合蛋白、突触结合蛋白、突触蛋白和 SNAP-25 分布的显着变化（所有这些都显示出酒精-与对照组相比，酒精依赖人类受试者的依赖性）。与突触相关的星形胶质细胞标记物应该发生平行变化。进一步提出，在具有戒断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，据预测，通过对酒精依赖的实验啮齿动物进行神经保护治疗，动物模型中的突触和神经胶质改变将被逆转或大大减少。上述假设将通过以下具体目标进行检验： 具体目标 1：使用分为以下主要组的对照组和酒精偏好大鼠，检查酒精依赖大鼠模型前额皮质中突触蛋白和星形胶质细胞标记的分布：诱导性酒精依赖大鼠、诱导性酒精依赖且缓解期大鼠、诱导性酒精依赖且戒断一段时间后再次饮酒的大鼠、长期饮酒且戒断一段时间的大鼠两个月内，老鼠没有接受酒精治疗。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细胞标记物分布的保护作用。这将通过测量和比较经过治疗的酒精依赖动物与未经治疗的酒精依赖啮齿动物的突触蛋白变化来完成。具体目标3：检查缓解的酒精依赖受试者、未缓解的酒精依赖受试者和非精神病对照的前额皮质三个区域中突触蛋白和星形胶质细胞的分布和含量。因此，该提案旨在评估酒精依赖动物模型中治疗干预措施维持正常突触功能的能力。