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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。酒精依赖者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维持突触内稳态所必需的神经胶质支持。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胶质细胞环境（即星形胶质细胞）的改变是可以预期的。然而，关于慢性酒精中毒后参与神经递质释放的突触蛋白的变化和突触胶质支持的变化，我们知之甚少。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死后背外侧、眶额叶和前扣带前额叶皮层（所有显示酒精依赖的功能改变）中，将观察到突触蛋白、突触蛋白、syntaxin和SNAP-25的分布发生显著变化。与突触相关的星形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对象中存在的变化相当。此外，预测在动物模型突触和神经胶质的改变将被逆转或大大减少神经保护治疗酒精依赖实验啮齿动物。上述假设将以以下具体目的进行检验：具体目的1：研究酒精依赖大鼠模型中突触蛋白和星形胶质细胞标记物的分布，将对照组和酒精偏好大鼠分为以下主要组：与诱导大鼠酒精依赖、老鼠与诱导酒精依赖和缓解,与诱导大鼠酒精依赖和一段时间的撤军之前复发酒精,老鼠在长期消费和禁欲两个月,老鼠不接受酒精。具体目的2：评估神经营养因子和抗氧化剂治疗对动物模型突触蛋白和星形细胞标志物分布的保护作用。这将通过测量和比较酒精依赖动物与未治疗的酒精依赖啮齿动物突触蛋白的变化来完成。具体目的3：研究酒精依赖缓解者、酒精依赖非缓解者和非精神病学对照者前额叶皮层三个区域突触蛋白和星形胶质细胞的分布和含量。因此，本研究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。