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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 酒精依赖受试者前额叶皮质的功能和结构变化可能与信息传递的基本结构单位--突触的变化有关。这涉及突触的神经元成分和对其动态平衡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，即星形胶质细胞的变化是可以预料的。然而，对于参与神经递质释放的突触蛋白的变化以及慢性酒精中毒后突触的神经胶质支持的变化，人们知之甚少。因此，在本项目中，假设与对照组相比，酒精依赖者死后背外侧、眶前和前扣带前额叶皮质(均显示出酒精依赖的功能变化)中突触素、突触素、突触素和SNAP-25的分布将发生显著变化。与突触相关的星形细胞标志物应该发生平行的变化。进一步提出，在有戒断和复发时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的情况类似。此外，据预测，对酒精依赖的实验性啮齿动物进行神经保护治疗后，动物模型中的突触和胶质细胞的变化将被逆转或大大减少。本研究的具体目的如下：1.研究酒精依赖大鼠模型前额叶皮质突触蛋白和星形胶质细胞标志物的分布。方法：将酒精依赖大鼠分为以下几组：诱导酒精依赖大鼠、诱导酒精依赖大鼠和缓解期酒精依赖大鼠、诱导酒精依赖大鼠和戒酒前戒断大鼠、长期饮酒并戒酒两个月的大鼠、未接受酒精治疗的大鼠。具体目的2：评价神经营养因子和抗氧化剂对动物模型突触蛋白和星形胶质细胞标志物分布的保护作用。这项研究将测量和比较酒精依赖治疗的动物和未治疗的酒精依赖啮齿动物的突触蛋白的变化。具体目的3：检测酒精依赖缓解期、未缓解期酒精依赖者和非精神对照组前额叶皮质三个区域突触蛋白和星形胶质细胞的分布和含量。因此，这项建议的目的是在酒精依赖的动物模型中评估治疗干预在保持正常突触功能方面的能力。

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.