CHRONIC ETOH--PATHOBEHAVIORAL LESIONS/ THIAMINE STATUS

酗酒与广泛的认知和记忆有关 脑部损伤和结构性改变。最严重和最好的 公认的与酒精相关的损害类型包括酒精性痴呆和 韦尼克-科萨科夫综合征。据报道，酗酒被诊断为 7%的痴呆症患者和酗酒者的病因 公立精神病院的入院率约为20%。尽管 与酒精相关的痴呆的意义、病因作用 酒精、硫胺素缺乏及其相互作用仍不清楚。 动物模型的研究表明，长期暴露于大鼠 饮酒会导致不可逆转的学习和记忆障碍，以及 海马区和新皮质胆碱能区的病理生理变化 系统。其他研究未能证明行为或 病理变化。到目前为止还没有研究评估区域大脑 长期酒精暴露后的硫胺素状态。硫胺素 仅在人类和动物中缺乏就会导致病理损害 丘脑，哺乳动物小体，可能还有新皮质。最新研究 证明长期饮酒既会损害 硫胺素在肠道中的吸收及抑制脑焦磷酸激酶的作用 合成硫胺素活性形式所必需的活性。 这项拟议研究的主要目标是检验我们的假设 新皮质和海马区损伤是酒精诱导的结果 这些结构和相关皮质下的硫胺素缺乏症 投影区。然后这些数据将被用于指导和设计更多 对潜在的病理生理机制的广泛研究 生化和病理改变。以下具体研究将 在长期饮酒的大鼠中进行(32周20%乙醇在 饮用水)，并喂食硫胺素强化饮食或 至3次硫胺素缺乏症；L)戒断康复后， 测量保存、参照和短期工作记忆，以及 习惯化；2)测定硫胺素、硫胺素酯和 额叶、顶叶和扣带回皮质中的硫胺素依赖酶， 海马体、隔核、丘脑和乳头体的行为 受试动物和分成不同的组在第三轮结束时被处死 硫胺素缺乏症(7个月)；3)确定：i)白色厚度 物质与额叶和顶叶皮质；II)额叶神经元密度 和顶叶皮质以及CA1和CA3区；iii)数量 内侧隔、斜角带垂直支的胆碱能神经元， 蓝斑的基底核和去甲肾上腺素能神经元； 胆碱乙酰转移酶、M受体和突触素结合 皮质和海马区密度；以及，v)Wernike型的存在 丘脑、乳头体和脑干的病理改变；4) 确定哪些治疗条件与 行为、病理和生化紊乱。

Alcohol abuse is associated with a wide range of cognitive and memory impairments and structural brain changes. The most severe and best recognized types of alcohol-related damage are alcoholic dementia and Wernicke-Korsakoff syndrome. Alcoholism is reportedly diagnosed as the etiologic factor in 7% of all demented patients and alcoholics represent approximately 20% of the admissions to state mental hospitals. Despite the significance of alcohol-related dementias, the etiological roles of alcohol, thiamine deficiency and their interactions remain unclear. Studies of animal models have revealed that long-term exposure of rats to alcohol causes irreversible learning and memory deficits, as well as pathophysiological changes in hippocampal and neocortical cholinergic systems. Other studies have failed to demonstrate behavioral or pathological changes. No studies so far have assessed regional brain thiamine status following prolonged chronic alcohol exposure. Thiamine deficiency alone in humans and animals produces pathologic lesions to thalamus, mammillary bodies, and possibly the neocortex. Recent studies demonstrate that long-term administration of alcohol both impairs intestinal absorption of thiamine and inhibits brain pyrophosphokinase activity necessary for synthesis of the active form of thiamine. The primary goal of the proposed study is to test our hypothesis that neocortical and hippocampal damage is the result of alcohol-induced thiamine deficiency in these structures and related subcortical projection areas. These data will then be used to direct and design more extensive studies of the pathophysiological mechanisms underlying biochemical and pathological changes. The following specific studies will be conducted in rats administered chronic alcohol (32 weeks 20% ETOH in the drinking water) and fed either a thiamine fortified diet or subjected to 3 bouts of thiamine deficiency; l) Following withdrawal and recovery, measure preservation, reference and short-term working memory, and habituation; 2) Determine the levels of thiamine, thiamine esters, and thiamine dependent enzymes in frontal, parietal, and cingulate cortex, hippocampus, septum, thalamus, and mammillary body of both behaviorally tested animals and in separate groups sacrificed at end of 3rd bout of thiamine deficiency (7th month); 3) Determine: i) thickness of white matter and frontal and parietal cortex; ii) neuronal density in frontal and parietal cortex and CA 1 & 3 sectors of hippocampus; iii) number of cholinergic neurons in medial septum, vertical limb of the diagonal band, and nucleus basalis and noradrenergic neurons in the locus coeruleus; iv) choline acetyltransferase, muscarinic receptors and synaptophysin binding densities in cortex and hippocampus; and, v) presence of Wernicke-type pathologic changes in thalamus, mammillary bodies, and brainstem; 4) Determine which of the treatment conditions correlate with the behavioral, pathologic and biochemical disturbances.