Cortical Biobehavioral Disruption after Thiamine Deficiency and Chronic Alcohol

硫胺素缺乏和长期饮酒后皮质生物行为破坏

• 批准号: 8900087
• 负责人: Lisa M Savage
• 金额: $ 4.28万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900087
• 关键词: A-factor (Streptomyces); Abstinence; Acetylcholine; Affect; Alcohol Nutrition; Alcohol consumption; Alcohol dependence; Alcohol-Related Disorders; Alcoholism; Alcohols; Alzheimer' s Disease; Animal Model; Attention; Autopsy; Behavior; Behavioral; Biological Markers; Brain; Brain Injuries; Brain Pathology; Cell Differentiation process; Cell Survival; Cells; Cellular Structures; Chronic; Combined Modality Therapy; Coupled; Decision Making; Dementia; Demyelinations; Development; Diagnostic; Differential Diagnosis; Disease; Disease Progression; Drug Addiction; Elements; Encephalitis; Ethanol; Exercise; Figs - dietary; Flushing; Functional disorder; Goals; Health; High Prevalence; Hippocampus (Brain); Human; Impaired cognition; Impairment; Informatin; Laboratories; Lead; Life Style; Measures; Medial; Mediating; Mediator of activation protein; Modeling; Motor; Myelin; Nerve Growth Factors; Neurologic; Nutrient; Oligodendroglia; Outcome; Outcomes Research; Pathology; Patients; Pattern; Phenotype; Prevalence; Production; Prosencephalon; Proteins; Recovery; Relative (related person); Reporting; Short-Term Memory; Symptoms; System; Therapeutic; Thiamine; Thiamine Deficiency; Tissues; Wernicke-Korsakoff Syndrome; alcohol behavior; basal forebrain; behavior test; biobehavior; cholinergic; cholinergic neuron; chronic alcohol ingestion; cognitive function; discounting; drinking; frontal lobe; gliogenesis; improved; myelination; nerve supply; nervous system disorder; neurochemistry; neurogenesis; neuropathology; neurotoxic; neurotoxicity; neurotrophic factor; novel; novel strategies; nutrition; oligodendrocyte precursor; pre-clinical; precursor cell; problem drinker; progenitor; relating to nervous system; restoration; white matter

DESCRIPTION (provided by applicant): Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology including cell loss and tissue shrinkage. A factor confounded with alcohol-related behaviors and alcohol consumption is poor nutrition. Specifically, many alcoholics are thiamine deficient. Thiamine is a vital nutrient that is criticalfor normal brain health and functioning. Thus, thiamine deficiency has emerged as a key factor underlying alcohol-induced brain damage. Thiamine deficiency in humans can lead to Wernicke encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. However, these disorders are commonly misdiagnosed, particularly in alcoholics. It is difficult, if not impossible, to disentangle the neurotoxic effecs of chronic alcohol consumption and thiamine deficiency in human patients. Therefore, animal models are critical for determining the exact contribution of alcohol- and thiamine deficiency-induced neurotoxicity, as well as the synergistic interaction of those factors, to brain and behavioral dysfunction. However, few such models have been developed, particularly pertaining to forebrain pathology and cortical-dependent behaviors. In this proposal, we use our recently developed translational animal model of chronic ethanol treatment (CET) combined with thiamine deficiency (TD) to determine both the independent actions of CET and TD as well as how these factors synergistically interact to affect neurotrophin adaptation, cognitive functioning and activation of the fronto-cortico-limbic network (AIM 1). We will determine whether basal forebrain cholinergic cell loss, altered cortical cellular structure and dysfunctional acetylcholin (ACh) release are critical mediators of alcohol-related cognitive impairment. Furthermore, we will determine whether exercise can restore behavior, cholinergic innervation, and behaviorally stimulated ACh efflux across the hippocampus and frontal cortex (AIM 2). The final AIM (3) will determine whether a moderate TD episode during CET leads to greater disruption of cytogenesis (neurogenesis in the hippocampus and gliogenesis in the frontal cortex). In addition, we will examine alternations in oligodendrocyte differentiation and myelin related proteins as a function of alcohol-related disease progression. This critical pre-clinical informatin is needed to improve the diagnostic criteria for alcohol-related neurological disorders and to develop therapeutic strategies that are effective for the recovery of cognitive functions after chronic alcohol addiction.

描述（由申请人提供）：许多酗酒者表现出中度至重度认知功能障碍，伴随着脑病理学，包括细胞丧失和组织收缩。与酒精有关的行为和饮酒混淆的因素是营养不佳。具体而言，许多酗酒者是硫胺素不足的。硫胺素是一种重要的养分，对于正常的脑健康和功能至关重要。因此，硫胺素缺乏已成为酒精引起的脑损伤的关键因素。人类的硫胺素缺乏会导致Wernicke脑炎，可以发展为Wernicke-Korsakoff综合征，并且这些疾病在酗酒者中的患病率很高。但是，这些疾病通常被误诊，尤其是在酗酒者中。消除人类患者的慢性饮酒和硫胺素缺乏的神经毒性效果是困难的，即使不是不可能的。因此，动物模型对于确定酒精和硫胺素缺乏引起的神经毒性以及这些因素的协同相互作用，对大脑和行为功能障碍的协同相互作用至关重要。但是，很少开发此类模型，尤其是与前脑病理学和皮质依赖性行为有关的模型。在该提案中，我们使用最近开发的慢性乙醇治疗的转化动物模型（CET）与硫胺素缺乏症结合（TD）来确定CET和TD的独立作用，以及这些因素如何协同相互作用以影响神经营养蛋白适应，认知功能，认知功能 并激活额叶 - 纤维膜网络（AIM 1）。我们将确定基础前脑胆碱能细胞损失，皮质细胞结构改变和功能失调的乙酰胆碱（ACH）释放是与酒精相关的认知障碍的关键介体。此外，我们将确定运动是否可以恢复行为，胆碱能神经以及在海马和额叶皮层跨行为刺激的ACH外排（AIM 2）。最终目的（3）将确定CET期间中等的TD发作是否会导致细胞生成更大的破坏（海马中的神经发生和额叶皮层中的神经胶质发生）。此外，我们将研究少突胶质细胞分化和髓磷脂相关蛋白的交替，这是与酒精相关疾病进展的函数。需要这种关键的临床前信息素来改善与酒精相关的神经系统疾病的诊断标准，并制定治疗策略，这些策略有效地有效地在慢性酒精成瘾后恢复认知功能。