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: 9210578
• 负责人: Lisa M Savage
• 金额: $ 41.79万
• 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/9210578
• 关键词: Abstinence; Acetylcholine; Ache; 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; Disease model; Drug Addiction; Elements; Encephalitis; Ethanol; Etiology; Exercise; 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; Neuronal Dysfunction; Nutrient; Oligodendroglia; Outcomes Research; Pathology; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Prevalence; Production; Prosencephalon; Proteins; Recovery; Reporting; Short-Term Memory; System; Therapeutic; Thiamine; Thiamine Deficiency; Tissues; Wernicke-Korsakoff Syndrome; alcohol behavior; basal forebrain; behavior test; biobehavior; brain dysfunction; brain health; cholinergic; cholinergic neuron; chronic alcohol ingestion; cognitive function; cognitive recovery; common symptom; discount; discounting; drinking; frontal lobe; gliogenesis; improved; myelination; nerve supply; nervous system disorder; neurochemistry; neurogenesis; neuropathology; neurotoxic; neurotoxicity; neurotrophic factor; neurotropin; novel; novel strategies; nutrition; oligodendrocyte precursor; oligodendrocyte progenitor; pre-clinical; problem drinker; public health relevance; 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(申请人提供)：许多酗酒者表现出中度至严重的认知功能障碍，并伴有脑部病理，包括细胞丢失和组织萎缩。与酒精相关的行为和饮酒混淆的一个因素是营养不良。具体地说，许多酗酒者缺乏硫胺素。硫胺素是一种至关重要的营养物质，对正常的大脑健康和功能至关重要。因此，硫胺素缺乏已成为酒精所致脑损伤的一个关键因素。人类缺乏硫胺素可导致韦尼克脑炎，进而发展为韦尼克-科萨科夫综合征，这些疾病在酗酒者中有很高的患病率。然而，这些疾病经常被误诊，特别是在酗酒者中。要消除长期饮酒和硫胺素缺乏对人类患者的神经毒性影响是困难的，如果不是不可能的话。因此，动物模型对于确定酒精和硫胺素缺乏诱导的神经毒性的确切贡献，以及这些因素对大脑和行为功能障碍的协同作用至关重要。然而，很少有这样的模型被开发出来，特别是关于前脑病理和皮质依赖行为的模型。在这个建议中，我们使用我们最近开发的慢性乙醇治疗(CET)合并硫胺素缺乏(TD)的翻译动物模型来确定CET和TD的独立作用，以及这些因素如何协同作用影响神经营养素适应和认知功能。 激活额叶-皮质-边缘网络(AIM 1)。我们将确定基底前脑胆碱能细胞丢失、皮质细胞结构改变和乙酰胆碱(ACh)释放功能障碍是否是酒精相关认知障碍的关键介质。此外，我们将确定运动是否可以恢复行为、胆碱能神经支配和行为刺激的ACh流出穿过海马体和额叶皮质(AIM 2)。最终的目的(3)将确定CET期间的中度TD发作是否会导致细胞发生(海马区的神经发生和额叶皮质的胶质形成)的更大破坏。此外，我们还将研究少突胶质细胞分化和髓鞘相关蛋白在酒精相关疾病进展过程中的变化。这一关键的临床前信息是提高酒精相关神经疾病的诊断标准和开发有效恢复慢性酒精成瘾后认知功能的治疗策略所必需的。