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: 8696330
• 负责人: Lisa M Savage
• 金额: $ 37.34万
• 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/8696330
• 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; 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（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，伴有脑病理学，包括细胞丢失和组织萎缩。与酒精相关行为和酒精消费混淆的一个因素是营养不良。具体来说，许多酗酒者缺乏硫胺素。硫胺素是一种重要的营养素，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引起的脑损伤的关键因素。人体缺乏硫胺素可导致韦尼克脑炎，可进展为韦尼克-科萨科夫综合征，这些疾病在酗酒者中的患病率很高。然而，这些疾病通常被误诊，特别是在酗酒者中。这是困难的，如果不是不可能的，解开慢性酒精消费和硫胺素缺乏症在人类患者的神经毒性作用。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相互作用至关重要。然而，很少有这样的模型已经开发，特别是有关前脑病理和皮质依赖的行为。在本提案中，我们使用最近开发的慢性乙醇治疗（CET）结合硫胺素缺乏症（TD）的转化动物模型来确定CET和TD的独立作用以及这些因素如何协同相互作用以影响神经营养因子适应、认知功能 以及激活额叶-皮质-边缘网络（AIM 1）。我们将确定是否基底前脑胆碱能细胞的损失，改变皮质细胞结构和功能障碍的乙酰胆碱（ACh）释放是酒精相关的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，行为刺激乙酰胆碱流出海马和额叶皮质（AIM 2）。最终的AIM（3）将确定CET期间的中度TD发作是否会导致细胞发生（海马中的神经发生和额叶皮质中的胶质细胞发生）的更大破坏。此外，我们将研究少突胶质细胞分化和髓鞘相关蛋白的变化作为酒精相关疾病进展的函数。这一重要的临床前信息有助于提高酒精相关神经系统疾病的诊断标准，并有助于制定有效的治疗策略，以恢复慢性酒精成瘾后的认知功能。