The effect of alcohol withdrawal on molecular and behavioral circadian rhythms

酒精戒断对分子和行为昼夜节律的影响

• 批准号: 8149916
• 负责人: Walter Francis Wiggins
• 金额: $ 4.68万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149916
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; American; Attenuated; Behavior; Behavioral; Brain; Calcium Channel; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Circadian Rhythms; Electromyography; Ethanol; Ethosuximide; Exhibits; Functional disorder; Gene Expression; Genes; Genetic; Habits; Hour; Hypothalamic structure; Individual; Kindling (Neurology); Knock-out; Knockout Mice; Laboratories; Link; Measures; Mediating; Messenger RNA; Methods; Molecular; Monitor; Mus; Pathology; Pattern; Periodicity; Phase; Physiological; Physiological Processes; Physiology; Polymerase Chain Reaction; Postdoctoral Fellow; Process; Proteins; Public Health; Regulation; Relapse; Relative (related person); Research; Research Training; Reverse Transcription; Risk; Saline; Severities; Sleep; Sleep Disorders; Sleep disturbances; Symptoms; T-Type Calcium Channels; Techniques; Temperature; Thalamic structure; Time; Training; United States; United States National Institutes of Health; Variant; Western Blotting; Withdrawal; Withdrawal Symptom; alcohol exposure; behavior measurement; circadian behavioral rhythms; high risk drinking; innovation; mathematical model; mouse model; public health relevance; research study; skills training; suprachiasmatic nucleus; training project; voltage

DESCRIPTION (provided by applicant): The focus of the research training project is the effect of multiple chronic alcohol exposure-withdrawal cycles on molecular and behavioral circadian rhythms. Sleep is possibly the most critical physiologic process regulated by circadian rhythms of activity in the brain. While not much is understood regarding the specific mechanisms underlying sleep and its importance, sleep disturbances can have devastating physiologic consequences, including death, if they persist over time. Problems with sleep are one of the most common complaints from individuals undergoing withdrawal from alcohol and also one of the more common reasons given for relapse into alcohol abuse. Recent research has highlighted the importance of the T -type voltage gated calcium channels in the regulation of the molecular "clock" believed to generate circadian rhythms in the brain. Our lab has identified a specific variant of the T-type calcium channels - called Ca(v)3.2 - whose expression correlates strongly with the circadian disturbances associated with chronic alcohol exposure and withdrawal. The aims of the project seek to evaluate the effect of multiple chronic alcohol exposure-withdrawal cycles on normal molecular and behavioral circadian rhythms in a mouse model in which this T -type calcium channel has been either pharmacologically inhibited or genetically silenced. The approach will provide training in both molecular and behavioral laboratory techniques, including relative quantitation of gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and Western blot techniques, as well as behavioral analysis and sleep scoring using continuous electroencephalographic (EEG) monitoring. Furthermore, the analysis of the results will provide training in the mathematical modeling of physiologic rhythms, as well as the statistical analysis and interpretation of subsequent findings. The guidance and training provided by the advisor, research associates, and postdoctoral fellows in the lab will assist the applicant in troubleshooting experiments, analyzing pitfalls and unexpected results, and developing innovative approaches to answering the questions that arise at each point in the process of completing the project. In summary, this project will provide the training and skills necessary to develop and carry out a rigorous study of a physiologic problem related to alcohol abuse on both a molecular and behavioral level. PUBLIC HEALTH RELEVANCE: According to the NIH and CDC, respectively, approximately 43 percent of Americans exhibit moderate-to-high risk drinking habits and 70 percent do not get enough sleep. Furthermore, 36 to 72 percent of chronic drinkers cite sleep problems as a major reason for their relapse into alcoholism from 'withdrawal and at least 30 percent of insomniacs use alcohol as a sleep-aid, putting them at increased risk of alcoholism. Hence, the relationship between alcohol and sleep disturbance is a matter of great importance to public health in the United States.

描述（由申请人提供）：研究培训项目的重点是多个慢性酒精戒断周期对分子和行为昼夜节律的影响。睡眠可能是由大脑活动的昼夜节律调节的最关键的生理过程。虽然对睡眠的具体机制及其重要性了解不多，但如果睡眠障碍持续存在，可能会产生毁灭性的生理后果，包括死亡。睡眠问题是戒酒者最常见的抱怨之一，也是酗酒者复发的最常见原因之一。最近的研究已经强调了T型电压门控钙通道在调节分子“时钟”中的重要性，该分子“时钟”被认为在大脑中产生昼夜节律。我们的实验室已经确定了T型钙通道的一种特殊变体-称为Ca（v）3.2 -其表达与慢性酒精暴露和戒断相关的昼夜节律紊乱密切相关。该项目的目的是在小鼠模型中评估多个慢性酒精戒断周期对正常分子和行为昼夜节律的影响，其中该T型钙通道被抑制或遗传沉默。该方法将提供分子和行为实验室技术方面的培训，包括使用定量逆转录聚合酶链反应（qRT-PCR）分析和蛋白质印迹技术对基因表达进行相对定量，以及使用连续脑电图（EEG）进行行为分析和睡眠评分监测。此外，对结果的分析将提供生理节律的数学建模以及后续发现的统计分析和解释方面的培训。由顾问，研究助理和博士后研究员在实验室提供的指导和培训将帮助申请人排除实验故障，分析陷阱和意外结果，并开发创新方法来回答在完成项目过程中出现的每个问题。总之，该项目将提供必要的培训和技能，以制定和开展一项严格的研究，生理问题有关的酒精滥用的分子和行为水平。 公共卫生相关性：根据NIH和CDC的数据，大约43%的美国人表现出中度至高度风险的饮酒习惯，70%的人睡眠不足。此外，36%至72%的长期饮酒者认为睡眠问题是他们从戒断状态重新陷入酗酒的主要原因，至少30%的失眠症患者使用酒精作为睡眠辅助，使他们增加了酗酒的风险。因此，酒精和睡眠障碍之间的关系对美国的公共卫生非常重要。