Abnormal Olivocerebellar Synchrony: A Possible Cause of Alcohol Withdrawal Tremor

描述(申请人提供)：这项建议的实验将检验一种假设，即橄榄球小脑系统中异常高水平的复杂棘波(CS)同步性和节律性是戒酒期间观察到的震颤的基础。这一假设是由一系列发现推动的。当正常同步时，CS活动与协调运动有关，但当超同步时，会导致震颤。这些震颤表现出与撤退震颤的相似之处，并可被乙醇拮抗。此外，乙醇对橄榄小脑的放电频率有强烈和长期的影响，我们的初步数据表明，剧烈的乙醇作用于抑制CS的同步性。这些发现与一般的观点是一致的，即酒精在很大程度上通过降低NMDA介导的活性和/或增加GABA-A介导的活性来抑制大脑活动，随着酒精暴露时间的延长，GABA-A和NMDA功能分别发生代偿性下调和上调。GABA-A活性的丧失，特别是在下橄榄(IO)，会导致超同步CS活动和震颤。因此，我们假设在戒断过程中，IO中的神经递质功能异常会导致CS的超同步活动，进而导致震颤。在这项提议中，有两个与检验这一假设相关的具体目标。第一个目的是利用多电极记录戒断过程中的CS活动，以确定CS在戒断过程中的同步性和节律性模式，并将这些模式与震颤特征相关联。第二个目标是建立橄榄球小脑活动和震颤特征之间的因果联系。为此，在对震颤进行肌电记录的同时，将通过直接向IO内注射微量药物来操纵橄榄小脑活动的特征，以评估由此导致的肌肉活动模式的变化。人们希望，通过将震颤作为一种工具来证明，橄榄球小脑系统是酒精作用于运动异常的部位，这些初步研究的结果将成为未来研究的基础，即酒精对橄榄球小脑活动的作用是否至少部分地基于酒精对运动协调的破坏性影响。拟议中的实验将提供有关酒精戒断震颤背后大脑活动的具体变化的信息，这可能有助于设计新的、更成功的治疗方法，不仅针对戒酒症状，而且针对与急性和慢性酒精使用和滥用相关的运动协调问题。特别是，作为酒精作用靶点的橄榄小脑系统的演示应该会增加我们对酒精如何影响运动协调性的理解。据估计，有1760万成年人要么是酗酒者，要么是酗酒者，成为酗酒者的风险增加，酒精中毒显然是美国的一个主要健康问题。此外，由于运动协调性受损是酒精导致交通事故和死亡的主要原因，了解酒精对运动系统的作用具有明显的医学意义。

DESCRIPTION (provided by applicant): The experiments of this proposal will test the hypothesis that abnormally high levels of complex spike (CS) synchrony and rhythmicity in the olivocerebellar system underlie the tremor observed during alcohol withdrawal. This hypothesis is motivated by a series of findings. CS activity when normally synchronized is associated with coordinated movement, but when hypersynchronized causes tremors. These tremors show similarities to withdrawal tremor and can be antagonized by ethanol. Moreover, ethanol affects olivocerebellar firing rates, acutely and chronically, and our preliminary data suggests that acutely ethanol acts to suppress CS synchrony. These findings are in line with the general idea that ethanol acutely acts to depress brain activity in large part via a reduction of NMDA-mediated activity and/or an increase in GABA-A-mediated activity, and that with prolonged ethanol exposure, compensatory down and up regulation of GABA-A and NMDA functioning, respectively, occurs. Loss of GABA-A activity, in particular, in the inferior olive (IO), leads to hypersynchronized CS activity and tremor. Thus, we are led to the hypothesis that during withdrawal, abnormal neurotransmitter functioning in the IO leads to hypersynchronized CS activity that in turn causes tremor. There are two specific aims in this proposal related to testing this hypothesis. The first aim centers on using multiple electrode recording of CS activity during the withdrawal process to determine the patterns of CS synchrony and rhythmicity during withdrawal, and to correlate these patterns with the tremor characteristics. The second aim centers on establishing a causal link between olivocerebellar activity and the tremor's characteristics. To this end the characteristics of olivocerebellar activity will be pharmacologically manipulated using direct microinjections into the IO while EMG recordings are being made of the tremor in order to assess the resulting changes in muscle activity patterns. It is hoped that by using tremor as a tool for demonstrating that the olivocerebellar system is a site at which alcohol acts to cause movement abnormalities, the results of these initial studies will form a basis for future investigations into whether alcohol's action on olivocerebellar activity underlies, at least in part, alcohol's disruptive effects on motor coordination. The proposed experiments will provide information on the specific changes in brain activity that underlie alcohol withdrawal tremor, which may aid in designing new and more successful treatments not only for withdrawal symptoms, but for the motor coordination problems associated with acute and chronic alcohol use and abuse. In particular, demonstration of the olivocerebellar system as a target of alcohol's actions should increase our understanding of how alcohol affects motor coordination. With an estimated 17.6 million adults being either alcoholics or alcohol abusers with an increased risk of becoming alcoholics, alcoholism is clearly a major health problem in the United States. Moreover, with impaired motor coordination a major reason for alcohol being a factor in traffic accidents and deaths, understanding alcohol's actions on motor systems is of obvious medical significance.