Abnormal Olivocerebellar Synchrony: A Possible Cause of Alcohol Withdrawal Tremor

描述（由申请人提供）：本提案的实验将验证一个假设，即在酒精戒断期间观察到的脑小脑系统中异常高水平的复杂尖峰（CS）同步性和节律性是震颤的基础。这一假设是由一系列的发现所推动的。正常同步时的CS活动与协调运动有关，而超同步时则引起震颤。这些震颤与戒断性震颤相似，可由乙醇拮抗。此外，乙醇影响左小脑放电速率，急性和慢性，我们的初步数据表明，急性乙醇抑制CS同步性。这些发现与一般观点一致，即乙醇在很大程度上通过降低NMDA介导的活性和/或增加GABA-A介导的活性来急剧抑制大脑活动，并且随着乙醇暴露时间的延长，分别发生GABA-A和NMDA功能的代偿性下调和上调。GABA-A活性的丧失，特别是在下橄榄（IO），导致超同步的CS活动和震颤。因此，我们得出这样的假设：在戒断期间，IO神经递质功能异常导致CS活动过度同步，进而引起震颤。在这个提议中，有两个与检验这个假设有关的具体目的。第一个目标是在戒断过程中使用多个电极记录CS活动，以确定戒断过程中CS同步性和节律性的模式，并将这些模式与震颤特征联系起来。第二个目标是建立左小脑活动与地震特征之间的因果关系。为此目的，在对震颤进行肌电图记录的同时，利用直接显微注射的方法对左小脑活动的特征进行药理学处理，以评估肌肉活动模式的变化。人们希望，通过使用震颤作为证明左小脑系统是酒精作用导致运动异常的一个部位的工具，这些初步研究的结果将为未来的研究奠定基础，以确定酒精对左小脑活动的作用是否至少部分地是酒精对运动协调的破坏性影响的基础。拟议的实验将提供关于酒精戒断性震颤背后的大脑活动的具体变化的信息，这可能有助于设计新的和更成功的治疗方法，不仅针对戒断症状，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，证明橄榄小脑系统是酒精作用的目标，应该增加我们对酒精如何影响运动协调的理解。估计有1760万成年人是酗酒者或酗酒者，成为酗酒者的风险增加，酗酒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成为交通事故和死亡因素的主要原因，因此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.