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. ? ? ?
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| Lang, Eric J; Blenkinsop, Timothy A (2011) Control of cerebellar nuclear cells: a direct role for complex spikes? Cerebellum 10:694-701 |
| Katori, Yuichi; Lang, Eric J; Onizuka, Miho et al. (2010) QUANTITATIVE MODELING OF SPATIO-TEMPORAL DYNAMICS OF INFERIOR OLIVE NEURONS WITH A SIMPLE CONDUCTANCE-BASED MODEL. Int J Bifurcat Chaos 20:583-603 |
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| Hirata, Yoshito; Katori, Yuichi; Shimokawa, Hidetoshi et al. (2008) Testing a neural coding hypothesis using surrogate data. J Neurosci Methods 172:312-22 |
