The cerebellum is vulnerable to shrinkage in alcohol abuse and alcoholism. Neuropathological studies of alcoholic cerebellar degeneration (ACT) in humans as well as animal models of chronic ethanol exposure have demonstrated that chronic ethanol can lead to loss of cerebellar granule cells and Purkinje cells. More recent lines of evidence have further indicated ethanol-induced thinning of the dendritic branches of Purkinje cells and reduction in the number of cerebellar synapses prior to cell losses. Significantly, these dendritic and synaptic changes suggest a dynamic ethanol-induced reorganization of the neuronal circuits centered on the gopc synapses between the granule cells and Purkinje cells. Dynamic reorganization of gcPc synaptic circuits is now more relevant as the cerebellum, beyond its known motor functions, is also essential for many cognitive non-motor functions involving both integration and adaptation. A novel concept of generalized ataxia has been previously proposed to explain cerebellar functional deficits, be it motor or non- motor, clinical or sub-clinical. Our long-term goal is to understand the synaptic and cellular mechanisms of ACT, specifically the neuroplasticity mechanisms for the maintenance of cerebellar cells and synapses and function. Our working hypothesis is that the cerebellar vulnerability to ethanol is rooted in cerebellar neuroplasticity. A corollary is that regionality may be related to regional differences in gcPc circuits. Failure of the glutamatergic gcPc synaptic circuit may to generalized ataxia. Here we hypothesize that the glutamatergic gcPc synapse is a primary target of ethanol action, and that the earliest and most critical structural effect of chronic ethanol exposure is a complex and dynamic reorganization/loss of these glutamatergic gcPc synapses circuit, which, in turn, may cause functional deficit, prior to significant cell loss in the cerebellum. Specifically, we propose to investigate at the synaptic and cellular level with structure-function correlation in an adult rat model (NIA F344 rats, 10 months old) of chronic ethanol exposure. Two cerebellar regions will be studied: the anterior lobe (lobule V) and HVI of the cerebellar hemisphere. Four timed points are selected: 0,24,and 48 weeks of ethanol, followed by 20 weeks of abstinence. Synaptic analysis will be pursued by a novel and sensitive experimental protocols developed in our laboratory. Anterior lobe function will be evaluated with a modified rotarod designed specifically to test the animal's locomotive integrative behavior under altered acceleration. HVI function will be monitored with the classical eyeblink conditioning, an adaptive leaning and memory task. To ensure that the observed synaptic reorganization/loss and functional deficit occur without significant cell loss, we will employ unbiased stereology to evaluate the number of granule cells and Purkinje cells.
