Targets of low dose alcohol during cerebellar-driven behavior in mice

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PROJECT SUMMARY Cerebellar neurons are among the most sensitive targets of alcohol in the nervous system. At concentrations just above the legal limit for driving in the United States (>17mM BAC), alcohol causes cerebellar dysfunction, leading to impairments in gait, balance and motor coordination that are responsible for thousands of injuries and deaths every year. There is also evidence from electrophysiology experiments in cerebellar slices that at lower concentrations (<10mM), alcohol alters the function of multiple neurons in the cerebellum. However, our understanding of the action of low doses of alcohol in the cerebellum is still in its infancy. A critical barrier to progress in the field has been to understand how the effects of low dose alcohol observed in vitro translate to the unanesthetized animal and lead to impaired function during cerebellar-driven behaviors. The goal of this proposal is to overcome this prior limitation, by being the first to measure the impact of low doses of alcohol in the cerebellum of behaving mice. Mice will be trained in cerebellum-dependent eyeblink conditioning because our preliminary data indicates that low doses of alcohol (<5mM BAC) impair performance in this task. Our general strategy is to search for cell-specific targets of low dose alcohol during eyeblink conditioning, by recording and manipulating the activity of cerebellar circuits at three different stages of processing: the output stage, processed by neurons of the interpositus nucleus (specific aim 1), the intermediate stage, processed by Purkinje cells (specific aim 2), and the input stage, processed by granule cells (specific aim 3). The proposed experiments will break new ground and advance the field substantially: By combining the simplicity of eyeblink conditioning with new technologies for optogenetics, electrophysiology, and two-photon calcium imaging, this project will provide a first look at the mechanistic links between low dose alcohol, the cerebellum, and behavior.