Computation of negative prediction error in the inferior olive and its role in cerebellar motor learning

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PROJECT SUMMARY/ABSTRACT Neurological diseases of the olivo-cerebellum result in crippling motor impairments associated with ataxia and dystonia, reflecting this system’s critical role in the generation and coordination of movement. The proposed research focuses on the mechanisms by which the olivo-cerebellum learns to suppress, or extinguish, behaviors that are no longer adaptive. To understand the mechanisms of extinction during cerebellar learning, I will measure and manipulate the activity of neurons in the olivo-cerebellum of mice, while they are being trained in delay eyeblink conditioning (dEC). During this cerebellum-dependent task, mice receive repeated trials on which a neutral stimulus like an LED precedes a periocular airpuff. Over time, the mice learn to blink during the LED presentation and protect their eyes from the puff. After this learning occurs, it is possible to extinguish the blink by repeatedly presenting the LED without the puff, removing the blink’s adaptive value. According to long- standing theories of cerebellar function, blink extinction is caused by activation of the GABAergic nucleo-olivary (NO) projection, which results in inhibition of the inferior olive (IO). Due to technological limitations, no studies to date have established causal links between NO activity, IO inhibition, and extinction. To resolve this issue, I will leverage recently developed techniques allowing for simultaneous dEC and optogenetic manipulation in mice. By using transgenic mouse lines and viral vectors, I will express opsins in IO or NO cells, enabling me to manipulate these populations’ firing in a cell-type-specific manner on behaviorally relevant timescales in vivo. In the first aim of the proposed project, I will test the hypothesis that IO inhibition is sufficient for extinction, by optogenetically suppressing IO activity during paired LED-puff trials in well-trained mice and examining if the photostimulation causes extinction. In my second aim, I will test the hypothesis that NO activity is both sufficient and necessary for extinction, by using optogenetic tools to selectively stimulate or suppress the firing of NO neurons in well-trained mice, while measuring their blink responses to the LED stimulus. Together, the results of aims 1 and 2 will demonstrate whether there are causal links between NO activation, IO inhibition, and extinction. My experiments will be the first to directly test the prevailing theory of cerebellar-dependent extinction. In addition, my results could help identify new therapeutic targets for treating maladaptive cerebellar motor symptoms, by taking advantage of the extinction principles revealed in my work.