Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Regulation of instructive signaling in the cerebellum

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Project Summary/Abstract My long-term goal is to understand how neural circuits in the cerebellum ensure accurate movement through the acquisition of motor learning. When cued by performance errors, climbing fiber excitation triggers a response in postsynaptic Purkinje cells that involves both a complex spike in their somata and calcium spikes in their dendrites. While climbing fibers are highly reliable at driving complex spikes in Purkinje cells, they are not always effective at inducing learning. This indicates that there are specific processes during behavior that regulate the conversion of climbing fiber activity into adaptive information for the circuit. By regulating climbing fiber-mediated learning, inappropriate motor associations may be rejected and/or allow for other instructive signals to engage mechanistically-distinct types of plasticity. Ultimately, these mechanisms could underlie a range of adaptive responses that vary in time, amplitude, and direction. In this proposal, we explore the possible role of molecular layer interneurons (MLIs) in regulating Purkinje cell excitation in response to climbing fiber activation, with special focus on dendritic Ca2+ spikes that are particularly relevant to known mechanisms of plasticity at coactive parallel fiber synapses. We will use quantitative measurements afforded by ex-vivo brain slice preparations to mechanistically dissect the interplay of climbing fiber excitation and ML inhibition at Purkinje cell dendrites, and the influence of these interactions on the climbing fiber?s ability to generate synaptic plasticity. In conjunction, we will use in vivo methods to measure and manipulate neural activity during the acquisition of adaptive motor responses in vestibulo-ocular system to gauge how learning is affected by MLI inhibition. Our study intersects cellular and systems approaches to link the cell-level signaling mechanisms to synaptic plasticity and the circuit processes that encode adaptive behavior. Because cerebellar pathology may manifest as inappropriate learning rather than the inability to learn, completion of these aims will provide novel insight into the development of new therapies to treat cerebellar disorders that affect motor control.
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