Our long-term goal is to generate a complete understanding of how the cerebellum learns to improve movement in response to motor errors. Climbing fibers are thought to play an essential role in this process because they fire during erroneous movement. Their activity reliably excites Purkinje cells, eliciting calcium spikes in their dendrites that can trigger long-term synaptic plasticity at coactive parallel fiber inputs. Plasticity induction ultimately leads to corrective behavior by altering the cerebellum?s response to sensorimotor stimuli that predict mistakes. Importantly, inhibition from molecular layer interneurons (MLIs) that target Purkinje cell dendrites suppresses climbing-fiber-evoked calcium signaling, opposing or ?gating? plasticity induction. Because MLIs are activated by movement, this suggests Purkinje cell disinhibition is required during motor learning. As MLIs inhibit other MLIs, their interconnections could support a circuit for Purkinje cell disinhibition during behavior. The objective of this proposal is to examine the possibility that MLI circuits are structured to support a context- dependent engagement that allows climbing fibers to instruct plasticity and learning in response to motor errors. To accomplish this, we will employ a multidisciplinary approach using cutting-edge molecular-genetic techniques, functional recordings, circuit mapping, and behavioral analysis. In the first aim, we will test whether ablating MLI- to-MLI connections that normally support Purkinje cell disinhibition affect the ability of climbing fibers to evoke full-blown calcium signals in response to motor errors, and whether loss of MLI-MLI circuit function affects cerebellar-dependent motor learning. In the second aim, we will establish an MLI taxonomy and use it to survey for previously unknown MLI subtypes. We will also use functional recordings to test whether there is evidence for bias connectivity within the MLI network that supports a dedicated circuit for Purkinje cell disinhibition. In the third aim, we will use anatomical tracing to ascertain the MLI connectome. In this way we will determine if there is a structural basis for the independent actuation of MLI subtypes through their afferent inputs and the cell-type selectivity of their efferent outputs. Completion of these aims will lead to an unprecedented understanding of the organizational logic of the molecular layer. In particular, we expect to reveal how circuits within the molecular layer control the induction of climbing-fiber-mediated learning. This knowledge will not only help develop theories/models of cerebellum function but will also provide insight into the processes underlying learning in general.
The cerebellum?s role in motor learning is dependent on the computations performed by neurons that compose its circuits. Yet the heterogeneity and functional organization of the neuron types in cerebellar cortex are not fully known, preventing elucidation of how the cerebellum implements adaptive behavior. Therefore, the goal of this study is to characterize the diversity of inhibitory molecular-layer-interneuron subtypes and determine how their neural connections allows for them to play a determinant role in error-driven motor learning, insight that is required to understand how the cerebellum operates in health and disease.
