Context-Dependent Modulation of Cerebellar Climbing Fiber Activity Enables Flexible Teaching Signals to Guide Behavior

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2023

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Abstract

The cerebellum plays a key role in motor coordination and learning. Classical models posit that cerebellar learning is instructed by teaching signals from climbing fibers that act according to supervised learning principles by reporting motor errors. However, the climbing fibers can also signal reward-related information in some behaviors, and cerebellar learning can be enhanced by certain internal behavioral states. To understand how the cerebellum guides behavior in different contexts, it is important to reveal what learning rules the cerebellar teaching signals obey and how different behavioral context modulates these teaching signals. My thesis research addresses these two questions through two main studies.To test whether climbing fibers can operate according to reinforcement learning principles, we have measured climbing fiber responses in Purkinje cells in the lobule simplex during a classical conditioning task using two-photon imaging. By performing a modified version of the reward conditioning task, we find that climbing fiber signals exhibit central hallmarks of reinforcement learning. By using an optogenetic approach, we find that the climbing fiber response to the unconditioned stimulus is necessary for establishing a learned climbing fiber response to the conditioned stimulus, and the climbing fiber teaching signals also contribute to generating reliable, well-timed, behavioral responses. These results suggest that the cerebellum can use reinforcement learning rules to guide behavior. To test how an internal behavior state that is known to promote learning modulates cerebellar processing, we have measured climbing fiber responses in Purkinje cells in vermis V/VI during self-paced and motorized locomotion. While head-fixed mice are running on the treadmill, wide-field or two-photon imaging is done to record Ca2+ activity in Purkinje cell dendrites, and an airpuff is delivered to the lower facial area as a sensory stimulus. We find that both the spontaneous and sensory-evoked Ca2+ activity in Purkinje cell dendrites in vermis V/VI are suppressed during locomotion, and this suppression is caused by both a decreased spike probability and event amplitude, suggesting both a decreased pre-synaptic climbing fiber excitation and a post-synaptic inhibition due to locomotion. These results provide insights into how a specific internal state modulates cerebellar processing and enhances learning.

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Jin, Shuyang (2023). Context-Dependent Modulation of Cerebellar Climbing Fiber Activity Enables Flexible Teaching Signals to Guide Behavior. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/27733.

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