Principles of operation of a neural learning circuit - PROJECT SUMMARY We can learn and successfully recall faces, events, language, concepts, places, facts, things that were frightening or rewarding, and the movement commands required to skillfully move our motor effectors. Decades of scientific research have pointed to the role of synaptic plasticity as the basic currency of the brain’s ability to learn and remember. While we have a fairly detailed understanding of the rules that govern changes in synaptic strength and modifications of a neuron’s intrinsic membrane excitability, our understanding of how these plastic changes lead to behavioral learning and memory is still in its infancy. Behavioral learning is an emergent property of a complete neural learning circuit in which the sites and mechanisms of plasticity are embedded. Without an understanding of the effects of plasticity at the circuit-level, we cannot truly understand learning and memory. Arguably, motor adaptation is the domain where we have best chance to understand the circuit-level rules that govern learning, due to the exquisite relationship between sensory stimuli and adaptive behavior. The cerebellum has been shown to be the brain structure crucial for motor learning, and provides a neural locus to begin to outline the circuit rules that govern learning. Our goal is to leverage the highly conserved cytoarchitecture of the cerebellar circuit to identify the principles of operation that underpin neural learning circuits more generally. During the mentored phase of this award, we will focus on a well-described cerebellar-dependent behavior: pursuit direction learning. Even after the occurrence of a single movement error in this task, the brain learns from the mistake, attempting to minimize the error in the next trial. In the first aim, we will characterize the signals that drive the error-dependent acquisition of this motor memory at a specific synapse in the cerebellar circuit, which is thought to contribute to the bulk of behavioral motor learning. During the second aim, we will record from the complete cerebellar circuit. Our goal is to describe how individual elements and synapses in the cerebellar circuit contribute to behavioral adaptation, including constraints on the site(s) of plasticity that cause behavioral learning and allowing conclusions about the extent to which learning occurs before, inside, or downstream of the cerebellar cortex. During the independent phase, we will again record from the complete cerebellar circuit during a different cerebellar learning task: saccadic adaptation. Using an adaptive behavior that relies on a different cerebellar region, we can begin to dissect the circuit-level principles that generalize broadly across cerebellar learning. Together, our results will provide the first circuit-level rules that underlie behavioral learning. These results should have broad implications across other learning and memory systems, all of which exist as complex circuits that drive behavior.
