Project Summary/Abstract: One of the least understood computations in the brain is timing. We propose to combine large-scale simulations with eyelid conditioning experiments to reveal temporal coding mechanisms that underlie the cerebellum’s capacity for timing. The feasibility and power of this approach is facilitated by several related factors. Eyelid conditioning provides the ability to control cerebellar inputs and infer its output. Indeed, cerebellar timing is most clearly revealed in this way. This eyelid conditioning-cerebellum connection makes it possible to test large-scale cerebellar simulations in quantitative and biological relevant ways. There is also a natural synergy arising from combining simulations with experiments when each can be related with the other – simulation results suggest better experiments and interpretation of data, experiments inform simulations and make them more relevant and useful. The proposed studies are based on two relatively new discoveries about cerebellar connectivity: Golgi cells inhibit each other and deep cerebellar nucleus (DCN) neurons send collateral axons back to cerebellar cortex as mossy fibers. Preliminary data from simulations and experiments suggest these two connections confer the cerebellum with its capacity for timing and temporal coding. Simulations suggest specific predictions that can be tested with eyelid conditioning studies that include behavioral analysis, tetrode recordings and opto-genetic silencing of specific neurons. Results will inform more general theories of how neurons and synapses can implement temporal coding.

Project Narrative: Timing and temporal coding is important aspect of many brain systems and the underlying mechanisms play a role in numerous neurological disorders including dyslexia and autism. The cerebellum currently represents the best opportunity to brain understand mechanisms of timing. A better understanding of these processes could open doors for innovative treatment strategies for a variety of disorders.