The cerebellum occupies a near-constant fraction of the mammalian brain and exchanges information with a wide range of brain regions: sensory, motor, and regions that are neither. The cerebellum appears to be a general detector of unexpected events, and is implicated in associative learning (eyeblink, vestibuloocular reflex), sensory surprise (failure of self-tickling), language, cognition, and autism. It also has a characteristic cellular architecture that takes the form of modular, repeating motifs that recur, no matter what kind of information is represented in the incoming mossy fiber and climbing fiber pathways. What is this circuitry doing?

 We are applying advanced optical methods to study the function of the mammalian cerebellum. Using multiphoton optical microscopy and rapid patterned uncaging of caged neurotransmitters in brain slices, we can monitor and perturb individual Purkinje and deep nuclear neurons. Multiphoton microscopy is also useful in vivo for observing activity from dozens of neurons at once. In conjunction with floating-ball technology with head-fixed mice, it is possible to record from awake, locomoting animals.

Our recent work focuses on the canonical olivocerebellar triangle of connections joining the inferior olive, the Purkinje cells of the cerebellar cortex, and the deep nuclei which constitute the cerebellum’s output. By imaging Purkinje cell dendrites, we find that synchronous firing in olivary neurons can encode either unexpected external events or internal events, depending on whether mice are resting or running. These events may initiate or refine movement, respectively. By imaging granule cells, we see that pathway also changes its coding, in concert with olivary switching. Therefore both major excitatory pathways to the cerebellum are under common gated control.

Synchronous olivary firing appears to be well suited for driving rebound firing events in the deep nuclei. We find that in brain slices, these conditions also trigger regenerative calcium entry in deep nuclear dendrites. Just as one climbing fiber can evoke dendritic calcium entry as an instructive signal to Purkinje cells, multiple climbing fibers firing together may play a similar role in the deep nuclei.

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References

D.A. Clark, P.P. Mitra, and S.S.-H. Wang (2001) Scalable architecture in mammalian brains. Nature, 411:189-193 (also see News & Views by Kaas and Collins, 411:141-142).

S. Shoham*, D.H. O’Connor*, D.V. Sarkisov, and S.S.-H. Wang (2005) Rapid neurotransmitter uncaging in spatially defined patterns. Nature Methods, 3:837-843. doi:10.1038/NMETH793.

S.S.-H. Wang, J.R. Shultz, M.J. Burish, K.H. Harrison, P.R. Hof, L.C.Towns, M.W. Wagers, and K.D. Wyatt (2008) Functional trade-offs in white matter axonal scaling. Journal of Neuroscience, 28:4047-4056.

I. Ozden*, M.R. Sullivan*, H.M. Lee, and S.S.-H. Wang (2009) Reliable coding emerges from coactivation of climbing fibers in microbands of cerebellar Purkinje neurons. Journal of Neuroscience, 29:10463-10473.

A.E. Granstedt, M.L. Szpara, B. Kuhn, S.S.-H. Wang, and L.W. Enquist (2009) Fluorescence-based monitoring of activity in virally traced neural circuits. PLoS ONE, 9:e6923.