The cerebellum, a brain structure found in all vertebrates, is thought to guide motor learning based on sensory inputs. The overall goal of this project is to understand, at a fundamental level, how sensory information is integrated by Purkinje neurons. Purkinje neurons are of interest because they are the point of convergence for the two main input streams to the cerebellum, the mossy fiber/parallel fiber pathway and the inferior olive/climbing fiber pathway. In addition, Purkinje neurons are the cerebellum?s sole output and are thought to play a key role in modulating motor and cognitive activity. Two-photon microscopy, which allows optical sectioning and imaging deep in brain tissue, will enable the observation of dendritic processing in brain slices, and observation of many neurons at once in living animals. Patterned photolysis of caged neurotransmitters and second messengers will allow spatially complex dendritic activity to be manipulated with millisecond resolution. This proposal will test the following three ideas. (1) Complex patterns of granule cell inputs are integrated by Purkinje cells according to two kinds of rules, a dendritic integration rule for local changes and a somatic rule for determining firing output. (2) Purkinje cells have single synapse-level mechanisms for detecting the timing of granule cell activity relative to two kinds of instructive input: climbing fiber activity and local dendritic depolarization. (3) Purkinje cells are activated in vivo in subdendritic and multicellular patterns to generate signals that drive output firing and synaptic plasticity. Taken together, these three ideas contribute to a model in which patterns of activity in granule cells undergo plasticity, and can themselves drive plasticity, to shape Purkinje cell output.

Public Health Relevance

The results of this research project will be a highly significant step in the overall understanding of sensory processing in the cerebellum. Because of the cerebellum?s central role in motor coordination, these experiments will help understanding of the mechanisms underlying movement disorders associated with cerebellar trauma. It is also believed that the cerebellum is associated with autism, a disease that affects as many as 500,000 people in the United States. Recent theories suggest that autism may be the result of an inability to process and integrate sensory inputs properly, and the cerebellum is a prime candidate as a neurological locus for this disorder. This research may ultimately open the door to more effective sensory integration therapies for autistic patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Talley, Edmund M
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Princeton University
Schools of Arts and Sciences
United States
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Najafi, Farzaneh; Giovannucci, Andrea; Wang, Samuel S-H et al. (2014) Sensory-driven enhancement of calcium signals in individual Purkinje cell dendrites of awake mice. Cell Rep 6:792-8
Piochon, Claire; Kloth, Alexander D; Grasselli, Giorgio et al. (2014) Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun 5:5586
Shi, Diana D; Trigo, Federico F; Semmelhack, Martin F et al. (2014) Synthesis and biological evaluation of bis-CNB-GABA, a photoactivatable neurotransmitter with low receptor interference and chemical two-photon uncaging properties. J Am Chem Soc 136:1976-81
Najafi, Farzaneh; Giovannucci, Andrea; Wang, Samuel S-H et al. (2014) Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice. Elife 3:e03663
Wang, Samuel S-H; Kloth, Alexander D; Badura, Aleksandra (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518-32
Sun, Xiaonan R; Badura, Aleksandra; Pacheco, Diego A et al. (2013) Fast GCaMPs for improved tracking of neuronal activity. Nat Commun 4:2170
Schneider, Eve R; Civillico, Eugene F; Wang, Samuel S-H (2013) Calcium-based dendritic excitability and its regulation in the deep cerebellar nuclei. J Neurophysiol 109:2282-92
Kuhn, Bernd; Hoogland, Tycho M; Wang, Samuel S-H (2011) Cerebellar craniotomy for in vivo calcium imaging of astrocytes. Cold Spring Harb Protoc 2011:1224-7
Hoogland, Tycho M; Kuhn, Bernd; Wang, Samuel S-H (2011) Preferential loading of bergmann glia with synthetic acetoxymethyl calcium dyes. Cold Spring Harb Protoc 2011:1228-31
Kuhn, Bernd; Hoogland, Tycho M; Wang, Samuel S-H (2011) Injection of recombinant adenovirus for delivery of genetically encoded calcium indicators into astrocytes of the cerebellar cortex. Cold Spring Harb Protoc 2011:1217-23

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