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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045193-07
Application #
7751827
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Talley, Edmund M
Project Start
2002-12-01
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
7
Fiscal Year
2010
Total Cost
$302,930
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Giovannucci, Andrea; Badura, Aleksandra; Deverett, Ben et al. (2017) Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning. Nat Neurosci 20:727-734
Giovannucci, A; Pnevmatikakis, E A; Deverett, B et al. (2017) Automated gesture tracking in head-fixed mice. J Neurosci Methods :
Cope, Elise C; Briones, Brandy A; Brockett, Adam T et al. (2016) Immature Neurons and Radial Glia, But Not Astrocytes or Microglia, Are Altered in Adult Cntnap2 and Shank3 Mice, Models of Autism. eNeuro 3:
Kloth, Alexander D; Badura, Aleksandra; Li, Amy et al. (2015) Cerebellar associative sensory learning defects in five mouse autism models. Elife 4:e06085
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
Badura, Aleksandra; Sun, Xiaonan Richard; Giovannucci, Andrea et al. (2014) Fast calcium sensor proteins for monitoring neural activity. Neurophotonics 1:025008
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 6:792-798
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
Wang, Samuel S-H; Kloth, Alexander D; Badura, Aleksandra (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518-32

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