The cerebellum is important for the control of movement, sensory processing, and regulation of cognitive and emotional function. In adulthood, damage to this region in adulthood leads to debilitating problems with everyday life;in infancy, cerebellar damage dramatically increases the risk of autism, a neurodevelopmental disorder. The long-term goal of this laboratory is to understand how early damage to the cerebellum can lead to symptoms of autism. In particular, the proposed experiments will use new technologies to study the function of individual cerebellar neurons that are involved in learning to anticipate predictable events in both awake mice, both normal and in mice with genetic defects that cause autism in humans. The overall objective of this application is to understand the function of the cerebellum in awake, behaving animals and then to use that information to understand how this circuit malfunctions in mouse models of autism spectrum disorder. This contribution is significant because it will produce detailed and integrated knowledge of the function of an important neural circuit under realistic conditions and apply that knowledge to a common neurodevelopmental disorder. This approach is innovative because this laboratory has developed tools that allow the study of cells that previously could not be examined in awake animals. The work proposed in this application will therefore advance knowledge of how the genetic mutations that cause autism influence the function of neural circuits. In the long run, this information could lead to new approaches to diagnosis, treatment, and prevention of autism spectrum disorder.

Public Health Relevance

The proposed research is relevant to public health because our ability to diagnose and treat neuropsychiatric disorders, including autism, is currently limite by a lack of information about the function of brain circuits that control learning and sensory processing under realistic conditions. Because of the evolutionary conservation of brain structure and function, the study of model organisms such as the mouse should yield fundamental concepts that contribute to understanding the human brain. This work is therefore relevant to the NINDS mission to use fundamental knowledge about the brain to reduce the burden of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS045193-10A1
Application #
8820398
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Talley, Edmund M
Project Start
2002-12-01
Project End
2019-05-31
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$428,215
Indirect Cost
$163,885
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Badura, Aleksandra; Verpeut, Jessica L; Metzger, Julia W et al. (2018) Normal cognitive and social development require posterior cerebellar activity. Elife 7:
Giovannucci, A; Pnevmatikakis, E A; Deverett, B et al. (2018) Automated gesture tracking in head-fixed mice. J Neurosci Methods 300:184-195
Deverett, Ben; Koay, Sue Ann; Oostland, Marlies et al. (2018) Cerebellar involvement in an evidence-accumulation decision-making task. Elife 7:
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
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
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
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
Wang, Samuel S-H; Kloth, Alexander D; Badura, Aleksandra (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518-32

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